The Commission tries to make its consultation procedure as thorough and open as possible. Responses to this
consultative document will be lodged in the Health and Safety Executive’s Information Centres after the close of the
consultation period where they can be inspected by members of the public or be copied to them on payment of the
appropriate fee to cover costs.
Responses to this consultative document are invited on the basis that anyone submitting them agrees to their being dealt
with in this way. Responses, or parts of them, will be withheld from the Information Centres only at the express request
of the person making them. In such cases a note will be put in the index to the responses identifying those who have
commented and have asked that their views, or part of them, be treated as confidential.
CONSULTATIVE
DOCUMENT
Further single copies of this document may be obtained from HSE Books – see back cover
European Commission Directive 2000/39/EC establishing a First List of Indicative
Occupational Exposure Limit Values at European Community level in implementation
of council directive 98/24/EC on the protection of the health and safety of workers from
the risks related to chemical agents at work.
CONSULTATION DOCUMENT
Contents Page
SUMMARY 1
INVITATION TO COMMENT 19
Appendices
i
SUMMARY
Indicative Occupational Exposure Limit Values (IOELVs) are concentrations of a hazardous
substance in air proposed by the European Commission under the framework of the Chemical
Agents Directive (CAD). Member States are obliged to introduce an occupational exposure
limit (OEL) for these substances in accordance with national legislation and practice that
takes the IOELV into account.
The first IOELV Directive (2000/39/EC) is due to be implemented by 31 December 2001 and
lists 63 substances. In May 2000 the Health and Safety Commission (HSC) consulted on
proposals to implement IOELVs for 29 substances (CD156) and for a further 6 substances
(CD157). For 19 substances the existing national limit was considered to meet the
requirements of the Directive (although we have now decided to consult on Cumene).
This document (CD166) sets out HSC’s proposals for 9 substances as well as proposals for
three substances already partly covered by earlier CDs:
Chlorobenzene** Phenol**
Cumene 1,2,4-Trichlorobenzene
Dihydrogen selenide Xylene, mixed isomers
Ethylbenzene* m-Xylene
2-Methoxy-1-methylethyl acetate o-Xylene
Orthophosphoric acid p-Xylene
* see also CD156 **see also CD157
This document also contains an amendment to CD156 and CD157 with revised proposals
for 7 substances. The reasons for the need to reconsult are summarised in the main text
(paragraphs 7-9). If you commented on CD156 or CD157 you may wish to check the revised
proposals. For one remaining substance, Piperazine, HSE is not yet able to present formal
proposals. These will be consulted on early in 2001 via HSE’s web site at
http://www.hse.gov.uk (paper copies of the proposals will be available on request).
All the agreed limits must be in place by 31 December 2001 and will be published in the 2001
or the 2002 edition of HSE’s ‘EH40 - occupational exposure limits’. Limits resulting from
IOELV proposals will not come into effect until 31 December 2001.
We would like your comments on these proposals. A form is included at the back of this
booklet to help you to do this. It summarises the questions set out in the main text.
Please feel free to copy this consultative document more widely. Further copies are available
from the address on the back cover and on the Internet on the HSE web site (see above). The
HSC seeks to inform its decision-making by consulting a wide range of interested bodies.
Although these proposals have already been discussed by a panel of scientific experts you
may have views or further information of which they are not aware. For example, you may
have data relating to whether a particular limit can reasonably be achieved in the workplace.
Your comments are important. Please do take a few minutes to fill in the response form at the
back of this booklet.
1
WHAT ARE INDICATIVE OCCUPATIONAL EXPOSURE LIMIT VALUES
(IOELVs)?
1. IOELVs, previously known as Indicative Limit Values (ILVs), are European legal
limits which are set to protect the health of workers in the European Union from the ill health
effects of hazardous substances in the workplace. IOELVs are therefore broadly the same as
the Occupational Exposure Standard element of the British system of limits to protect
workers against ill-health. The European Commission (EC) made proposals for IOELVs for
63 substances and these have been agreed by Member States. A copy of the Directive
(2000/39/EC) which was published in the Official Journal on 8 June 2000 is at Appendix 1.
Member States must have limits in place for all these substances by 31 December 2001.
2. The Annex of Appendix 1 lists the IOELVs substance by substance. These limits are
based on recommendations by the European Commission’s (EC) Scientific Committee on
Occupational Exposure Limits (SCOEL) which has considered the scientific information
available on each substance. They do not address practicability of the proposals in appropriate
workplaces; such issues can be raised by Member States through the EC’s committee system
and can be taken into account when setting national limits. Member States are obliged,
however, to set a legal limit that takes the IOELV into account.
2
4. OESs and MELS are legal limits. They are approved each year by the Health and
Safety Commission (HSC) and published in HSE’s publication ‘EH40 - occupational
exposure limits’. A MEL is set for substances which may cause the most serious health
effects, such as cancer and occupational asthma: health effects for which no ‘safe’ levels of
exposure can be determined or for which safe levels may exist but at a concentration that is
not yet achievable in the workplace. To comply with COSHH, exposure should be reduced as
far below the MEL as is reasonably practicable and should not exceed the MEL when
averaged over the specified reference period. For substances given a short term MEL (15
minute reference period) the level of exposure should never be exceeded.
6. Domestic limits are normally set on the recommendations of the Health and Safety
Commission’s Advisory Committee on Toxic Substances (ACTS) and its Working Group on
the Assessment of Toxic Chemicals (WATCH). The recommendations are based on a
thorough critical assessment of the available information on the substance in question.
Information on WATCH and ACTS, the agendas and summaries of their meetings are
available on the Internet on the HSE home page at http://www.hse.gov.uk. For more
information on employers’ duties under COSHH, see HSE’s leaflet ‘COSHH - a brief guide
to the regulations’ INDG136 (rev1): available from HSE Books.
CAN HSC SET A DIFFERENT LIMIT TO THE IOELV - AND IF SO, HOW
DIFFERENT AND ON WHAT GROUNDS?
7. While each substance will need individual consideration, it is clear that any
substantial deviation from the IOELV will need to be justified. While a range of technical
factors may be relevant in any particular case, grounds of reasonable practicability will
always need to be considered.
3
8. ACTS and HSC have considered this view when formulating these proposals. Your
comments would be especially appreciated on the question of reasonable practicability.
9. HSE has looked again at all the IOELV proposals contained in CD156 and CD157
and has reconsidered the limit values for 7 substances based on the views set out in paragraph
7 - the new proposals are listed on page 20 in an amendment to the earlier CDs. HSC's
proposals have been amended accordingly and we are now taking this opportunity to
reconsult on the revised proposals.
12. HSE’s scrutiny revealed that the limits for the remaining four of the 23 substances do
not yet comply with the requirements of CAD. The four substances which do not fully take
account of the IOELV are:
Ÿ 2-Methoxy-1-methylethyl acetate;
4
Ÿ Orthophosphoric acid;
Ÿ 1,2,4-Trichlorobenzene;
Ÿ Dihydrogen selenide.
HSC’s proposals for these four substances and Cumene are set out in this CD; and
NEW LIMITS
13. The EC is introducing new limits for 40 substances in this consolidated IOELV
directive. After scrutiny by HSE to establish those IOELVs that were broadly acceptable,
ACTS agreed a list of substances that required more detailed review. The list included
substances where there were issues over practicability, scientific soundness, and the degree of
discrepancy between the existing British limit and the proposed IOELV. Substances which
were judged not to require a detailed review and substances which were already being
reviewed as part of the domestic programme were the subject of two previous consultation
documents. This document covers all but one of the remaining substances, which have now
been reviewed. We are not yet in a position to make formal proposals for Piperazine; these
will be consulted on early in 2001 via HSE’s web site at http://www.hse.gov.uk (paper copies
of proposals will be available on request).
5
SUMMARY OF CONSULTATION DOCUMENTS ISSUED:
CD 156:
mid May - mid August 2000
IOELV substances judged not to require review by HSC/E:
Acetone† Heptan-3-one†
Ammonia, anhydrous n-Heptane
2-Butanone Hydrogen fluoride
2-Butoxyethanol 1-Methoxypropanol-2
2-Butoxyethyl acetate 5-Methylheptan-3-one
e-Caprolactam 5-Methylhexan-2-one†
Chloroform 4-Methylpentane-2-one†
1,2-Dichlorobenzene 2-Phenylpropene
1,4-Dichlorobenzene Phosgene
1,1-Dichloroethane Silver, metallic
Dimethylether Sodium azide
Ethylbenzene - see also CD166 Sulfotep
Ethylene glycol Tetrahyrofuran†
Fluorides, inorganic 1,1,1-Trichloroethane
Fluorine
CD 157: CD 166:
mid May - mid August 2000 February - May 2001
IOELV substances already being IOELV substances judged to be most in
reviewed under the domestic programme: need of detailed review:
n-Butylacrylate Chlorobenzene - MEL proposal
Cyclohexanone† Phenol - MEL proposal
Diethylether† Xylene, mixed isomers, pure
Triethylamine o-Xylene
Chlorobenzene - OES withdrawal p-Xylene
Phenol - OES withdrawal m-Xylene
[Note: Chloroethane is a 2nd IOELV Former ILV substances which have not
Directive proposal] fully taken account of the IOELV:
2-Methoxy-1-methylethylacetate
Orthophosphoric acid
1,2,4-Trichlorobenzene
Dihydrogen selenide - MEL proposal
Cumene
IOELV substance not reviewed by
HSC/E
Ethylbenzene - Skin notation
† = substances covered by the amendment to CD156 and CD157 which is included in this CD
HSE is not yet able to consult on formal proposals for Piperazine which will be consulted on
via HSE’s web site at http://www.hse.gov.uk in the new year.
6
PROPOSALS FOR IMPLEMENTING IOELV SUBSTANCES INTO THE
NATIONAL LIMIT SETTING SYSTEM.
14. HSC’s proposals for implementing 12 IOELV substances (including one substance
carried forward from CD156) into the national limit setting system are set out in the
following paragraphs and are summarised substance by substance in Table A below. An
amendment which covers 7 substances previously consulted on in CDs 156 and 157 is also
included at Table B (page 17). HSE has decided to reconsult on these proposals in the light of
more recent legal advice (see paragraphs 7 to 9).
15. Included at Appendix 3 is a summary criteria document for each of the 20 substances
under discussion to help you to understand the reasons why the limit is being proposed. All of
the summaries are in EH64 format. The grey box in the top left corner indicates whether the
limit has been changed to reflect SCOEL recommendations or is an existing domestic
occupational exposure limit. Where no recent WATCH review has been conducted the
summary has been prepared using the relevant SCOEL review document (known as a
SCOEL-SEG/SUM). For substances which had previously been reviewed by WATCH (so
already had a summary document) the existing document has been revised to incorporate both
SCOEL’s and WATCH’s views and retain the analytical method. For substances which have
recently been reviewed by WATCH, and where WATCH have taken into account the IOELV,
the summary has been prepared using the WATCH review package and subsequent
discussions. Copies of the full WATCH documentation are available through HSE public
information centres (see back cover).
7
Table A IOELV HSE current OEL HSC WATCH
proposal reviews
MEL OES
Substance Name
a) 8-hr TWA a) 8-hr TWA a) 8-hr TWA
b) STEL b) STEL b) STEL
CAS number
c) Notation c) Notation c) Notation
Chlorobenzene a) 10 ppm a) - a) 50 ppm - Withdraw 2000
108-90-7 OES* and
introduce 8 hr
TWA MEL of
1 ppm
b) 20 ppm b) - b) - - Introduce
STEL MEL of
3 ppm
c) - c) - c) - - Introduce Sk
notation
c) Sk c) - c) - - Introduce Sk
notation
8
Table A IOELV HSE current OEL HSC WATCH
proposal reviews
MEL OES
Substance Name
a) 8-hr TWA a) 8-hr TWA a) 8-hr TWA
b) STEL b) STEL b) STEL
CAS number
c) Notation c) Notation c) Notation
Orthophosphoric a) 1 mg.m-3 a) - a) - - Introduce 8 1998
acid hr TWA OES
7664-38-2 of 1 mg.m-3
b) 2 mg.m-3 b) - b) 2 mg.m-3 - Retain STEL
OES
c) - c) - c) - - No change
* Consulted on in CD157
9
PROPOSALS FOR CHANGES TO THE LIST OF MAXIMUM EXPOSURE LIMITS
Proposals for new substances
16. It is proposed that the following three substances be added to the list of MELS. HSE
has issued Chemical Hazard Alert Notices (CHANs) for these substances in the interim.
Summary criteria documents explaining the rationale behind the proposals are attached at
Appendix 3.
Reference Periods
Chlorobenzene
17. Chlorobenzene was one of the IOELV substances judged to be in need of further
review by ACTS/WATCH. These recommendations reflect their latest advice.
18. You will see from Table A that the HSC proposal for chlorobenzene is lower than the
IOELV Directive which recommends an 8 hour limit of 10 ppm and a STEL of 20 ppm. Also,
HSC is recommending a Sk notation. HSE based its review to WATCH on a collaborative
review by the Swedish National Institute for Occupational Health and the USA National
Institute for Occupational Safety and Health, first published in 1992. This post-dated the EU
criteria document SEG/CDO/22B used by SCOEL to make its recommendation summarised
in SEG/SUM42C. Both the collaborative review and the SCOEL summary were included in
the information presented to WATCH.
19. The proposal to withdraw the OES was included in a Consultative Document
(CD157) agreed by HSC and published in May 2000.
Question 1: Do you agree with the 8 hour TWA MEL proposal for chlorobenzene?
10
Question 2: Do you agree with the STEL MEL proposal for chlorobenzene?
If you disagree, please explain why.
Dihydrogen selenide
20. Dihydrogen selenide is one of the substances previously covered by the 2nd ILV
Directive. WATCH considered the occupational exposure limits for hydrogen selenide in
1998 and concluded that there was insufficient data to identify a safe level of exposure.
ACTS endorsed WATCH's recommendation to withdraw the existing OES and considered
setting a MEL. But ACTS concluded that because usage patterns showed very few people are
exposed to this substance; and those levels of exposure are negligible, a MEL was not
appropriate. However, HSE is now required to set a limit in order to meet the requirements of
CAD. The MEL proposal reflects the values in the IOELV Directive.
21. No RIA for this MEL proposal has been conducted. This is because a preliminary cost
assessment based on information provided by the industry indicated that costs would be
negligible because the substance is well controlled already.
Question 4: Do you agree that the IOELV should be adopted as an 8 hour TWA MEL
for dihydrogen selenide?
If you disagree, please explain why.
Question 5: Do you agree that the IOELV should be adopted as a STEL MEL
for dihydrogen selenide?
If you disagree, please explain why.
Phenol
22. Phenol has been in the ACTS/WATCH review programme since 1992: A key issue
of mutagenicity took some time to resolve, because of the need to acquire further scientific
11
information. In 2000 WATCH and ACTS agreed that consideration of a MEL was warranted
and agreed that a proposal to withdraw the current OES should go to external consultation.
23. The proposal to withdraw the OES was included in a Consultative Document
(CD157), agreed by HSC and published in May 2000. The MEL proposal reflects the value
and notation in the IOELV Directive.
Question 6: Do you agree that the IOELV should be adopted as an 8 hour TWA MEL
for phenol?
If you disagree, please explain why.
Question 7: Do you agree that it is not necessary to set a STEL MEL for phenol?
If you disagree, please explain why.
12
PROPOSALS FOR CHANGES TO THE LIST OF OCCUPATIONAL EXPOSURE
STANDARDS
24. Summary criteria documents explaining the rationale behind the proposed
occupational exposure limits for the substances detailed in this section are attached at
Appendix 3. They reflect the views of SCOEL and/or WATCH, as appropriate.
26. WATCH concluded that the data support the maintenance of OESs for xylenes and
recommended an 8-hour TWA OES of 50 ppm which directly corresponds to the 8-hour
TWA IOELV. The maintenance of a Skin notation was also supported as was HSE’s proposal
to establish a BMGV for xylenes. However, for the STEL OES, WATCH recommended 150
ppm, in contrast to the STEL IOELV of 100 ppm. The reasons for this are summarised in the
draft EH64 summary criteria document. ACTS recommended the adoption of the IOELV
STEL.
Question 9: Do you agree with the 8 hour TWA OES proposal for xylenes?
If you disagree, please explain why.
Question 10: Do you agree with the STEL OES proposal for xylenes?
If you disagree, please explain why.
Question 12: Do you agree with the proposal to develop a BMGV for xylenes?
If you disagree please explain why.
13
Ethylbenzene
27. Proposals for an 8 hour OES and STEL OES for ethylbenzene were consulted on in
CD156. A decision on the skin notation was deferred until the review of xylenes was
completed. It is now proposed to adopt the skin notation proposed in the IOELV Directive.
Orthophosphoric acid
28. In 1998 WATCH decided that an 8 hour TWA OES was not needed because the
STEL would be protective of health. However an 8 hour TWA IOELV has been set and so we
are proposing to amend the entry in order to comply with CAD.
Question 14: Do you agree that the IOELV should be adopted as an 8 hour TWA OES
for Orthophosphoric acid?
If you disagree, please explain why.
1,2,4-Trichlorobenzene
29. In 1998 WATCH decided that a STEL OES was not needed because the 8 hour TWA
OES would be protective of health. However a STEL IOELV has been set and so we are
proposing to amend the entry in order to comply with CAD.
Question 15: Do you agree that the IOELV should be adopted as a STEL OES
for 1,2,4-Trichlorobenzene?
If you disagree, please explain why.
2-Methoxy-1-methylethylacetate
30. In 1998 WATCH decided that a STEL OES was required and set this at 150 ppm
based on the three times rule. However, an IOELV STEL has been set at 100 ppm. In order to
comply with CAD we are proposing to revise the STEL OES to 100 ppm.
14
31. In 1998 WATCH decided that a Sk notation was not necessary, however one is now
needed to comply with CAD.
Question 16: Do you agree with the STEL OES proposal for 2-Methoxy-1-methylethyl
acetate?
If you disagree please explain why.
Question 17: Do you agree with the Sk notation proposal for 2-Methoxy-1-methylethyl
acetate?
If you disagree please explain why.
Cumene
32. Cumene was last considered by WATCH in 1991. The STEL OES WATCH
recommended was 75 ppm, in contrast to the STEL IOELV of 50 ppm and this difference is
considered to be significant. The reasons for SCOEL’s recommendation are summarised in
the draft EH64 summary criteria document. SCOEL based its evaluation on the same data as
WATCH and so there are not considered to be any scientific grounds on which to challenge
the IOELV.
Question 18: Do you agree with the STEL OES proposal for Cumene?
If you disagree please explain why.
15
REGULATORY IMPACT/COST BENEFIT ASSESSMENTS
33. Before any new piece of legislation can be introduced, the Health and Safety
Commission is obliged to have carried out an assessment of the costs it would impose on
industry and the benefits it is expected to bring. Since October 1998, this assessment is
included in the Regulatory Impact Assessment (RIA). Annex 4 of this document gives a
description of the methodology behind the formulation of cost benefit assessments (CBAs)
for RIAs and a general statement on their application. An RIA is not carried out when the
legislation does not impose additional costs to industry.
34. HSE has examined what costs and benefits will result from the implementation into
the national limit setting system of the directive as a whole. This RIA shows that total one-off
costs, as a result of capital expenditure, were estimated to be about £0.4 million (1999/2000
prices), while the ten-year present value of the recurring costs was £8.8 million (1999/2000
prices). Recurring costs are incurred mainly as a result of increased use of respiratory
protective equipment (RPE) and increased monitoring to check compliance with the new
limit. Thus, the total cost to society of implementing the whole Directive is £9.2 million
(1999/2000 prices) over 10 years, in present value terms. The RIA could not quantify any of
the health benefits resulting from the introduction of this Directive. However, it was noted
that there are negative health effects associated with exposure to the substances covered by
the Directive and that reducing exposure may lead to health benefits.
35. In addition, individual RIAs were carried out for two of the three MEL proposals and
summaries are presented at Annex 4A. An initial assessment for one MEL proposal,
dihydrogen selenide, indicated that costs would be negligible and so a full RIA was not
conducted.
36. Copies of the RIA for the directive as a whole and individual RIAs for two of the four
MEL candidates are available on request from the HSE. If you would like a copy of any of
these documents, please contact Carole Sullivan in the Chemical Policy Division, Health and
Safety Executive, Rose Court, 2 Southwark Bridge, London SE1 9HS. If you have any
comments on the RIAs we would welcome these also.
16
AMENDMENT TO CD 156 AND CD 157
37. The following substances were first consulted on in CD156 or CD157 and are subject
to an existing domestic limit or a proposed domestic limit which is significantly higher than
the IOELV. Proposals for limits that are lower than the IOELV or only slightly higher are not
affected. This is in the light of new advice that significantly higher limits could be open to
challenge.
38. The following substances are affected (revised proposals are in italics):
CD 156
Acetone a) 750 ppm a) 500 ppm a) Consult on IOELV
b) 1500 ppm b) - b) Retain STEL
Heptan-3-one a) 50 ppm a) 20 ppm a) Consult on 35 ppm
(health-based SCOEL
recommendation prior
to applying ‘preferred
number’ system).
b) 100 ppm b) - b) Retain STEL
c) Sk c) - c) Retain Skin notation
5-Methylhexan-2-one a) 50 ppm a) 20 ppm a) Consult on IOELV
b) 100 ppm b) - b) Retain STEL
c) Sk c) - c) Retain Skin notation
4-Methylpentan-2-one a) 50 ppm a) 20 ppm a) Consult on IOELV
b) 100 ppm b) 50 ppm b) Consult on IOELV
c) Sk c) - c) Retain Skin notation
Tetrahyrofuran a) 100 ppm a) 50 ppm a) Consult on IOELV
b) 200 ppm b) 100 ppm b) Consult on IOELV
c) Sk c) Sk c) Retain Skin notation
CD 157
Cyclohexanone a) 20 ppm a) 10 ppm a) Consult on IOELV
b) 50 ppm b) 20 ppm b) Consult on IOELV
c) Sk c) Sk c) Retain Skin notation
Diethyl ether a) 400 ppm a) 100 ppm a) Consult on IOELV
b) 500 ppm b) 200 ppm b) Consult on IOELV
17
39. A higher limit than the IOELV could be set if certain criteria are met. The position is
further explained in paragraph 7 of this CD and it is important that you consider this carefully
when formulating your response.
40. We propose that the above values are adopted as OESs unless we receive information
from this consultation exercise to suggest that there are grounds by which HSE could
justifiably recommend setting a higher limit to HSC. Summary criteria documents explaining
the rationale behind the revised proposals are attached at Appendix 3.
Question 19: Do you agree with the proposal to adopt the IOELVs for Acetone,
Cyclohexanone, Diethyl ether, 5-Methylhexan-2-one,
4-Methylpentan-2-one and Tetrahyrofuran and the health-based SCOEL
recommendation for Heptan-3-one?
Bearing in mind the position set out at paragraph 7 of the main CD, if
you disagree with any of these proposals please state which ones and
explain why.
18
INVITATION TO COMMENT
41. The Health and Safety Commission would welcome comments on proposals set out in
this Consultative Document. We will acknowledge all responses and give full consideration
to the substance of arguments in the development of proposals; we may also contact you
again, if, for example, we have a query. For the convenience of readers, all the questions are
repeated in a form set out in Appendix 5 which you may find helpful to use for your reply.
42. If you reply to this consultative document in a personal capacity, rather than as a
postholder of an organisation, you should be aware that information you provide may
constitute “personal data” in the terms of the Data Protection Act 1998. For the purposes of
this Act, HSE is the “data controller” and will process the data for health, safety and
environmental purposes. HSE may disclose these data to any person or organisation for the
purposes for which it was collected, or where the Act allows disclosure. You have the right to
ask for a copy of the data and to ask for inaccurate data to be corrected. Please note all replies
will be made public unless you specifically state you wish yours to be made confidential.
43. The Health and Safety Commission/Executive would also like to know what you think
about this consultation, both the content and layout. The response form at Appendix 5
includes a few separate questions on this aspect of the consultation. Your views may help to
improve further consultations. If you are not satisfied with the way in which this consultation
exercise has been conducted you can complain by contacting:
Mr Chris Rowe
Health and Safety Executive
Room 602
Rose Court
2 Southwark Bridge
London
SE1 9HS.
19
APPENDIX 1 - DIRECTIVE
16.6.2000 Official Journal of the European Communities L 142/47
COMMISSION DIRECTIVE 2000/39/EC
of 8 June 2000
establishing a first list of indicative occupational exposure limit values in implementation of
Council Directive 98/24/EC on the protection of the health and safety of workers from the
risks related to chemical agents at work
(Text with EEA relevance)
(3) For any chemical agent for which indicative (10) For some agents, it is necessary to have regard also to
occupational exposure limit values are established at the possibility of penetration through the skin, in order
Community level, Member States are required to to ensure the best possible level of protection.
establish a national occupational exposure limit value,
taking into account the Community limit value, (11) This Directive constitutes a practical step towards the
determining its nature in accordance with national achievement of the social dimension of the internal
legislation and practice. market.
(4) Indicative occupational exposure limit values should be (12) The measures provided for in this Directive are in
regarded as an important part of the overall approach to accordance with the opinion of the Committee
ensuring the protection of the health of workers at the instituted by Article 17 of Council Directive
workplace, against the risks arising from hazardous 89/391/EEC of 12 June 1989 on the introduction of
chemicals. measures to encourage improvements in the health and
safety of workers at work (6),
(5) A first and a second list of indicative occupational
exposure limit values were established by Commission HAS ADOPTED THIS DIRECTIVE:
Directives 91/322/EEC(3) and 96/94/EC(4) in the Article 1
framework of Council Directive 80/1107/EEC of 27
November 1980 on the protection of workers from the Community indicative occupational exposure limit values
risks related to exposure to chemical, physical and are hereby established for the chemical agents set out in the
biological agents at work(5). Annex.
Article 2 Article 4
Member States shall establish national occupational Directive 96/94/EC is repealed with effect from the date
exposure limit values for the chemical agents listed in the referred to in Article 3(1).
Annex, taking into account the Community values.
Article 5
Article 3
This Directive shall enter into force on the 20th day
1. Member States shall bring into force the laws, following its publication in the Official Journal of the
regulations and administrative provisions necessary to European Communities.
comply with this Directive by 31 December 2001 at the
latest. They shall forthwith inform the Commission thereof. Article 6
When Member States adopt these provisions, they shall This Directive is addressed to the Member States.
contain a reference to this Directive or be accompanied by
such a reference at the time of their official publication. Done at Brussels, 8 June 2000.
Member States shall determine how such reference is to be
made.
21
ANNEX
Limit values
(4)
Eight hours Short-term(5) Notation(3)
Einecs(1) CAS(2) Name of agent
3(6) (7) 3(6) (7)
mg/ m ppm mg/ m ppm
200-467-2 60-29-7 Diethylether 308 100 616 200 -
200-662-2 67-64-1 Acetone 1210 500 - - -
200-663-8 67-66-3 Chloroform 10 2 - - Skin
200-756-3 71-55-6 1,1,1-Trichloroethane 555 100 1110 200 -
200-834-7 75-04-7 Ethylamine 9,4 5 - - -
200-863-5 75-34-3 1,1-Dichloroethane 412 100 - - Skin
200-870-3 75-44-5 Phosgene 0,08 0,02 0,4 0,1 -
200-871-9 75-45-6 Chlorodifluoromethane 3600 1000 - - -
201-159-0 78-93-3 Butanone 600 200 900 300 -
201-176-3 79-09-4 Propionic acid 31 10 62 20 -
202-422-2 95-47-6 o-Xylene 221 50 442 100 Skin
202-425-9 95-50-1 1,2-Dichlorobenzene 122 20 306 50 Skin
202-436-9 95-63-6 1,2,4-Trimethylbenzene 100 20 - - -
202-704-5 98-82-8 Cumene 100 20 250 50 Skin
202-705-0 98-83-9 2-Phenylpropene 246 50 492 100 -
202-849-4 100-41-4 Ethylbenzene 442 100 884 200 Skin
203-313-2 105-60-2 e-Caprolactam (dust and vapour) 10 - 40 - -
203-388-1 106-35-4 Heptan-3-one 95 20 - - -
203-396-5 106-42-3 p-Xylene 221 50 442 100 Skin
203-400-5 106-46-7 1,4-Dichlorobenzene 122 20 306 50 -
203-470-7 107-18-6 Allyl alcohol 4,8 2 12,1 5 Skin
203-473-3 107-21-1 Ethylene glycol 52 20 104 40 Skin
203-539-1 107-98-2 1-Methoxypropanol-2 375 100 568 150 Skin
203-550-1 108-10-1 4-Methylpentan-2-one 83 20 208 50 -
203-576-3 108-38-3 m-Xylene 221 50 442 100 Skin
203-603-9 108-65-6 2-Methoxy-l-methylethylacetate 275 50 550 100 Skin
203-604-4 108-67-8 Mesitylene (Trimethylbenzenes) 100 20 - - -
203-628-5 108-90-7 Chlorobenzene 47 10 94 20 -
203-631-1 108-94-1 Cyclohexanone 40,8 10 81,6 20 Skin
203-632-7 108-95-2 Phenol 7,8 2 - - Skin
203-726-8 109-99-9 Tetrahydrofuran 150 50 300 100 Skin
203-737-8 110-12-3 5-Methylhexan-2-one 95 20 - - -
203-767-1 110-43-0 Heptan-2-one 238 50 475 100 Skin
203-808-3 110-85-0 Piperazine 0,1 - 0,3 - -
203-905-0 111-76-2 2-Butoxyethanol 98 20 246 50 Skin
203-933-3 112-07-2 2-Butoxyethyl acetate 133 20 333 50 Skin
22
Limit values
(4)
Eight hours Short-term(5) Notation(3)
Einecs(1) CAS(2) Name of agent
3 (6) (7) 3 (6) (7)
mg/ m ppm mg/ m ppm
204-065-8 115-10-6 Dimethylether 1920 1000 - - -
204-428-0 120-82-1 1,2,4-Trichlorobenzene 15,1 2 37,8 5 Skin
204-469-4 121-44-8 Triethylamine 8,4 2 12,6 3 Skin
204-662-3 123-92-2 Isopentylacetate 270 50 540 100 -
204-697-4 124-40-3 Dimethylamine 3,8 2 9,4 5 -
204-826-4 127-19-5 N,N-Dimethylacetamide 36 10 72 20 Skin
205-480-7 141-32-2 n-Butylacrylate 11 2 53 10 -
205-563-8 142-82-5 n-Heptane 2085 500 - - -
208-394-8 526-73-8 1,2,3-Trimethylbenzene 100 20 - - -
208-793-7 541-85-5 5-Methylheptan-3-one 53 10 107 20 -
210-946-8 626-38-0 1-Methylbutylacetate 270 50 540 100 -
211-047-3 628-63-7 Pentylacetate 270 50 540 100 -
620-11-1 3-Pentylacetate 270 50 540 100 -
625-16-1 Amylacetate, tert 270 50 540 100 -
215-535-7 1330-20-7 Xylene, mixed isomers, pure 221 50 442 100 Skin
222-995-2 3689-24-5 Sulphotep 0,1 - - - Skin
231-634-8 7664-39-3 Hydrogen fluoride 1,5 1,8 2,5 3 -
231-131-3 7440-22-4 Silver, metallic 0,1 - - - -
231-595-7 7647-01-0 Hydrogen chloride 8 5 15 10 -
231-633-2 7664-38-2 Orthophosphoric acid 1 - 2 - -
231-635-3 7664-41-7 Ammonia, anhydrous 14 20 36 50 -
231-954-8 7782-41-4 Fluorine 1,58 1 3,16 2 -
231-978-9 7783-07-5 Dihydrogen selenide 0,07 0,02 0,17 0,05 -
233-113-0 10035-10-6 Hydrogen bromide - - 6,7 2 -
247-852-1 26628-22-8 Sodium azide 0,1 - 0,3 - Skin
252-104-2 34590-94-8 (2-Methoxymethylethoxy)- 308 50 - - Skin
propanol
Fluorides, inorganic 2,5 - - - -
1
EINECS: European inventory of existing chemical substances
2
CAS: Chemical abstract service registry number
3
A skin notation assigned to the OEL identifies the possibility of significant uptake through the skin
4
Measured or calculated in relation to a reference period of eight hours time weighted average
5
A limit value above which exposure should not occur and is related to a 15-minute period, unless otherwise specified
6
mg/m3 : milligrams per cubic metre of air at 20oC and 101,3 KPa
7
ppm : parts per million by volume in air (ml/m3)
23
APPENDIX 2 - Summary of progress
CAS No. NAME OF AGENT Existing ILV limit CD156 CD157 CD166 WATCH
meets does consider-
CAD not ation of
reqt. meet IOELV
CAD [or ILV]
reqt
60-29-7 Diethylether ü ü« -
67-64-1 Acetone ü ü« -
67-66-3 Chloroform ü -
71-55-6 1,1,1-Trichloroethane ü -
75-04-7 Ethylamine ü -
75-34-3 1,1-Dichloroethane ü -
75-44-5 Phosgene ü -
75-45-6 Chlorodifluoromethane ü -
78-93-3 Butanone ü -
79-09-4 Propionic acid ü -
95-47-6 o-Xylene ü 2000
95-50-1 1,2-Dichlorobenzene ü -
95-63-6 1,2,4-Trimethylbenzene ü -
98-82-8 Cumene ü ü [1991]
98-83-9 2-Phenylpropene ü -
100-41-4 Ethylbenzene ü ü -
105-60-2 e-Caprolactam (dust and ü -
vapour)
106-35-4 Heptan-3-one ü ü« -
106-42-3 p-Xylene ü 2000
106-46-7 1,4-Dichlorobenzene ü -
107-18-6 Allyl alcohol ü -
107-21-1 Ethylene glycol ü -
107-98-2 1-Methoxypropanol-2 ü -
108-10-1 4-Methylpentan-2-one ü ü« -
108-38-3 m-Xylene ü 2000
108-65-6 2-Methoxy-l-methyl- ü ü [1998]
ethylacetate
108-67-8 Mesitylene ü -
(Trimethylbenzenes)
108-90-7 Chlorobenzene ü ü 2000
108-94-1 Cyclohexanone ü ü« 1999
108-95-2 Phenol ü ü 2000
109-99-9 Tetrahydrofuran ü ü« -
110-12-3 5-Methylhexan-2-one ü ü« -
110-43-0 Heptan-2-one ü -
24
CAS No. NAME OF AGENT Existing ILV limit CD156 CD157 CD166 WATCH
111-76-2 2-Butoxyethanol ü -
112-07-2 2-Butoxyethyl acetate ü -
115-10-6 Dimethylether ü -
120-82-1 1,2,4-Trichlorobenzene ü ü [1998]
121-44-8 Triethylamine ü 1999
123-92-2 Isopentylacetate ü -
124-40-3 Dimethylamine ü -
127-19-5 N,N-Dimethylacetamide ü -
141-32-2 n-Butylacrylate ü 2000
142-82-5 n-Heptane ü -
526-73-8 1,2,3-Trimethylbenzene ü -
541-85-5 5-Methylheptan-3-one ü -
626-38-0 1-Methylbutylacetate ü -
628-63-7 Pentylacetate ü -
620-11-1 3-Pentylacetate ü -
625-16-1 Amylacetate, tert ü -
1330-20-7 Xylene, mixed isomers, ü 2000
pure
3689-24-5 Sulphotep ü -
7664-39-3 Hydrogen fluoride ü -
7440-22-4 Silver, metallic ü -
7647-01-0 Hydrogen chloride ü -
7664-38-2 Orthophosphoric acid ü ü [1998]
7664-41-7 Ammonia, anhydrous ü -
7782-41-4 Fluorine ü -
7783-07-5 Dihydrogen selenide ü ü [1998]
10035-10-6 Hydrogen bromide ü -
26628-22-8 Sodium azide ü -
34590-94-8 (2-Methoxymethyl ü -
ethoxy)-propanol
Fluorides, inorganic ü -
Totals 18 5 29 6 12 +
«7
« Reconsulting following adoption of recent legal advice
Note: HSE is not yet able to present formal proposals for piperazine.
25
APPENDIX 3
26
MEL PROPOSAL
R36/37/38: Irritating to eyes, respiratory system and
skin
CHLOROBENZENE
It is possible that the UK will submit a proposal to the
maximum exposure limits relevant European Working Group with a view to
getting the CHIP classification amended in this way.
8-hour TWA: 1 ppm (4.7 mg.m-3)
OCCURRENCE AND USE
15-minute STEL: 3 ppm (14 mg.m-3)
Chlorobenzene is not manufactured in the UK and is
Notation: Skin only used as a process solvent or chemical intermedi-
subject to consultation ate and as a laboratory reagent. Approximately 20
companies use chlorobenzene as a process solvent or
chemical intermediate. The numbers exposed during
its use in the chemical industry is estimated to be
IDENTITY AND PROPERTIES between 100 and 300. The numbers exposed during its
Chemical Name Chlorobenzene use as a laboratory reagent could be more, however,
CAS No: 108-90-7 such workers are likely to have very infrequent
exposures.
EEC No: 602-033-00-1
Formula: C6 H5 Cl EXPOSURE
Synonyms: monochlorobenzene, MCB Of 38 reported recent personal air sampling results
chlorobenzol, CB, from a user of chlorobenzene, one was at 3 ppm
phenyl chloride, 8-hour TWA, the others all below 1 ppm. Earlier
chlorobenzol, results at one chemical site were up to 6 ppm 8-hour
TWA, with 83% of results less than 1 ppm 8-hour
benzene chloride TWA. At another site the highest personal air
Molecular weight: 112.56 sampling result was 0.2 ppm 8-hour TWA. The
Physical state: Colourless liquid highest exposure data received was from a company
who used chlorobenzene until the end of 1998 as a
Boiling Point: 131.6 oC
chemical intermediate. Exposures were up to 329 ppm
Melting point: - 44.9 oC for the duration of the task (1 to 2 hours) and 59 ppm
Vapour pressure: 15.81 hPa at 25 oC when time weighted over the 8 hour shift. Peak
exposures would have been higher than these values.
11.73 hPa at 20 oC
Exposure data modelled with the Estimation and
Solubility in water: 293 mg.l-1 at 25 oC
Assessment of Substance Exposure (EASE) model
LogPo/w: 2.84 gave results of 4.6 to 6.7 ppm 15-min TWA for
Saturated vapour concentration: 15526 ppm (1.55%) sampling, 1.3 to 50 ppm 15-min TWA for tanker
unloading, and 1 to 100 ppm 15-min TWA for vessel
charging. These represent short term exposures. These
Conversion factors: 1 ppm = 4.68 mg.m-3 at 20 oC are likely to be overestimates and will be dependent
1 mg.m-3 = 0.21 ppm on the nature of the controls in place. The above short
term exposure compares reasonably well with the full
shift exposure. For example, 3.5 ppm 8-hour TWA for
Chlorobenzene is currently classified for health effects
a worker exposed during tanker unloading (30
under the Chemicals (Hazard Information and Packag-
minutes) and quality control sampling (2 periods of 15
ing for Supply) Regulations 1994 (CHIP) as Harmful,
minutes). Occupational exposure during repackaging
to be labelled with the following risk phrases:-.
of chlorobenzene and laboratory use are thought to be
R10: Flammable generally lower than the above values.
R20: Harmful by inhalation It is therefore concluded that exposure is generally
R51/53: Toxic to aquatic organisms, may cause below 50 ppm 8-hour TWA and in most cases below
long term adverse effects in the aquatic 10 ppm 8-hour TWA. It is further concluded that the
environment data demonstrates that it is likely that control to less
than 5 ppm 8-hour TWA is reasonably practicable.
The available data for chlorobenzene indicate that it Although exposures of higher than this have been
also meets the criteria for classification as Irritant, obtained it was not felt that these represented the
and that the following risk phrase may be majority of exposures and what it is reasonably practi-
appropriate:- cable to achieve.
27
MEL PROPOSAL
There is little information about short-term exposures. unlikely to be suitable for 15 minute sampling below
Short term exposures of up to 100 ppm 15-min TWA 25 ppm. Users must verify the solvent desorption
were modelled using EASE. However, the higher efficiency of chlorobenzene with their chosen collec-
values represented only modest assumptions about tion medium, otherwise their procedure may not
standards of control. If realistic controls are incorpo- comply with EN 1076 or EN 8388 at low concentra-
rated, the model predicts exposures below 10 ppm. tions. Thermal desorption diffusive tube samplers are
Dermal exposure can occur during the use of chloro- feasible (MDHS 80)9 and have adequate sensitivity for
benzene, where operators come into contact with the measurement of <0.1 ppm for 8-hr sampling and
surfaces contaminated from splashing or condensed of <3 ppm for 15 minute sampling.
vapour, or as a result of direct contact onto the skin.
BIOLOGICAL MONITORING
During its use in chemical plants, where it is used in
generally closed systems, dermal exposure is only Biological monitoring may be a useful aid to the
likely during activities such as sampling and the assessment of occupational exposure to
uncoupling of pipes. A range of 0 to 0.1 mg.cm-2.day-1 chlorobenzene. There are no data to relate metabolite
was predicted using EASE assuming that there may be concentrations to health effects but there are data to
at most incidental (i.e. one significant) contact in a show a good correlation between levels of
shift. However, on most days no such accidental 4-chlorocatechol in urine samples collected at the end
contacts will occur and exposure will towards the of shift and inhaled chlorobenzene. After exposure to
bottom of this range. chlorobenzene at 1 ppm for 8 hours, the urine concen-
tration of 4-chlorocatechol would be around 5
ATMOSPHERE MEASUREMENT mmol.mol-1creatinine (6.4 mg.g-1).
There are several methods for the determination of
Indicating colourimetric tubes for short-term measure- 4-chlorocatechol in urine10,11,12,13. All are based on
ments of chlorobenzene in air are commercially avail- hydrolysis of glucuronide and sulphate conjugates of
able and capable of detecting 0.5 ppm. Other 4-chlorocatechol and HPLC with UV detection. The
chlorinated hydrocarbons can interfere with different most recent and well validated method is that of
sensitivities. Real-time instruments with infra-red or Heinrich-Ramm. This method was developed and
photo-acoustic detection that can detect less than 1 evaluated to support the DFG biological monitoring
ppm are also available. Personal exposure to vapour in programme.
air can be measured by pumped sampling on charcoal Briefly: the method hydrolyses 5ml of urine, contain-
tubes (solvent desorption method NIOSH 1003)1 or ing 3-ethylphenol internal standard, in 25% HCl at
Tenax (thermal desorption method MDHS 72)2 and 90oC for 2 hours and after cooling extracts the chloro-
analysis by gas chromatography. Earlier NIOSH data catechol into diethyl ether. The ether extract is trans-
published as method S1333 suggests that the carbon ferred to a clean vial and the ether removed under
tube method, with carbon disulphide and coconut shell nitrogen. The residue is redissolved in HPLC mobile
charcoal, may not meet the >75% desorption phase and injected into a C18 column at 34 oC. Detec-
efficiency criterion below 5 ppm at the maximum tion is at 205 nm. The method is linear from 0.5
sample volume of 40 litres. This factor is sensitive to mg.l-1 to 50 mg.l-1 with a detection limit of 0.1 mg.l-1
the type of carbon and the addition of solvent modifi- and a coefficient of variation for within-day impreci-
ers. Synthetic carbons are better than coconut shell sion of 2.3% and a day to day imprecision of 4.9%.
charcoal. OSHA have indicated a preference for 1% No interfering peaks have been found in chroma-
dimethylformamide in carbon disulphide4. With tograms at levels greater than 0.5 mg.l-1 from people
respect to other factors, solvent desorption methods not occupationally exposed to chlorobenzene.
would generally comply with EN 4825 on overall
uncertainty and with EN 10766 on environmental TOXICOKINETICS
effects above 5 ppm. The pumped thermal desorption
method MDHS 72 has a detection limit of <0.02 ppm Few data on the toxicokinetics of chlorobenzene in
for a 10 litre sample. MDHS 72 has been partially humans are available. The data which are available
validated for chlorobenzene and is likely to comply relate to metabolism and excretion. The available
with EN 482 and EN 1076 for both long-term and animal data largely relate to the inhalation and oral
short-term sampling at <1 ppm where desorption routes of exposure. There are no data regarding the
efficiency was >97%. Diffusive sampling is feasible dermal route of exposure.
on carbon-type badge devices with solvent desorption Human and animal studies show that chlorobenzene is
(MDHS 88)7. However, uptake rates are generally absorbed to a substantial extent via the oral and
lower than pumped flow-rates and the desorption inhalation routes, but do not allow quantification of
efficiency criterion of >75% may not be met below 15 absorption via these routes. From the physico-
ppm for 8 hours. Carbon-type diffusive badges are chemical properties of chlorobenzene and by analogy
28
MEL PROPOSAL
with other chlorobenzenes it is predicted that chloro- Signs of acute toxicity in animals exposed to chloro-
benzene will be readily absorbed via the dermal route. benzene via all routes include hyperaemia of the
Following absorption chlorobenzene is distributed mucous membranes, increased salivation and lacrima-
throughout the body, principally to the fat, liver, lungs tion and evidence of disturbance of the central
and kidneys. Given the lipid solubility of chloroben- nervous system. Pathological findings of hypertrophy
zene it is likely to accumulate in body fat, although and necrosis of the liver and of the proximal tubules
this may depend on the extent of metabolism. of the kidneys are reported. In all acute exposure
studies death generally occurred as a result of respira-
Comparative in vitro studies suggest qualitatively tory failure.
similar metabolic profiles in rats, mice, rabbits, Limited animal data indicate that direct contact with
guinea-pigs and humans. In vitro data also indicate liquid chlorobenzene is irritating to both the skin and
that human liver microsomes are twice as efficient as eyes. No useful data are available regarding the
mouse liver microsomes in metabolising chloroben- potential of chlorobenzene to cause irritation to the
zene and also that human liver microsomes have a respiratory tract. However, given the skin/eye irritancy
greater affinity for chlorobenzene than mouse liver it can be predicted that chlorobenzene is likely to be
microsomes. capable of causing respiratory tract irritation.
In vitro and in vivo human and animal data indicate Chlorobenzene did not induce skin sensitisation in a
that chlorobenzene is initially oxidised by the micro- guinea-pig maximisation study. There are no data
somal cytochrome P450 system to a reactive arene regarding the potential of chlorobenzene to cause
oxide, which has the potential to bind with rat and respiratory tract sensitisation.
mouse liver, kidney and lung DNA, RNA and With respect to repeated dose toxicity, animal data
proteins. indicate that the liver, kidneys and possibly the
The arene oxide is subsequently converted either via haematopoietic tissues are the target organs of chloro-
non-enzymic reactions to 3 and 4 isomers of chloro- benzene toxicity.
phenol or via enzymic activity to a glutathione (GSH) Inhalation studies demonstrate that in rats no effects
conjugate or to dihydrodiol derivatives. The GSH on the liver occurred following chlorobenzene
conjugates are either eliminated unchanged in the exposures of up to 75 ppm for 24 weeks . At 250 ppm
faeces or are transformed to more water soluble for 24 weeks and at 150 and 450 ppm for ~22 weeks
products and are excreted in the urine as liver weights were increased by 13 to 36% compared
4-chlorophenylmercapturic acid. The dihydrodiol with controls with evidence of minimal to moderate
derivatives are converted principally to hepatocellular hypertrophy in males at 150 and
4-chlorocatechol and to a lesser extent to 450 ppm for ~22 weeks but not in animals at 250 ppm
3-chlorocatechol which are also excreted in the urine. for 24 weeks. In dogs no adverse liver effects were
Animal and human studies have shown that excretion observed following exposures to 165 or 300 ppm for
of chlorobenzene and/or its metabolites in the urine is 90 days. Decreased liver weights (magnitude not
rapid (within 24 hours). In instances of high exposure reported) and vacuolisation of the hepatocytes were
concentrations, both inhalatory and orally, unchanged reported following exposures to 440 ppm for 90 days.
chlorobenzene has also been detected in expired air, No adverse liver effects were reported in rabbits at
the proportion of chlorobenzene exhaled increasing exposures of up to 250 ppm for 24 weeks.
with increasing exposure concentration, indicating Data from 90-day and 2-year oral gavage studies in
saturation of metabolism. both rats and mice suggest that the liver changes
induced are similar to those following inhalation
exposure but also indicate a sensitive marker for
HEALTH EFFECTS MCB-induced liver changes is elevated levels of
Animal studies urinary porphyrin. No adverse liver effects, including
Chlorobenzene is of moderate acute toxicity in rats changes in porphyrin levels were observed in either
and mice following single inhalation exposures of species at doses of 60, 125 or 250 mg.kg-1.day-1 for
chlorobenzene vapour, with 6-hour LC50 values of 13 90 days. At 500 and 750 mg.kg-1.day-1 for 90 days
and 8.6 mg.l-1 in rats and mice respectively. Chloro- increased liver weights (up to ~100%), increased
benzene is of low acute toxicity following single oral urinary porphyrin levels and centrolobular hepatocel-
exposure in rats, rabbits and guinea-pigs, with LD50 lular degeneration were observed in rats (all mice in
values of >2250 mg.kg-1. The mouse however appears these test groups had died). No evidence of liver
to be slightly more sensitive following single oral damage was reported in rats in a 2-year study at doses
exposures, with LD50 values in the range 1400 - 2300 up to 120 mg.kg-1.day-1 (the highest dose tested) or in
mg.kg-1. Chlorobenzene is of low acute toxicity in the mice at 60 mg.kg-1.day-1. In male mice and only at
rabbit following single dermal exposures with LD50 120 mg.kg-1 bw.day-1 an increased incidence of
values of >2000 and >7500 mg.kg-1 being identified. neoplastic nodules in the liver was observed. No
evidence of liver toxicity in dogs was reported to
occur in animals administered 27 mg.kg-1 bw.day-1 for
29
MEL PROPOSAL
13 weeks. Hepatotoxicity (nature and severity not In the repeated inhalation study in mice, haemato-
reported) was reported in dogs administered 54 and logical effects (changes in white blood cell, lympho-
273 mg.kg-1.day-1 for 90 days. cyte, monocyte and neutrophil numbers) were
Although data from a 2-year oral study in mice clearly observed at exposures of 21 ppm for 3 months and at
indicate a NOAEL for liver effects of 60 mg.kg-1 550 ppm for 3 weeks. As these were the only concen-
bw.day-1 hepatotoxicity (not specified) was reported trations and time points investigated a no effect level
in dogs at 54 mg.kg-1.day-1 for 90 days. Overall there- cannot be identified for haematological changes in the
fore, it is it is not possible to identify a clear NOAEL mouse exposed via inhalation. No changes in standard
for the liver effects resulting from chlorobenzene haematological parameters were reported in the
exposure. animals at doses of up to 250 mg.kg-1.day-1 for 90
Kidney damage was observed in male rats (increased days, or up to 120 mg.kg-1.day-1 for 2 years (the
incidence of tubular and interstitial kidney lesions and top-dose tested). However, blood analysis was only
proximal tubule degeneration, regeneration & conducted at the end of the dosing period in both of
necrosis) and in the dog (cytoplasmic vacuolisation of these studies. In the 90 day study animal deaths
the epithelium of the collecting tubules or unspecified prevented blood analysis at the higher doses (500 and
histopathological changes) following both inhalation 750 mg.kg-1.day-1). However, at necropsy evidence of
and oral exposures, and in the mouse following oral mild to moderate myeloid depletions of the bone
exposure (proximal tubule degeneration, regeneration marrow and minimal to moderate lymphoid necrosis
& necrosis). However in each species the kidney or depletion of the thymus were observed in animal at
effects were only manifest at exposure concentrations 250, 500 and 750 mg.kg-1.day-1 for 90 days.
or doses equal to or greater than those inducing liver In the repeated inhalation study in rabbits haemato-
damage. No evidence of kidney damage was reported logical changes (changes in PMNs, platelets, white
in the available rabbit inhalation study. blood cell, reticulocyte and monocyte numbers) were
observed following exposure to 75 and 250 ppm, the
Animal data also indicate that haematological changes only concentrations tested. No oral rabbit studies are
occur in rats, mice, rabbits and dogs following inhala- available.
tion exposures to chlorobenzene, and in rats, mice and In the available repeated inhalation exposure studies
dogs following oral exposures. The inhalation data in dogs, haematological analysis was only conducted
suggest that the mouse is the more sensitive species in the 90 day study. In this study, no treatment-related
with respect to the development of haematological haematological changes were reported at 165 or 330
changes. ppm. At 440 ppm, reduced leukocyte counts (not
Data from the available repeated rat inhalation study quantified) were reported, as well as evidence of
show no haematological changes following exposure aplastic bone marrow at necropsy. No findings were
to 75 ppm for 11 or 24 weeks (the 11 week time-point reported in animals at lower exposure concentrations.
being an interim sacrifice in the 24 week study). In the repeat oral study in dogs no effects on haema-
Haematological changes were observed in the same topoietic tissues were reported at doses of 27 mg.kg-1
study in animals at 250 ppm both at 11 and 24 weeks; bw.day-1 for 90 days. An increased number of
changes reported were in PMNs, platelets, white immature leukocytes was observed at 54 mg.kg-1
blood cell, reticulocyte and monocyte numbers. In the bw.day-1, and histopathological changes in the haema-
two available rat oral studies (a 90-day and a 2-year topoietic tissues (nature and severity of response not
study) in which haematological analysis was reported) were observed in animals administered 273
conducted (no interim analyses were conducted in mg.kg-1 bw.day-1.
either study), no haematological changes were Taking all of the available data together there are
reported at dose levels of 60, 120 (the top-dose tested) some indications that chlorobenzene may produce
mg.kg-1.day-1 for 2 years or at 60, 125 or 250 changes in haematological parameters. However, there
mg.kg-1.day-1 for 90 days. An increased mortality rate is clearly significant variation in the observations
in animals administered 500 mg.kg-1.day-1 for 90 days made and uncertainty remains over whether or not the
limited the extent of haematological analyses changes are chance findings or indicative of a real
conducted, consequently no adverse findings in treatment-related effect. Furthermore, if the findings
standard haematological parameters were reported. are considered to be related to treatment, then there is
However at necropsy an increased incidence of uncertainty in the identification of a NOAEL.
myeloid depletions in bone marrow were observed in In terms of genotoxicity, negative results have been
these animals. In animals administered 750 reported in bacterial studies and in studies in mammal-
mg.kg-1.day-1 for 90 days, (the increased mortality rate ian cells in vitro with respect to chromosome aberra-
did not limit haematological analyses in this group) tions, SCE and UDS at non-cytotoxic concentrations.
reduced white blood cell and reticulocyte counts and However, a clear and dose-related positive result has
lymphoid and/or myeloid depletions in thymus, spleen been reported in an in vitro gene mutation assay in
and bone marrow were reported. mouse lymphocytes, in the presence of metabolic
activation.
30
MEL PROPOSAL
There are no reliable data from mutagenicity studies The only information available on the effects of
conducted in vivo according to validated test methods. chlorobenzene in humans derive from isolated case
Overall, in light of the positive in vitro data and the reports of poisoning, occupational exposure studies or
fact that chlorobenzene has not been adequately tested one volunteer study. No data on the actual levels of
in vivo uncertainties remain with respect to the in vivo exposure are reported in any of the case reports, and
genotoxic potential of chlorobenzene. interpretation of the occupational exposure studies is
Oral (gavage) carcinogenicity studies with chloroben- confounded by exposure to mixtures of other
zene did not induce an increased incidence in any substances. In a human volunteer study, some
tumour type in rats of either sex at doses of up to 120 individuals self-reported sensations of disagreeable
mg.kg-1.day-1 or in mice of either sex at doses of up to odour and drowsiness (4/4), a heavy feeling in the
60 mg.kg-1.day-1. Although survival rates in top-dosed head and/or headache (3/4), a throbbing pain in the
animals were slightly reduced compared with controls, eyes (2/4) and a sore throat (1/4) during exposure to
no clinical signs of toxicity, changes in body weights 60 ppm chlorobenzene of an unspecified purity for
or gross treatment-related lesions were observed. 3-hours in the morning, followed by a 4-hour exposure
Therefore it is uncertain whether the top-doses tested period in the afternoon, with a 1-hour interval in
were actual maximum tolerated doses (MTDs) and between.
therefore whether the studies were in fact adequate for
the determination of carcinogenic potential. BASIS FOR SETTING THE LIMIT
No carcinogenicity studies via the inhalation or
dermal routes are available. There are no reliable human data available on which
No evidence for effects on fertility or reproductive to base an occupational exposure limit for chloroben-
performance were observed in a two generation study zene. The evidence from a range of animal species
in which rats were exposed to up to 450 ppm chloro- indicates that the liver and bone marrow are the key
benzene vapour. No adverse histopathalogical target organs of chlorobenzene toxicity in experimen-
findings in the gonads were observed in males at up to tal animals. From the information available, the
150 ppm or in females at up to 450 ppm An increased relevance of the animal data on these effects to human
incidence (severity not reported) of degeneration of health is uncertain. Given that they might be relevant,
the testicular germinal epithelium in males exposed to it is not possible to identify a clear NOAEL for the
450 ppm was noted at necropsy. Despite these lesions liver effects of chlorobenzene in animals.
there were no adverse effects on the fertility or repro- In relation to the haematological effects observed with
ductive performance of these animals. No adverse chlorobenzene, the pattern of information suggests
histological findings were observed in the gonads of that the mouse may be more sensitive to these effects
rats or rabbits, following repeated inhalation than other experimental species. However, haemato-
exposures of up to 250 ppm (1138 mg.m-3) for logical investigations have not been systematically
24 weeks. carried out in all studies, and there is significant
Bilateral atrophy of the seminiferous epithelium was variability in the results available from different
noted in dogs exposed to 273 ppm (~1500 mg.m-3) studies. This leads to uncertainty as to whether or not
chlorobenzene vapour for 90 days. the reported changes in individual studies represent
No adverse histological findings were observed in the reliable toxicological observations or chance findings.
gonads of rats or mice following repeated oral dosing However, it is perhaps significant that chlorobenzene
of up to 750 mg.kg-1.day-1 for 90 days or 120 is structurally similar to benzene, which is metabo-
mg.kg-1.day-1 and 60 mg.kg-1.day-1 for 2 years, respec- lised in a similar manner to chlorobenzene, both
tively, or in dogs following administration of up to molecules undergoing initial ring hydroxylation.
273 mg.kg-1.day-1 for 90 days. Therefore, the well-documented haematological
No evidence of any chlorobenzene treatment-related effects of benzene add weight to the concern for
developmental effects have been observed in rats, haematological changes with chlorobenzene. From
mice or rabbits, at doses up to 590 ppm on days the information available for chlorobenzene, it is not
5-16/18 of gestation, this being the highest concentra- possible to identify a clear NOAEL for haematologi-
tion tested. Evidence of some degree of maternal cal changes across the experimental species examined;
toxicity (reduced food consumption and body weight changes were reported in mice following repeated
gain and increased liver weights) was observed at exposure to 21 ppm, the lowest airborne concentration
590 ppm (2685 mg.m-3) in all species tested. tested.
Overall, it is concluded that chlorobenzene is not a In light of the positive in vitro genotoxicity data and
reproductive toxicant. the inadequate in vivo testing of chlorobenzene there
are uncertainties regarding the in vivo mutagenic
potential of chlorobenzene.
Human data
In the only available carcinogenicity study, no
increase in the incidence of any tumour type was
31
MEL PROPOSAL
observed in rats or mice. However, as it is uncertain ChemSamp_data/CH_227000.html.
whether the top doses tested were maximum tolerated 5. British Standards Institution, Workplace atmos-
doses (MTDs). the adequacy of this study and there- pheres - General requirements for the performance of
fore of the negative result is questionable Therefore procedures for the measurement of chemical agents,
in the absence of any other relevant data, there remain European Standard BS EN 482:1994, ISBN 0 580
uncertainties with respect to the carcinogenic potential 23644 7.
of chlorobenzene.
6. British Standards Institution, Workplace atmos-
Exposure data demonstrate that control to less than pheres - Pumped sorbent tubes for the determination
5 ppm (8-hour TWA) is reasonably practicable, and of gases and vapours, European Standard BS EN
that most results are below 1 ppm. Although higher 1076:1997, ISBN 0 580 28358 5.
exposure results have been obtained, these are not
typical and exceed what it is reasonably practicable to 7. Health and Safety Executive Methods for the Deter-
achieve. The available toxicological data do not mination of Hazardous Substances, Volatile organic
identify clear positive evidence for serious effects on compounds in air... diffusive samplers, solvent desorp-
human health at 1 ppm or 5 ppm; rather, the position tion, MDHS 88 HSE Books 1997 ISBN 0 7176 2401
is one of uncertainty. 3.
WATCH concluded that chlorobenzene did not fulfill 8. British Standards Institution, Workplace atmos-
the criteria for an OES and recommended that ACTS pheres - Diffusive samplers for the determination of
should give consideration to setting a MEL. Because gases and vapours - Requirements and test methods,
an occupational exposure limit is required to fulfill European Standard BS EN 838:1996, ISBN 0 580
British obligations under the Chemical Agents Direc- 26240 5.
tive and the Indicative Occupational Exposure Limit 9. Health and Safety Executive, Volatile organic
Value (IOELV) Directive, a MEL is necessary. compounds in air... diffusive samplers, thermal
Taking into account the above information and the desorption, MDHS 80, HSE Books 1995, ISBN 0
IOELV, ACTS considered that values of 1 ppm 7176 0913 8.
(8-hour-TWA) and 3 ppm (STEL) are appropriate. 10. Heinrich-Ramm R. 3,4 Dihydrochlorobenzene
Based on the predicted high level of dermal absorp- (4-chlorocatechol). In DFG Deutsche Forschungsge-
tion, it is concluded that a ‘Skin’ notation is required. meinschaft Analyses of Hazardous Substances in
Biological Materials volume 6 Jurgen Angerer &
Although no biological monitoring guidance value has Karl-Heinz Schaller eds published by Wiley-VCH
been set, the methods and relationships set out in the 1999 ISSN 0179-7247.
biological monitoring section above may be useful in
monitoring exposure. 11. Kumagai S, Matsunaga I (1995) Effect of varia-
tion of exposure to airborne chlorobenzene on internal
This substance is included in the 1st Consolidated exposure an concentrations of urinary metabolite.
Indicative Limit Occupational Exposure Limit Values Occupational & Environmental Health 52: 65-70.
Directive (2000/39/EC), with values of 10 ppm
(8-hour TWA) and 20 ppm (STEL). WATCH and 12. Kusters E, Lauwreys R (1990) Biological monitor-
ACTS took into account the limit values in this Direc- ing of exposure to monochlorobenzene. Int Arch
tive in their deliberations on British limit values for Occup & Environ Health 62: 329-331.
this substance. 13. Ogata M., Taguchi T., Hirota N., Shimada Y. and
Nakae S. (1991) Quantitation of urinary chloroben-
zene metabolites by HPLC: concentration of
REFERENCES 4-chlorocatechol and chlorophenols in urine and of
1. NIOSH Manual of Analytical Methods, Method chlorobenzene in biological specimens of subjects
1003 (1994), Hydrocarbons, halogenated, 4th Ed., exposed to chlorobenzene. Int. Arch. Occup. Environ.
National Institute of Occupational Safety and Health, Health. 63, 121-128.
Cincinatti, USA. 14. Hellman B. (1993) NIOH and NIOSH basis for an
2. Health and Safety Executive Methods for the Deter- occupational health standard: Chlorobenzene. Arbete
mination of Hazardous Substances, Volatile organic Och Hälsa1992:31 ISBN: 91-7045-183-4.
compounds in air... pumped solid sorbent tubes, 15. Cole J. and Skopek T.R. (1994) Somatic mutant
thermal desorption, MDHS 72, HSE Books 1993, frequency, mutation rates and mutational spectra in
ISBN 0 11 885692 8. the human population in vivo. Mutation Research.
3. Taylor D G, Kupel R E and Bryant J M (1977), 304, 33-105.
Documentation of NIOSH validation tests, DHEW 16. Dilley J.V. (1977) Toxic evaluation of inhaled
(NIOSH), Publ No 77-185. chlorobenzene (monchlorobenzene) - Final report.
4. OSHA Chemical Sampling Information, Chloroben- Stanford Research Institute for National Institute for
zene (1998), http://www.osha-slc.gov/
32
MEL PROPOSAL
Occupational Safety and Health, USA. Project number
PB276623.
17. Dilley J.V. and Lewis T.R. (1978) Toxic evalua-
tion of inhaled chlorobenzene. Toxicol. and Appl.
Pharmacol. 45, 327.
18. Fel’dt E.G. (1985) Evaluation of the mutagenic
hazards of benzene and some of its derivatives.
Gigiena I Sanitariya 7, 21-23.
19. Kluwe W.M., Dill G., Persing R. and Peters A.
(1985) Toxic responses to acute, subchronic and
chronic oral administration of monochlorobenzene to
rodents. J. Toxicol. Environ. Health. 15, 745-767.
20. Major J., Kemeny G. and Tompa A. (1992/3)
Genotoxic effects of occupational exposure in the
peripheral blood lymphocytes of pesticide preparing
workers in Hungary. Acta. Medica. Hungarica.
49(1-2), 79-90.
21. Mohtashamipur E., Triebel R., Straeter H. and
Norpoth K. (1987) The bone marrow clastogenicity of
eight halogenated benzenes in male NMRI mice.
Mutagenesis. 2(2), 111-113.
22. Nair R.S., Barter J.A., Schroeder R.E., Knezevich
A. and Stack C.R. (1987) A two generation reproduc-
tion study with monochlorobenzene vapor in rats.
Fundamental and Applied Toxicology. 9, 678-686.
23. NTP (1985) Toxicology and carcinogenesis
studies of chlorobenzene in F344/N rats and B6C3F1
mice (gavage studies). US Dept. of Health and Human
Services, NTP, Technical report Series No.261.
24. Zub M. (1978) Reactivity of the white blood cell
system to toxic action benzene and its derivatives.
Acta. Biologica Cracoviensia (Zoologia). 21,
163-174.
33
MEL PROPOSAL
Hydrogen selenide is not manufactured in the UK or
HYDROGEN SELENIDE the European Union. There are three major suppliers
of the substance in the UK. Approximately 60 kg per
maximum exposure limits
annum are used in the UK. It is transported in
8-hour TWA: 0.02 ppm (0.07 mg.m-3)
cylinders as a minor component (1% to 5%) in a
15-minute STEL: 0.05 ppm (0.17 mg.m-3)
carrier gas such as hydrogen.
subject to consultation The major use of hydrogen selenide world-wide is as a
dopant gas in the preparation of semiconductor
materials for use in lasers etc. It is also used in the
chemical synthesis of metallic selenides,
IDENTITY AND PROPERTIES organoselenium compounds and emulsions. Small
Chemical Name: Hydrogen selenide quantities of the gas may be liberated during a number
CAS No: 7783-7-5 of production processes in which selenium compounds
EC Index No: 034-002-00-8 (Selenium may be present such as the manufacture of glass and
compounds except ceramics, the vulcanisation of rubber and during the
cadmium sulphoselenide) manufacture of lead batteries.
34
MEL PROPOSAL
ppm. However, exposure would be negligible because Biological monitoring
the workers would wear self contained breathing There are no recent reports which describe biological
apparatus during cylinder changing. monitoring in hydrogen selenide exposure. The rapid
In the event of leakage in the reaction chamber and conversion of hydrogen selenide to selenium when in
release into the glove box and the surrounding contact with moist body surfaces suggests that
environment during the production of gallium arsenide hydrogen selenide exposure will contribute to body
wafers, the EASE model predicts that exposure would burden of selenium. Selenium intake can be
be between 0-0.1 ppm 8-hour Time Weighted monitored by urinary total selenium levels and
Average (TWA). As the process is complete within validated analytical methods are widely reported.
3 hours, the exposure is calculated to range between However, wide potential differences in dietary intake
0-0.0003 ppm using a 1% concentration. However, of selenium and possible dietary supplementation are
occupational exposure is expected to be negligible potential confounders in discriminating occupational
because of the safety procedures adopted including the exposure from environmental sources. Hydrogen
use of self contained breathing apparatus should selenide does not meet the criteria for a biological
workers re-enter a contaminated room. monitoring guidance value.
In those processes where there is the potential for
hydrogen selenide to be produced and liberated, such TOXICOKINETICS
as during lead battery manufacture, exposure is
expected to be negligible. When water or acid react There are very limited data on the toxicokinetics of
with selenium in slag, dross or waste, exposure may hydrogen selenide. As hydrogen selenide is a gas the
be higher. However, these events are infrequent and lungs are the main route of exposure. Observations of
any exposure is expected to be short lived because the the formation of deposits of red (elemental) selenium
gas will be quickly dissipated by natural ventilation. in the nasal passages of humans and animals following
It is expected that from the EASE data and from inhalation of hydrogen selenide indicate that it can be
discussions with industry that exposure to hydrogen oxidised to elemental selenium on contact with moist
selenide can be controlled to less than the 0.02 ppm surfaces. However, no quantitative absorption data are
8-hour TWA and 0.05 ppm STEL. Most exposure will available and it is unclear whether hydrogen selenide
be short term exposure such as cylinder changing and is directly absorbed. Though the absorption of
it is expected that here exposure will be much less elemental selenium has been demonstrated, there are
than the proposed limits. no data indicating how, or in what form, it is
MEASUREMENT absorbed. No reliable information is available on
distribution or excretion following exposure to
Workplace air monitoring
hydrogen selenide. There is also no information on
A method for the determination of volatile inorganic
skin absorption of hydrogen selenide gas, although as
hydrides in workplace air has been published by the
the substance is a gas, significant skin absorption is
National Institute for Occupational Health (NIOH) in
not anticipated.
Norway (Hetland et al, 1991). This method was
developed for measurement of arsine, stibine and
HEALTH EFFECTS
phospine, but NIOH have subsequently shown it to be
effective for measuring hydrogen selenide. Samples Animal studies
are collected on silver nitrate coated membrane filters Hydrogen selenide is very toxic, with a 4-hour LC50
and analysed, after digestion, by electrothermal atomi- value of 2.7 ppm (9 mg.m-3) in the guinea pig. Deaths
sation atomic absorption spectrometry. Alternative result from direct lung damage. Immediate eye and
means of analysis such as inductively coupled plasma nose irritation occur at concentrations above 64 ppm.
atomic emission spectrometry or inductively coupled As it is a gas, there are no oral or dermal studies. No
plasma mass spectrometry can be employed. Using reliable repeated exposure data are available.
any of these analytical techniques, the method has an There are no data available for sensitising, genotoxic,
adequate detection limit for making measurements for carcinogenic or reproductive effects.
comparison with the 0.02 ppm 8-hour TWA and 0.05
ppm STEL.
35
MEL PROPOSAL
Human data ppm (STEL). SCOEL applied an uncertainty factor of
Only limited data are available in humans. Following 20 to the NOAEL of 0.3 ppm to allow for limitations
single exposures to unknown concentrations in of the reporting. The values were then rounded up in
workers, severe irritation to the eyes and upper order to meet the requirements of the preferred value
respiratory tract and breathing difficulties have been approach of the SEG. This was felt to provide an
reported. Early reports (Dudley and Miller, 1941), of adequate margin of protection because the calculation
uncertain reliability, indicate that men could not work allowed for 100% absorption and the very steep dose
without respiratory protection at concentrations above response relationship is recognised as producing a
5.0 mg.m-3 (1.5 ppm). In relation to the effects of more reliable NOAEL. This resulted in a
repeated exposure there is an absence of reliable recommendation for an 8 hour TWA of 0.02 ppm,
exposure data. Symptoms of nausea, vomiting, which is not contradicted by the level indicated for
metallic taste in the mouth, dizziness and extreme systemic exposure to elemental selenium. A STEL (15
lassitude have been reported within one month of minutes) of 0.05 ppm was recommended to limit
exposure to hydrogen selenide at estimated levels of peaks in exposure which could result in irritation.
1-5 mg.m-3 (0.3-1.5 ppm) following the incorporation ACTS took into account the limit values in this
of selenious acid in etching ink. The exposure level Directive in their deliberations on British limit values
was estimated by using the subjective measurement of for this substance and recommended an 8-hour TWA
odour tolerance and hydrogen selenide concentration MEL at 0.02 ppm and a STEL at 0.05 ppm.
as reported by Dudley and Miller (1941). A laboratory There is no evidence to indicate that either a "skin"
worker exposed to hydrogen selenide at least once notation or a Sen notation is warranted for hydrogen
weekly for a year experienced health effects similar to selenide. The criteria for establishment of a biological
those associated with selenium; nausea, vomiting, monitoring guidance value are not met.
abdominal pain, garlicky breath, transverse ridges of
the nails and dental caries. In addition, the individual REFERENCES
also experienced chronic diarrhoea, conjunctivitis and SEG/CDO/18 (1991). Criteria document for an
nasal stuffiness. occupational exposure limit for hydrogen selenide.
There are no human data on sensitisation, Prepared by Industrial Toxicology Unit, Institute of
genotoxicity, carcinogenicity or reproductive toxicity Occupational Health, Birmingham.
of hydrogen selenide.
Dudley H C and Miller J W (1941) Toxicology of
BASIS FOR SETTING A LIMIT selenium. VI. Effects of subacute exposure to hydro-
gen selenide Journal of Industrial Hygiene and
There is a very limited toxicity database for hydrogen
Toxicology 23 (10) pp 470-477
selenide (Shackleton et al, 1992). The critical health
effect is severe irritation to the respiratory tract. Hetland S Martinsen I Radziuk B and Thomassen Y
Although marked respiratory tract irritancy has been (1991) Species analysis of inorganic compounds in
reported in humans exposed to hydrogen selenide, workroom air by atomic spectrometry Analytical
there are no reliable data from human studies Sciences Vol 7 Supplement pp 1029-1032
concerning the dose-response characteristics for this
effect. In guinea pigs, an 8-hour exposure to 0.3 ppm, Shackleton S Smillie M V Levy L S Fletcher A C
the lowest concentration tested, resulted in the deaths Harrington J M Binks S P Chipman J K and Glass D
of 50% of the animals due to direct lung damage. C (1992) Occupational Exposure Limits: Criteria
Overall, it is not possible from the limited data Document for Hydrogen Selenide. Commision of the
available to identify a NOAEL for respiratory European Communities EUR 14239 pp 1-58.
irritation. WATCH concluded that there were
insufficient data to derive an OES.
Hydrogen selenide is included in European Directive
2000/39/EC, with an Indicative Occupational
Exposure Limit of 0.02 ppm (8-hour TWA) and 0.05
36
MEL PROPOSAL
MEASUREMENT
PHENOL
Workplace air measurement
maximum exposure limit
Indicating colorimetric tubes for short-term measure-
8-hour TWA: 2 ppm (7.8 mg.m-3) ments of phenol in air are commercially available and
Notation: Skin capable of detecting 0.5 ppm. They are subject to
interferences from cresols. Instrumental methods
subject to consultation based on infra-red or photo-acoustic detection are
capable of selective detection of phenol in the low
ppm region. Long-term measurements may be made
IDENTITY AND PROPERTIES by pumped sampling on XAD-7 sorbent, desorbing
with methanol and analysis by high-performance
Chemical Name: Phenol liquid chromatography (OSHA 32) 1 or gas chroma-
Cas No: 108-95-2 tography (NIOSH 2546) 2,3. The detection limit of
OSHA 32 is less than 0.02 ppm for a 24 litre air
EINECS No: 203-632-7
sample. The performance of OSHA 32 complies with
Formula: C6H5OH EN 482 9 on overall uncertainty and substantially
Synonyms: Carbolic acid, complies with the storage, desorption efficiency and
oxybenzene, phenol environmental factor requirements of EN 1076 10.
alcohol NIOSH 2546 has the same sampling procedure as
OSHA 32 therefore similar compliance with EN
Saturated vapour
standards is likely, but the liquid chromatography
concentration: 200 ppm (20 oC) procedure of OSHA 32 is generally recommended,
Boiling point: 181.75 oC unless it is required to measure individual cresol
Conversion factor: 1 ppm = 3.91 mg.m3 isomers in addition to phenol, when NIOSH 2546
would be more suitable. Alternatively, thermal desorp-
(at 20 oC) tion of Chromosorb 106 or Tenax TA sorbent tubes
Phenol is a white crystalline solid which liquefies on followed by gas chromatography is feasible (MDHS
contact with water. It has a characteristically acrid 72) 4. This method has not been validated for phenol
odour and a sharp burning taste. with respect to storage and desorption efficiency at
Phenol is classified under the Chemicals (Hazard low concentrations. If these factors were addressed,
Information and Packaging for Supply) Regulations MDHS 72 would be suitable where it was required to
1994 (CHIP) as Toxic and Corrosive, to be labelled measure phenol and volatile organic compounds
with the R phrases: together.
R24/25: Toxic in contact with the skin and if Biological Monitoring
swallowed Biological monitoring may be a useful aid to the
R34: Causes burns assessment of occupational exposure to phenol. There
are no data to relate metabolite concentrations to
OCCURRENCE AND USE health effects but there are data to show a good corre-
lation between levels of total phenol (after hydrolysis
Phenol is not manufactured in the UK. The estimated
of conjugates) in urine samples collected at the end of
imports into the UK in 1998 amounted to around
shift and inhaled phenol. Two out of three studies
85,000 tonnes with less than 3000 tonnes exported. It show good agreement; for example exposure to
is used as a starting material for the production of a phenol at 2 ppm for 8h the urine concentration of
variety of chemicals, the most important being phenol would be around 100 mg.g-1 creatinine (120
phenolic resins. It has a minor use in specialised paint mmol.mol-1). Phenol is found in the urine of people
strippers. not occupationally exposed to phenol and comes from
EXPOSURE the diet.
Using more recent specific methods for urinary phenol
There are few people exposed to phenol as a chemical analysis the background levels are generally less than
starting material but very many are exposed varying 10 mg.g-1 creatinine (12 mmol.mol-1) and rarely above
concentrations of free phenol from the resins which 20 mg.g-1 creatinine (24 mmol.mol-1).
are ubiquitous. The Health & Safety Laboratory has analysed 92 urine
Around 25,000 people may be exposed to phenol from samples for phenol from a range of unknown
the use of resins as sand binders in foundries and exposures and 90% of the results were less than 14
thermal decomposition of the resins releases phenol mg.g-1 creatinine.
into the atmosphere.
37
MEL PROPOSAL
There are numerous methods for the determination of phenol vapour. Phenol did not cause skin sensitisation
phenol in urine and the wide range reflects the in a guinea pig maximisation test.
comparative ease of analysis of phenol by common Animal repeated inhalation studies are limited. Those
analytical techniques. The essential features of an available are old studies which are poorly reported;
analytical method for the determination of phenol in only a single modern good quality study (conducted in
urine are; an efficient hydrolysis of the glucuronide the rat) is available. Overall, the data indicate that in
and sulphate conjugates; a specific chromatographic the rat, the species which has been most extensively
separation of phenol form other urine components; a studied, no significant effects are observed following
detection limit of <1mg.l-1 and a coefficient of varia- exposure to 5 ppm phenol vapour continuously for 90
tion of <5% for within day determinations and <10% days or intermittently to concentrations somewhere in
for day to day determinations. the range of 25 - 52 ppm for 74 days. Continuous
There are two international quality assurance schemes exposure to 25 ppm produces some clinical evidence
which include urinary phenol in their list of analytes. of CNS effects. Studies in a number of other species
One is run by the University of Erlangen and one by indicate that there are some species differences.
the Finnish Institute of Occupational Health. Similar to the rat, the monkey and mouse show no
signs of toxicity following continuous exposure to 5
TOXICOKINETICS ppm phenol for 90 days; the effects of higher exposure
Some toxicokinetic data in humans are available and concentrations have not been investigated. In the
phenol has been extensively studied in toxicokinetic rabbit and guinea pig, degenerative damage to the
studies in animals5 Data show that phenol is well lung, liver, kidney and heart is seen at a concentration
absorbed via the oral, inhalation and dermal routes in somewhere between 26 - 52 ppm, with the guinea pig
both humans and animals. There are no data being the more sensitive species; lower exposure
concerning the tissue distribution of phenol in concentrations have not been investigated. It is not
humans. However, animal data indicate that phenol possible to clearly characterise the dose response
and its metabolites are widely distributed throughout relationship for inhalation exposure to phenol due to
the body. Once absorbed, phenol is rapidly and the fact that most studies have investigated only a
extensively metabolised. Metabolites identified in single exposure level. Repeated oral exposure studies
human serum and urine, following oral administration in the rat indicate that the kidney, liver, spleen and
of phenol, were mainly phenyl sulphate (~80%) and thymus are the main target organs, with some evidence
phenyl glucuronide (~15%). Small amounts of the of CNS effects also. Effects on these organs are
glucuronide and sulphate conjugates of hydroquinone observed, when phenol is administered via oral
and catechol are also formed. A similar profile of gavage, at 40 mg.kg-1.day-1 and above for 2 weeks,
metabolites has also been identified in animals; the with mortalities occurring at 120 mg.kg-1.day-1. No
proportion of conjugates of hydroquinone formed systemic effects are observed at 4 mg.kg-1.day-1.
increases with dose. Little or no free phenol is However, via drinking water, no toxicological
detected in the blood of animals. Elimination of significant effects are observed following treatment
phenol and its metabolites from the body occurs with up 334 mg.kg-1.day-1 for 13 weeks6. There is
rapidly via the urinary tract. Essentially all of the evidence, in mice, of a reduction in red blood cells at
absorbed dose (>95%) is excreted in the urine within doses of 1.8 mg.kg-1.day-1 and above7. However, this
24 hours. There is no evidence of accumulation in the effect has not been observed consistently across
body. No information is available on whether phenol species and therefore its reliability is uncertain.
can cross the placenta or whether it can be transferred The potential mutagenicity of phenol has been well
to pups via breast milk. investigated in bacterial and mammalian somatic cells
HEALTH EFFECTS in vitro and in somatic cells in vivo. Phenol is
negative in standard Ames tests with and without
Animal Studies metabolic activation. In mammalian cell assays in
Phenol is of moderate acute toxicity. Estimated oral vitro, overall the evidence indicates that phenol is
LD50 values of 400-550 mg.kg-1 in the rat and 300 genotoxic. Positive results have been obtained in
mg.kg-1 in mice have been obtained. Dermal LD50 standard gene mutation and chromosome aberration
values obtained for the rat and rabbit are 661 mg.kg-1 studies, with supporting evidence from a number of
non-standard studies (SCE, UDS, micronucleus
and 1400 mg.kg-1 respectively. There are no inhalation
assay).
LC50 data for phenol vapour.
In relation to effects in somatic cells in vivo, phenol
Studies in the guinea pig have shown phenol to be has been well explored in the bone marrow
corrosive to skin and eyes. Marked ocular and nasal micronucleus assay via the oral and intraperitoneal
irritation was reported in rats exposed to 234 ppm routes and in a transgenic mouse study8. In the bone
phenol vapour for 8 hours. In an Alarie sensory marrow micronucleus studies, although both positive
irritation study, evidence of sensory irritation was and negative findings have been obtained, overall, the
demonstrated in mice inhaling 166 ppm (0.637 mg.l-1) weight of evidence indicates that phenol has genotoxic
38
MEL PROPOSAL
activity in this assay. Phenol gave negative results in a tract in volunteers inhaling 2.6 - 5.2 ppm phenol
transgenic mouse assay, in the liver, lung and bone vapour for 8 hours in a toxicokinetics study or in
marrow; however, in this same study, the potential for workers exposed repeatedly to up to approximately 3
phenol to cause mutagenicity in tissues at the site of ppm for 7 hours per day.
contact (skin and nasal epithelium) could not be Phenol was reported to be negative in a human skin
adequately assessed. In overall conclusion, the weight sensitisation test. From a long history of phenol
of evidence indicates that phenol should be regarded exposure, there is no evidence for the ability of phenol
as having genotoxic potential in somatic cells in vivo. to cause occupational asthma in humans nor would
The Department of Health Committee on this potential be expected from its known properties.
Mutagenicity has also considered the available People accidentally receiving repeated oral exposure
mutagenicity data for phenol and concluded that
to phenol in solution at 10 - 240 mg.day-1, reported
"occupational exposure to phenol is associated with a
risk of mutagenicity, but it is not possible to quantify diarrhoea, mouth sores and darkened urine. No effects
this risk. Overall, there is insufficient evidence to were observed 6 months after exposure.
support a threshold approach to risk assessment with There are no human studies available on the
respect to inhalation or dermal exposure". genotoxicity of phenol. The epidemiological studies
Phenol has not been adequately tested for available investigating the carcinogenic potential of
mutagenicity in germ cells and no reliable conclusions phenol to humans are complicated by the lack of
in relation to the genotoxic potential of phenol in germ adequate exposure data for phenol, and by the
cells in vivo can be reached from the available data. confounding presence of other organic substances in
Phenol was not carcinogenic to rats and mice, in a the work place, and therefore no reliable conclusions
well conducted drinking water study in which animals can be drawn from them. However, in view of the
were given either 2500 or 5000 ppm phenol in positive genotoxicity findings in animals raising
drinking water for 103 weeks. However, its potential concerns for carcinogenicity, these endpoints are also
carcinogenicity via the inhalation route, particularly of concern for humans.
towards the respiratory tract, has not been explored
and, given its irritant and genotoxic properties there There are no human data available on the potential of
are concerns for potential carcinogenicity. phenol to affect reproduction. However, given the
Phenol has been tested in a number of studies for clear negative evidence for reproductive effects in
reproductive toxicity. A single multi-generation study animals, no concerns for humans are indicated.
is available in rats in which phenol was administered BASIS FOR A LIMIT
via the drinking water. No adverse effects on fertility
or reproductive performance were observed even at The lead health effect of concern for phenol is
exposure levels causing general toxicity in the parents.
In relation to developmental toxicity, there are a genotoxicity. WATCH endorsed the view of the
number of studies which have adequately explored the Committee on Mutagenicity, and agreed that it was
potential for developmental toxicity. In mice, a higher not possible to identify precisely a level of exposure
incidence of cleft palate was observed at 280 below which there would be no concern. Therefore,
mg.kg-1.day-1 only in the presence of severe maternal the OES criteria are not met. Given the concerns for
toxicity (mortalities). In rats, increased post genotoxicity at current occupational exposure levels,
implantation loss and reductions in fetal weight/litter the MEL criteria are met. In view of the concerns for
are observed at doses which also cause severe
genotoxicity, control of exposure over the work shift
maternal toxicity. These developmental effects are
considered likely to be a secondary non-specific is desirable and hence an 8-hour TWA MEL is
consequence of maternal toxicity. Overall, from the appropriate. WATCH was of the view, however, that
studies available there is no evidence that phenol the in vivo mutagenicity and carcinogenicity data
causes direct reproductive effects. suggested that phenol was not an especially potent
occupational genotoxin, and that this should have a
Human data
bearing on the magnitude of the MEL. As significant
There are numerous reports of lethality following skin absorption is predicted, with subsequent concerns
acute oral or dermal exposure to phenol, although for genotoxicity once absorbed, a ‘Skin’ notation is
there are few reliable quantitative exposure data considered appropriate. In view of the lack of
associated with them. Bronchospasm, nephrotoxicity,
evidence for occupational asthma a ‘Sen’ notation is
cardiac dysrhythmia and CNS effects have been
not warranted.
reported following non-lethal acute exposure, but
again, no reliable quantitative exposure data for In relation to biological monitoring, reliable,
situations concerned are available. non-invasive methods are available, and a relationship
between airborne levels and biological values has
Phenol itself is corrosive and diluted phenol solutions
may be corrosive or irritating to the skin, depending been established, as noted above. However, at this
on concentration and exposure duration. There was no stage no specific recommendation for a BMGV is
reporting of any irritation of the eyes or respiratory proposed.
39
MEL PROPOSAL
Taking account of the recommendations from Unpublished draft report of Covance. Report No.
WATCH, and the practicability, costs and benefits of 501/2-D5140.
levels of control, ACTS agreed that a MEL is
appropriate. Because an occupational exposure limit is 9. BSI, Workplace atmospheres - General
required to fulfill British obligations under the requirements for the performance of procedures for
Chemical Agents Directive and the Indicative the measurement of chemical agents, European
Occupational Exposure Limit Value (IOELV) Standard BS EN 482:1994, ISBN 0 580 23644 7.
Directive, a MEL is necessary. 10. BSI, Workplace atmospheres - Pumped
Taking into account the above information and the sorbent tubes for the determination of gases and
IOELV, ACTS considered that a value of 2 ppm vapours, European Standard BS EN 1076:1997,
(8-hour TWA), with a ‘Skin’ notation is appropriate. ISBN 0 580 28358 5.
This substance is included in the EU first consolidated
Indicative Limit Occupational Exposure Limit Values
Directive (2000/39/EC). WATCH and ACTS took
into account the limits shown in this Directive in
making recommendations for limit values for this
substance.
REFERENCES
1. Occupational Health and Safety
Administration, US Dept of Labor, Phenol and
Cresol, Method 32, November 1981.
40
REVISED OES PROPOSAL
ratings. It is used in chemical manufacture and as a
solvent. The isomer p-xylene is used to make
XYLENE dimethylterephthalate and terephthalic acid, which are
occupational exposure standards used in the production of polyester fibre, film and
fabricated items; o-xylene is used to produce phthalic
anhydride for phthalate plasticisers; m-xylene is used
8-hour TWA: 50 ppm (221 mg.m-3)
for manufacturing isophthalic acid which is an
15-minute STEL: 100 ppm (442 mg.m-3) intermediate in the manufacture of polyester resins.
Mixed xylenes are used in surface coatings, adhesives,
Notation: Skin printing inks, and rubber coatings.
Biological Monitoring
Health Guidance Value: 650 mmol.mol-1 *
EXPOSURE
* (methyl hippuric acid per mol creatinine
in urine) The total number of persons exposed to xylene in the
subject to consultation UK is not known, but because of its widespread use in
paints and varnishes, and petroleum, it is expected to
be tens of thousands.
IDENTITY AND PROPERTIES
Chemical Name: Xylene In general, the chemical and the oil/gas industries
have the lowest exposures as most processes are
CAS No: 1330-20-7 enclosed.
EEC No: 601-022-00-9
The highest reported result in the offshore industry
Empirical formula: C6H4(CH3)2
was 2.85 ppm for an 8hr TWA. For the onshore oil
(o, m, and p- isomers) industry the range of full shift exposures was broader;
Synonyms: xylol, dimethylbenzene less than 0.01 to 24.4 ppm, reflecting the more
dispersive uses of petroleum onshore, including
Sat. Vap. Concentration: about 8,000 ppm at 20 oC distribution and retail distribution and sale. The
Boiling point: 137-144 oC highest short term exposure reported for the onshore
oil industry was 37 ppm, 15 min TWA for top
Conversion factor: 1ppm = 4.34 mgm-3 at 20 oC loading road tankers.
Xylene is an aromatic hydrocarbon with a The highest result reported for this review was for
characteristic odour, perceptible at about 1 ppm. loading mixing vessels in the paint manufacturing
Commercial xylenes are mixtures of the three isomers industry with an exposure result of 458 ppm. The
and may contain up to 20% ethyl benzene. Xylene is circumstances under which that exposure was
measured were not reported but the geometric mean
a clear, colourless, mobile fluid which is insoluble in
for all loading activities in that company was 5.1 ppm,
water and miscible in organic solvents.
with a 95th percentile of 79 ppm, which suggests that
Xylene is classified as harmful and irritant under the
the high result may have been an outlier. Few short
Chemicals (Hazard Information and Packaging for
term exposures were reported; the highest was 133
Supply) Regulations 1994 (As Amended) and labelled ppm for floor cleaning with xylene. The potential for
as follows: higher short term exposures clearly exist where
controls are poor; particularly during loading, and
R20/21: Harmful by inhalation and in contact cleaning operations.
with skin
R38: Irritating to skin Paint spraying activities had a broad range of results
R10: Flammable which reflects the wide variation in the percentage
xylene in many of the products, and in the levels of
OCCURRENCE AND USE control achieved. Reported results varied from 0.2
Xylene is produced mainly from crude oil in the UK, ppm to 291 ppm. Exposures in the rubber coating
but some also arises from coking processes. Xylene is industry were up to 121 ppm, 8hr TWA. Short term
also recovered from waste solvent streams by exposures in the dispersive industries, such as painting
fractional or steam distillation. It is a component of and rubber coating ranged up to 155 ppm.
petrol; the use of xylene in petroleum products is
increasing due to the reductions in the benzene It is felt that, given the application of appropriate
content of petroleum and the need to maintain octane controls, all sectors can achieve control of exposure to
41
REVISED OES PROPOSAL
xylene to below 50 ppm, 8 hr TWA and most could short-term TWA personal exposure are based on
achieve 20 ppm within the bounds of reasonable collection on a sorbent such as charcoal or Tenax by
practicability. Some industries with less well diffusive1-3, or pumped1,4,5, sampling, followed by
developed controls in place could probably achieve 20 thermal or solvent desorption and gas
ppm, but would require changes to working practices. chromatography. The analytical method principles are
They would also require a higher level of investment well known and relatively straightforward. Both
in controls than other sectors. solvent and thermal desorption methods substantially
comply with EN 4826 with respect to overall
All industries with adequate controls in place can uncertainty. They also comply with EN 1076
achieve control to below 100 ppm for short term (pumped)7 and EN 838 (diffusive)8 standards with
exposures; the oil and chemical industries are already respect to storage, recovery and environmental
achieving control below 50 ppm. The more dispersive factors, except that the pumped thermal desorption
industries could meet this level of control with best method based on MDHS 72 is too sensitive for
practice. Some sectors would need to invest in more long-term monitoring around the level at the existing
controls and improve working practices to achieve this OES of 100 ppm. In 8-hour TWA monitoring with
level of control. any of these methods, the limit of quantitation is 0.05
ppm or better.
Dermal exposure during manufacturing processes is
likely to be low as most processes are largely Biological Monitoring
enclosed. The main opportunity for dermal exposures
arises during cleaning activities where thinners Biological monitoring may be a useful aid to the
containing xylene are in use for up to several hours assessment of occupational exposure to xylene. There
per day, for example when cleaning out reservoirs and is potential for systemic toxicity from dermal
filling lines during paint manufacture. absorption and biological monitoring may be a useful
The possibility of dermal exposure is also high in the aid to assessing the efficacy of PPE
rubber coating industry where manual handling of
dough containing xylene occurs frequently. For these There are readily available and widely used
activities dermal exposures of up to 5mg.cm-2.day-1 non-invasive methods for biological monitoring based
have been estimated using EASE. Although these on analysis of methyl hippuric acid (MHA)
estimates are likely to be higher than actual exposures metabolites in urine samples.
due to the percentage of xylene in the cleaning
solvents and the likely use personal protective There are ample data showing a good correlation
equipment, dermal exposure is likely to be a between levels of MHA and xylene in air although
significant route of exposure in these industries. the levels observed or predicted by regression
equations vary widely. The reasons for this variation
MEASUREMENT may include differences in isomer composition of
mixed xylenes and inter-individual differences in
Air Monitoring metabolism. However, the most significant reason for
differences in levels of MHA is a difference in
Xylene consists of o-, m- and p- isomers typically in absorbed dose. This could be caused by dermal as
the ratio 1:2:1, but usually technical or commercial well as inhalation exposure and/or increased
xylene also contains about 20% ethylbenzene. The ventilation rates due to body size or work activity.
ethylbenzene content can vary considerably depending Using the more controlled volunteer studies 9-13 as a
on origin and grade. guide the range of urinary MHA values that could be
Indicating detector tubes for short-term measurement expected in end of shift samples after exposure to
of xylene in air are commercially available. They may xylene at 50 ppm for 8 hours is 930 mg.g-1 to 1400
be subject to interferences from styrene, toluene and mg.g-1 with two studies around giving 1100 .mg.g-1
acetaldehyde. Instrumental methods based on Combining data from all five volunteer studies gives a
infra-red or photoacoustic detection are capable of mean MHA value of 1111 mg.g-1 after exposure to 50
selective detection of xylene down to the 1 ppm level. ppm m-xylene for the biological monitoring health
Xylene in air is primarily in the vapour phase. The guidance value. In SI units the value is 650
aerosol fraction may be significant when a product mmol.mol-1 creatinine. MHA values in people not
containing xylene is sprayed, although methods occupationally exposed are generally less than 2
intended to measure vapour alone are usually mg.g-1 (< 1 mmol.mol-1).
acceptable up to 100 ppm TWA. Where xylene
concentrations in spraying are high enough to justify Analysis of xylene in breath has also been used,
respiratory protection, diffusive methods may give though less widely than urinary methyl hippuric acid.
results biased high or low, depending on sampler Because of the rapid change in blood and breath
position. Recommended methods for long-term and xylene concentrations after the end of exposure the
42
REVISED OES PROPOSAL
timing of breath collection is important. In volunteer volunteers, only an estimated 4% of the administered
studies breath samples collected 30 min after exposure dose was retained in subcutaneous fat following
to 50 ppm show or predict values of 1 to 2.9 ppm9-13. intermittent inhalation exposure, suggesting low
However, for occupational studies a more convenient accumulation potential. Transplacental transfer of
sampling time could be 10 minutes after the end of xylene to the fetus occurs in experimental animals and
shift (so workers are not held up on their way home) humans. Xylene metabolism is extensive in both
and using the Loizou et al study11 as a guide, the experimental animals and humans, being metabolised
breath xylene concentration after exposure to 50 ppm to methylbenzoic acid and excreted in the urine
would be around 1.6 ± 0.3 ppm (66 ± 12 nmol.l-1) following conjugation with glycine or glucuronic acid,
with no differences between isomers. Small amounts
Measurement of methyl hippuric acid in urine of unchanged xylene can be detected in the expired
There are numerous methods for the determination of air.
methyl hippuric acid in urine either based on gas
chromatography after derivatisation14-16 or HPLC with HEALTH EFFECTS
UV detection 17-23 .
Animal studies 26
The wide range of methods used for MHA reflect the
comparative ease of analysis by common analytical Xylene is of low acute toxicity. Acute inhalation
techniques. The essential features of an analytical exposure of rats and mice produced 6-hour LC50
method for the determination of MHA are; a specific values of 3,900- 6,000 ppm. Oral LD50 values of
chromatographic separation of MHA isomers from 3,500 - 8,700 mg.kg-1 have been reported in the mouse
other urine components (for total MHA the separation and rat. Death is caused by respiratory failure
of m- and p- isomers is not needed); a detection limit following CNS depression.
of around 20 mg.l-1 and a coefficient of variation of
<5% for within day determinations and <10% for day A single application of liquid xylene can cause skin
to day determinations and internal quality assurance. irritation, with eschar formation and blistering
reported after repeated exposure. The limited data
There are two international quality assurance schemes available indicate that liquid xylene has eye irritation
which include urinary MHA in their list of analytes. potential. No skin sensitisation data and no
One is run by the University of Erlangen and one by information on respiratory sensitisation are available.
the Finnish Institute of Occupational Health. In repeated exposure studies the principal expression
of toxicity is ototoxicity in the rat; otherwise xylene
Confounding factors has been shown to have low toxicity via the oral and
Xylene is metabolised by Cyp 2E1, alcohol inhalation routes following repeated exposure. In a
dehydrogenase and aldehyde dehydrogenase to methyl study which specifically investigated hearing loss,
benzoic acid and then conjugated with glycine to form
deficits were reported mainly at high frequencies
methyl hippuric acid. Any co-administration of
following repeated exposure to 800 ppm, the lowest
substance which also use these pathways will
exposure used, and above for 6 weeks. A no effect
potentially interfere with xylene metabolism. The
level was not determined and reversibility was not
most likely interferences are alcohol and aspirin.
Alcohol taken during xylene exposure will tend to assessed. In more general toxicity studies, no
increase blood and breath xylene levels and reduce toxicologically significant findings were reported
MHA levels24. Aspirin, at therapeutic doses can following inhalation exposure for 5h per day for 13
reduce the concentration of MHA in end of exposure weeks to 810 ppm in rats and dogs, or oral
urine samples by 50%25. As a consequence, any administration to rats and mice at 1000 - 2000
coadministrtion of alcohol, aspirin or similar mg.kg-1.day-1 for 13 weeks. No data are available on
substances should be noted when collecting the systemic effects following repeated dermal exposure,
samples. but similarly low toxicity is anticipated .
TOXICOKINETICS26
Xylene has been well examined for genotoxic
In experimental animals, xylene is rapidly absorbed potential. No evidence of in vitro genotoxicity was
following inhalation exposure and well absorbed observed in tests involving in bacterial or mammalian
following exposure via the oral and dermal routes. In cells. Xylene was not genotoxic in vivo in mouse
humans, xylene is well absorbed via the inhalation and bone marow micronucleus or mouse bone marow
dermal routes. Xylene is highly soluble in blood and cytogenetics tests, liver UDS or rodent dominant
fat, and widely distributed around the body, including lethal tests. Overall, xylene is not genotoxic.
the brain. Accumulation of xylene in animal body fat
and brain tissue has been demonstrated following There was no evidence of carcinogenicity following
inhalation exposure for 1 or 2 weeks. In human oral administration in the rat or mouse although the
43
REVISED OES PROPOSAL
data in the male rat were limited. Overall, these data of exposure in this study, an observation not
provide reassurance that xylene does not have supported by the results of single exposure studies
carcinogenic potential. with exposures of up to 300 ppm for 4 hours, and in
this respect the results of the study seem inconsistent
with other reported findings. Overall, the results of
No fertility effects were observed in the rat following
this study suggest that repeated exposures to 100 ppm
inhalation at concentrations of up to 500 ppm in a one can affect CNS performance, although there is perhaps
single-generation study. A number of other older some uncertainty about the reliability of these results.
developmental toxicity studies are available which At higher levels of exposure, headache, nausea,
inconsistently report delayed development and vomiting, vertigo and dizziness have been reported
increased post-implantation loss at, and occasionally following single inhalation exposures to 700 ppm.
below, maternally toxic concentrations. However, These symptoms are consistent with the known CNS
these studies have severe limitations, in particular depressant effects of xylene exposure. Loss of
most are very briefly reported such that it is not consciousness occurs at an estimated level of 10,000
possible to judge their quality or draw any firm ppm. Extreme exposures can lead to death via
conclusions. Because of the difficulty in deriving respiratory depression.
reliable dose-response information from the older
studies, attention is focused on the recent good-quality There is only limited information available relating to
studies 27,28 for the identification of a NOAEL for eye, nose and throat irritancy. Human volunteers
developmental toxicity. In these studies, no have been exposed to xylene concentrations of up to
convincing evidence of developmental toxicity was 290 ppm for 4 hours in neurobehavioural studies and
seen at exposure levels of up to 500 ppm. There might although irritancy was not specifically investigated,
be concerns regarding developmental toxicity above complex vision tests were conducted and sometimes
questionnaires on subjective symptoms were
500 ppm, but the profile is unclear.
administered, and these indicated no local irritant
effects. No changes in respiratory rate measurements
Human studies 26
and no symptoms of nose and throat irritation were
The exposure-response relationships for the effects of reported in volunteers exposed to mixed xylenes at
xylene on the CNS have been reasonably well concentrations up to 400 ppm30. These findings were
investigated in human volunteer studies. In these supported by another study in which no symptoms of
studies, there was no reporting of CNS symptoms and throat irritation were reported at concentrations of up
no deficits in performance in neurobehavioural tests to 700 ppm31. In a study designed to investigate eye
with single exposures to constant concentrations up to irritancy in human volunteers, eye irritation was
300 ppm for up to 4 hours. However, effects on reported at concentrations of 460 ppm or above. There
reaction time were observed at 200 ppm 4-hour TWA were no symptoms of eye irritation following
when peak exposures of between 5-30 minutes exposure to 110 ppm for 15 minutes30. In an early
duration to 400 ppm were administered. Body sway study32 eye irritancy was reported with very brief (3-5
testing gave variable results, with both increases and minute) exposures of human volunteers to 200 ppm
decreases being reported for this endpoint, all of mixed xylenes, but the reliability of this information is
which were within the range of normal control values, doubtful taking into account the design and reporting
suggesting that these changes represent chance of the study, and the inconsistency with other more
findings and are not of biological significance. recent findings. Overall therefore, a clear threshold for
Overall, the results from studies involving single the development of eye irritation cannot be readily
exposures to xylene indicate that exposures to identified from the data available, but would appear to
constant concentrations up to 300 ppm for 4 hours lie somewhere between 290 - 460 ppm.
produce no effects on CNS performance or symptoms. In a human skin sensitisation study no evidence of
However, the introduction of short periods (5-30 skin sensitising potential was reported. From its
mins) of exposure to 400 ppm against a background widespread use, there is no evidence that xylene cause
of 200 ppm (4-hour TWA) leads to effects on reaction sensitisation by skin contact.
time, indicating CNS depression.
The only data available relating to repeated exposure
in the workplace comprise reports of subjective
There is only one study29 in which the effects of symptoms following exposure to mixtures of solvents
repeated exposure to xylene on the CNS have been including xylene. Therefore this information is of
investigated. In this study, volunteers were exposed to
limited use in the determination of effects of repeated
100 ppm for 6 hours per day over a one week period,
and the results showed a trend for a decline in exposure to xylene. There are no human data relating
performance in reaction time tests (by approximately to genotoxicity or carcinogenicity but the available
3-26%), with the magnitude of effect becoming animal evidence indicates that xylene would not be
greater throughout the study. However, genotoxic or carcinogenic in humans. There are no
exposure-related effects were observed on the first day human data concerning effects on fertility or
44
REVISED OES PROPOSAL
development. However, animal data indicate no appropriate. As there is no evidence for occupational
grounds for concern for these effects at occupationally asthma with exposure to xylene, a “Sen” notation is
relevant levels of exposure not warranted. Xylene meets the criteria for biological
monitoring given that control of inhalation exposure
alone may not be sufficient to control exposure, and
BASIS FOR THE LIMIT that biological monitoring methods and data are
available.
From the available toxicology and occupational
exposure information it was concluded that the data There are readily available and widely used
support an OES position for xylene. non-invasive methods for biological monitoring based
on analysis of methyl hippuric acid (MHA)
metabolites in urine. Data from five volunteer studies
The key health effects of relevance were eye irritancy gives a mean MHA value of 1111 mg.g-1 after
and CNS depression. exposure to 50 ppm. In SI units the value is 650
mmol.mol-1 creatinine, therefore it was recommended
There is only limited information available relating to that 650 mmol.mol-1 creatinine is an appropriate
local irritancy and a clear threshold for the Biological Health Guidance Value.
development of eye irritation cannot be readily
identified. However, from the data available, it would
appear to lie somewhere between 290 - 460 ppm. REFERENCES
1. OSHA Analytical Methods Manual, US Dept of
In relation to effects on the CNS, human volunteer Labour, Xylenes (o-, m-, p-isomers), Ethylbenzene,
data indicate that there is an absence of CNS effects method 1002, August 1999.
following single exposures to constant concentrations
up to 300 ppm for 4 hours. However, the introduction 2. Methods for the Determination of Hazardous
of short periods (5-30 mins) of exposure to 400 ppm Substances MDHS 80, Volatile compounds in
leads to effects on reaction time, indicating CNS air...diffusive samplers, thermal desorption,
depression. ISBN 0 7176 0913 8, HSE Books (1995).
There is only one study in which the effects of 3. Methods for the Determination of Hazardous
repeated exposure to xylene on the CNS have been Substances MDHS 88, Volatile compounds in
investigated. Although there is uncertainty about the air...diffusive samplers, solvent desorption ISBN 0
reliability of the results of this study, the findings 7176 2401 3, HSE Books (1997).
suggest the possibility that repeated exposures to 100
ppm can lead to effects on the CNS. In the absence of 4. NIOSH Manual of Analytical Methods, 4th Ed.,
other information to confirm or refute this finding and 1994, US Dept of Health and Human Services
in view of the achievability of an exposure level of 50 (NIOSH) Publ No 94-113, Hydrocarbons, Aromatic,
ppm (8-hour TWA), WATCH decided to express method 1501.
caution in making their recommendation for an OES
of 50 ppm 8-hour TWA. 5. Methods for the Determination of Hazardous
Substances MDHS 72, Volatile compounds in
A STEL OES is also considered appropriate to control air...pumped solid sorbent tubes, thermal desorption,
for short term peaks in exposure which might lead to ISBN 0 11 885692 8, HSE Books (1993).
eye irritancy and effects on the CNS. It was agreed 6. British Standards Institution, Workplace
that exposure-response information and achievability atmospheres - General requirements for the
of control of exposure indicate the suitability of a performance of procedures for the measurement of
STEL of 150 ppm 15-minute TWA. chemical agents, European Standard BS EN
Xylene is included in the 1st Consolidated Indicative 482:1994, ISBN 0 580 23644 7.
Limit Occupational Exposure Limit Values Directive
(2000/39/EC), with values of 50 ppm (8-hour TWA) 7. British Standards Institution, Workplace
and 100 ppm (STEL) and a skin notation. atmospheres - Pumped sorbent tubes for the
determination of gases and vapours, European
Taking into account the above information and the Standard BS EN 1076:1997, ISBN 0 580 28358 5.
IOELV, ACTS considered that values of 50 ppm
(8-hour-TWA) and 100 ppm (STEL) are appropriate. 8. British Standards Institution, Workplace
atmospheres - Diffusive samplers for the
Xylene is well absorbed across the skin following determination of gases and vapours - Requirements
dermal contact and thereby has the potential to and test methods, European Standard BS EN
contribute to systemic toxicity, hence “Sk” notation is 838:1996, ISBN 0 580 26240 5.
45
REVISED OES PROPOSAL
9. Jang JY, Droz PO, Berode M (1997)Ethnic 20. Moon HD, Paik NW, Shim YB (1997) Analysis of
differences in biological monitoring of several some metabolites of organicsolvents in urine by
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Arch Occup Environ Health 64, 569-580. extraction technique and high performance liquiud
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11. Loizou GD, Jones K, Akrill P, Dyne D, Cocker J Intern,J Environ Anal Chem 64, 1-9.
(1999) Estimation of the dermal absorption of
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47
REVISED OES PROPOSAL
and occurs in gasoline and, in small amounts, in
ETHYLBENZENE tobacco smoke. The production rate in the EU is in
Recommendation of the EC excess of 1 000 tonnes per annum. Occupational
Scientific Committee on exposure to pure ethylbenzene is uncommon as it
Occupational Exposure Limits usually occurs together with other solvents such as
xylene.
8 hour TWA: 100 ppm (442mg/m3)
Notation: Skin
HEALTH SIGNIFICANCE
occupational exposure standard Ethylbenzene is well-absorbed through the lungs and
3 skin. The majority is rapidly eliminated in the urine,
15-minute STEL: 150 ppm (663mg/m )
but small amounts may be retained in fatty tissues.
subject to consultation
With the exception of [ ] this summary is prepared
Ethylbenzene has anaesthetic properties at high
from the SCOEL SEG SUM.
exposure levels (Yant et al, 1930), suggesting that
CNS effects may also be important at lower
IDENTITY AND PROPERTIES exposures. Changes in noradrenaline and dopamine
Chemical name: Ethylbenzene levels in the hypothalamus have been observed in rats
exposed to 2 000 ppm (8840 mg/m3) ethylbenzene for
Synonyms: Phenylethane
6 hours/day for 3 days (Anderson et al, 1981),
EINECS No: 202-849-4 although no behavioural changes were reported.
EEC No: 601-023-00-4
CAS No: 100-41-4 In a 28 day inhalation study, the NOAELs were 382
MWt: 106.17 ppm (1688 mg.m-3) in rats and mice and 782 ppm
Vapour pressure: 2 kPa at 20 °C. (3456 mg.m-3) in rabbits. Minor effects, such as
increased liver weight and leukocyte counts, were
Melting Point: -94.9°C
seen at the LOAELs 7782 ppm (3456 mg/m3) in rats
Boiling Point: 136.2 °C and mice and 1610 m (7116 mg.m-3) in rabbits (Cragg
Conversion factor (20°C): 4.42 mg/m3 = 1 ppm et al, 1989). A subchronic inhalation study of
ethylbenzene (6 h/d, 5 d/week for 13 weeks) has also
been reported by NTP (1992). Increased liver weights
Ethylbenzene is a flammable, colourless liquid with an
were seen in male rats exposed to 250 ppm (1105
aromatic odour. It has a vapour density of 3.7 times
mg.m-3) and female rats exposed to 500 (2210
that of air and is explosive in the range 1.2 - 6.8 % in
mg.m-3). Increased kidney weights were seen at higher
air. The odour threshold is about 2 ppm (9 mg.m-3) .
exposure levels. No microscopic lesions associated
Ethylbenzene is listed in the current Approved Supply
with either liver or kidney weights were observed.
List under the Chemical (Hazard Information and
Increased lung weights and signs of lung inflammation
Packaging for supply) Regulations 1994 (CHIP) as
were seen in almost all rats exposed at and above 250
flammable and harmful, to be labelled with risk (R)
ppm (1105 mg/m3) ethylbenzene, but the incidence
phrases:
and severity of the lesions were not dose-related
R11: Highly flammable (NTP, 1992).
R20: Harmful by inhalation
49
REVISED OES PROPOSAL
for teratogenic potential', Scand. J. Work
Environ. Health Suppl., 4, pp. 66-75.
50
REVISED OES PROPOSAL
limit being applicable for coating or cleaning or in a refrigerator (+4 oC) for at least one month and
operations in which the operator does not wear any for more than 6 months when stored at -200 oC.
gloves.
TOXICOKINETICS
There are no data in relation to the toxicokinetics of
MEASUREMENT
PGMEA in humans. In animals, PGMEA is very well
Workplace air monitoring absorbed via the inhalation and oral routes7,8.
Short-term measurement in air can be performed by Although there are no data in relation to dermal
colourimetric detector tubes calibrated for some absorption, based on its physicochemical properties
ethers, but tubes that are manufacturer-calibrated and comparison with the corresponding glycol ether
specifically for PGMEA are not available. They are alcohol, PGME, PGMEA is predicted to be well
subject to interferences from alcohols, esters and absorbed across the skin. Once absorbed, PGMEA
aromatic compounds, therefore detector tubes may not and its metabolites are widely distributed around the
be suitable for the measurement of PGMEA in mixed body, with the greatest amounts found in the liver and
solvents. Long-term measurement is either by pumped skin following oral dosing and inhalation exposure in
sampling on charcoal followed by solvent desorption rats. Following absorption, PGMEA undergoes rapid
with dichloromethane/methanol and gas and extensive enzyme hydrolysis to PGME, with
chromatography1,2 or, alternatively, charcoal diffusive concomitant formation of acetic acid (although no
samplers may be used with a similar analytical studies to confirm this are available). PGME is then
method3. A pumped thermal desorption method based further metabolised by direct conjugation with
on MDHS 724, using Tenax or Chromosorb 106 sulphate and glucuronic acid or by O-demethylation to
packed tubes as sorbent, is suitable for measurement propylene glycol. No unchanged PGMEA is
of low concentrations in the range 0.001-10 ppm. detectable in plasma or urine in rats exposed orally or
Alternatively, thermal desorption may be used with by inhalation. The major routes of excretion are the
similar tubes sampling diffusively5. breath and urine, with about 60% of the administered
dose exhaled as CO2, derived from further metabolism
of propylene glycol, and 25% excreted as urinary
Biological monitoring metabolites within 48 hours post dosing. Minor faecal
The rapid hydrolysis of PGMEA in the body to excretion occurs. There is no evidence for
PGME means that the analysis of propylene glycol bioaccumulation.
monomethyl ether (PGME) can be used as a basis for
biological monitoring. There are analytical methods HEALTH EFFECTS
available for the determination of PGME in blood,
Animal studies
urine and breath. However, the invasive nature of
There are no data on the absorption of PGMEA, but,
blood sampling means that it is not a preferred
by analogy with PGMEA it is likely that it will be well
approach. Breath PGME analysis, although
absorbed by inhalation and percutaneously.
non-invasive, is very dependent on the time of sample
collection. Overall, biological monitoring based on The acute toxicity of PGMEA to experimental animals
measurement of PGME in end-of-shift urine samples is low. Direct application of the liquid is irritating to
is non-invasive and is the preferred approach. The the eyes of rabbits; irritation of the skin is described as
mean half life of PGME in urine is 120 minutes. mild.
The analytical method for PGME in urine is based on The critical effect of PGMEA is irritation of the nasal
solvent extraction with ethylacetate followed by mucosa. Repeated exposure of mice to 300, 1000 and
derivatisation with trimethylsyilyl imidazole and 3000 ppm (1650, 5500 and 16,500 mg.m-3) PGMEA,
detection by capillary gas chromatography-mass 6h/d, 4-5d/w for 2 weeks resulted in a dose-related
spectrometry6. The method has a detection limit of 1 degeneration of the olfactory epithelium in all
exposure groups, accompanied by metaplastic changes
µmol.l-1. PGME is stable in urine at room temperature
and signs of inflammation in the mid- and high- dose
52
REVISED OES PROPOSAL
groups (Miller et al, 1984)9. Degeneration of the biological monitoring would not provide any useful
olfactory epithelium was observed in rats only at the information directly related to toxicity. Therefore a
high exposure. The authors suggested that these biological monitoring guidance value is not proposed.
lesions were due to acetic acid resulting from the PGMEA is included in the 1st Consolidated Indicative
hydrolysis of PGMEA in the nasal epithelium. No Limit Occupational Exposure Limit Values Directive
signs of systemic toxicity were found in mice. In rats, (2000/39/EC), with values of 50 ppm (8-hour TWA)
increased liver weights were noted in the females and
and 100 ppm (STEL) and a skin notation. The
kidney changes in the males of the high exposure
following is an extract from the SCOEL
group.
SEG/SUM/39A:
There are no data concerning the genotoxicity,
The study of Miller et al (1984), establishing a
carcinogenicity or reproductive toxicity of PGMEA.
LOAEL of 300 ppm (1650 mg.m-3), for irritation
However, as PGMEA is rapidly hydrolysed to
of the olfactory epithelium of mice, was
PGME, similar negative results might be expected.
considered to be the best available basis for
Human data proposing occupational exposure limits. An
There are no human data available in relation to the uncertainty factor of 5 was considered appropriate
health effects of exposure to PGMEA. to allow for the absence of a NOAEL and of
human data. Taking into account the preferred
value approach, the recommended 8-hour TWA is
BASIS FOR SETTING THE LIMIT 50 ppm (275 mg.m-3). A STEL (15 minutes) of
PGMEA is of low systemic toxicity following single 100 ppm (550 mg.m-3) was proposed to limit peak
and repeated exposure. It is not a sensitiser and there exposure which could result in irritation. A skin
are no concerns for genotoxicity, carcinogenicity or notation was recommended as dermal absorption
reproductive toxicity. The lead health effect of could contribute substantially to the total body
concern for PGMEA is local degenerative damage to burden.
the nasal epithelium following repeated inhalation
exposure, for which there will be an identifiable
threshold of effect. Therefore, from consideration of REFERENCES
the health effects, the criteria for an Occupational 1 Health and Safety Executive (1987). Methods
Exposure Standard (OES) are met. There are no for the Determination of Hazardous Substances
human data relevant to the establishment of an OES. MDHS 21. Glycol ether and glycol ether acetate
A 2-week repeated inhalation exposure study in rats vapours in air. Laboratory method using charcoal
and mice is considered to be the most appropriate adsorbent tubes, solvent desorption and gas
basis from which to derive an OES. From this study, a chromatography ISBN 0 7176 0115 3 HSE Books.
LOAEL of 300 ppm was identified for slight 2 US Occupational Safety and Health
degenerative changes to the olfactory epithelium in Administration (1993). OSHA Manual of analytical
mice. Given that this study is of relatively short methods. 99 Propylene glycol monomethyl
duration, and does not allow the identification of a ethers/acetates. USDOL/OSHA.
clear NOAEL and in view of the absence of human
3 Health and Safety Executive (1997). Methods
data, it is considered appropriate to establish an OES
for the Determination of Hazardous Substances
at 50 ppm (8-hour TWA). This provides a six-fold
MDHS 88. Volatile Organic Compounds in Air.
margin below the LOAEL for minimal local tissue
Laboratory method using diffusive samplers, solvent
damage in mice.
desorption and gas chromatography. ISBN 0 7176
There is no evidence that PGMEA has sensitising 2401 3 HSE Books.
properties and thus a ‘Sen’ notation is not required.
4 Health and Safety Executive (1992). Methods
In relation to biological monitoring, although PGMEA for the Determination of Hazardous Substances
is predicted to be readily absorbed across the skin, MDHS 72. Volatile Organic Compounds in Air.
because there is no concern for systemic toxicity, Laboratory method using pumped solid sorbent tubes,
53
REVISED OES PROPOSAL
54
REVISED OES PROPOSAL
CAS No: 120-82-1 From the available industry data and EASE
predictions, inhalation exposures are generally below
EINECS No: 204-428-0
1 ppm 8-hour TWA with the highest being during the
Synonyms: 1,2,4-TCB,
manufacture of plastic pellets in the production of
unsymmetrical trichlorobenzene high performance wire and cable products. Short term
Formula: C6H3Cl3 (15-minute) exposures are generally below 2 ppm with
the highest occurring in the production of brightener
Melting point: 17 oC
solution and during re-packaging prior to sale.
Vapour pressure: 43.3 Pa at 25 oC
Odour threshold: 3 ppm MEASUREMENT
55
REVISED OES PROPOSAL
56
REVISED OES PROPOSAL
There are no reliable human data on which to base a 2 HSE (1990). MDHS 28 Chlorinated hydrocarbon
limit. However, animal evidence indicates that the solvent vapours in air. Health and Safety Executive,
liver is the key target organ of toxicity for 1,2,4-TCB, Methods for the determination of hazardous
and the most sensitive marker for liver changes substances. HMSO, London
appears to be an elevation in urinary porphyrins; the 3 HSE (1992). MDHS 72 Volatile organic
NOAEL and LOAEL for this effect from repeat compounds in air. Health and Safety Executive,
exposure inhalation studies were 3 and 10 ppm, Methods for the determination of hazardous
respectively. As the substance is not genotoxic, liver substances. HMSO, London
tumours produced in a mouse carcinogenicity study
4 HSE (1995). MDHS 80 Volatile organic
are thought likely to arise from chronic toxicity in this
compounds in air. Health and Safety Executive,
organ. Hence, control for hepatotoxicity would also
Methods for the determination of hazardous
control for any carcinogenic effects. Overall, based on
substances. HMSO, London.
the toxicological data, the criteria for an Occupational
Exposure Standard (OES) are met. 5 US EPA (1989). TO-14 (2nd supplement)
Compendium of methods for the determination of
The available evidence on the structural analogue
toxic compounds in ambient air. US Environmental
hexachlorobenzene suggests that for 1,2,4-TCB
Protection Agency, Research Triangle Park, NC
toxicity, the rat is a reasonable model for humans. An
27711.
OES of 1 ppm (8 hour TWA) is considered
appropriate to protect against health effects in 6 Henschler D (ed.) (1992). Trichlorobenzene (all
humans. This value is a factor of 3 below the NOAEL isomers). In: Occupational toxicants, critical data
in rats and a factor of 10 below the LOAEL in this evaluation for MAK values and classification of
species, which are considered an adequate margin carcinogens, Vol. 3. VCH, Weinheim.
taking account of the fact that lead effect is a very 7. SEG/SUM/35C: Henschler, D (ed): Criteria
sensitive marker for biochemical change. The document of occupational exposure limits: 1,2,4-
Trichlorobenzene (14.05.1990) VCH-Weinheim.
occupational hygiene assessment indicates that control
to the proposed OES is readily achievable across all
user industries.
A STEL (15-minutes) of 5 ppm has been proposed by
the EU Scientific Committee on Occupational
Exposure Limits (SCOEL)7 to limit peaks in exposure
which could result in irritation.
1,2,4-TCB can be absorbed across the skin and might
contribute to systemic toxicity as a consequence,
although there are few relevant data on this property.
Overall, the assignment of a Skin notation is deemed
to be warranted. There is no evidence of sensitising
properties, so a Sen notation is not warranted.
Adequately validated analytical methods for
biological monitoring are not available and there are
no data on which to base a BMGV.
REFERENCES
1 NIOSH (1994). (2) 5517 (Rev 15-8-94)
Polychlorobenzenes. National Institute of
Occupational Safety and Health, US Dept of Health
and Human Services.
57
REVISED OES PROPOSAL
from phosphatic ores by digestion of the rock by
ORTHOPHOSPHORIC ACID sulphuric acid. The furnace process burns elemental
phosphorus in excess air to give diphosphorus
Recommendation of the EC Scien-
pentoxide which is then hydrated. Orthophosphoric
tific Committee on Occupational
acid is used in the manufacture of fertilisers and
Exposure Limits
detergents.
8-hour TWA: 1 mg.m-3
occupational exposure standard EXPOSURE
15-minute STEL: 2 mg.m-3 Workplace exposures are likely to be minimal due to
containment of the processes during manufacture and
subject to consultation
use. The principle risk of exposure is from inhalation
of aerosol and from splashes and spillages.
IDENTITY AND PROPERTIES
No useful human data are available on the effects of 2 US National Institute For Occupational Safety and
repeated inhalation exposure. Consumption of Health. NIOSH Manual of analytical methods, 2nd
moderate amounts of orthophosphoric acid in the diet Edition, Volume 1: Method & CAM 216 - Phosphoric
failed to indicate any toxicity. acid in air. US Department of Health and Human
Services (NIOSH) Publication 82-100 (1982).
No reliable human data on the carcinogenic potential
of orthophosphoric acid are available. In addition, no 3 US National Institute For Occupational Safety and
human data are available on its potential to cause Health. NIOSH Manual of analytical methods, 3rd
genotoxicity or reproductive toxicity. Edition: Method 7903 - Acids, Inorganic. US
Department of Health and Human Services (NIOSH)
BASIS FOR SETTING THE LIMIT Publication 84-100 (1984).
Due to the minimal useful data available on
phosphoric acid, data on diphosphorus pentoxide was 4 US National Institute For Occupational Safety and
also considered (diphosphorus pentoxide readily Health. NIOSH Manual of analytical methods, 2nd
hydrolyses to phosphoric acid). The combined data Edition, Volume 7: Method & CAM 339 - Inorganic
suggested that the critical health effect is respiratory acids in air. US Department of Health and Human
irritation. An occupational exposure standard is Services (NIOSH) Publication 82-100 (1982).
proposed at 2 mg.m-3 over a 15-minute reference 5 Methods for the determination of hazardous
period. Control to below this limit should be substances MDHS 14 (Rev) General methods for the
achievable. This limit is proposed to be consistent gravimetric determination of respirable and total
with the OES set for diphosphorous pentoxide. inhalable dust. ISBN 0 7176 0509 4 HSE Books
Orthophosphoric acid is included in the 1st (1993).
Consolidated Indicative Occupational Exposure Limit 6 SEG/CDO/7 Criteria document for occupational
Values Directive (2000/39/EC), with values of 1 exposure limit values for phosphoric acid. Prepared by
mg.m-3 (8-hour TWA) and 2 mg.m-3 (STEL). SCOEL6 Environmental Resources Ltd., London (1990)
advised that further data allowing a more accurate
determination of the threshold level of irritation are OTHER USEFUL PUBLICATIONS
required. Data on diphosphorus pentoxide were taken Toxicity review of phosphoric acid, phosphorus
as the basis for setting a limit. SCOEL recommended pentoxide, phosphorusoxychloride, phosphorus
an 8 hour limit of 1 mg.m-3 and a 15 minute limit of 2 trichloride, phosphorus pentachloride and
mg.m-3 based on the limited data available and phosphorus pentasulphide HSE Toxicity Review 30
recommended that additional exposure studies are (Payne et al, 1994) ISBN 0 7176 0669 4 HSE Books.
required. The STEL is consistent with the STEL OES
set for diphosporus pentoxide.
59
REVISED OES PROPOSAL
[OCCURRENCE AND USE
CUMENE Cumene occurs as a minor constituent of petroleum
occupational exposure standard and of solvents derived from it. Over 100 000 tonnes
per annum are manufactured in the UK by reaction of
8 hour TWA: 25 ppm (125 mg.m-3)
benzene with propylene. The major part is used as
Recommendation of the EC Scien- raw material for the production of phenol and the
tific Committee on Occupational associated products, acetone and alpha-methylstyrene.
Exposure Limits
15-minute STEL: 50 ppm (250 mg.m-3)
EXPOSURE
Notation: Skin
About 100 workers in the UK are likely to be exposed
subject to consultation
to cumene during its production and main usage, with
some further exposures during loading and unloading
With the exception of [ ] this summary is prepared
of road tankers and ships. There are further
from the SCOEL SEG SUM
possibilities for exposure arising from minor
IDENTITY AND PROPERTIES applications and the handling of materials in which it
is a constituent. The limited data available indicate
Chemical Name: Cumene
that exposures are controlled to well below 50 ppm
CAS No: 98-82-8
(8-hour TWA) and generally below 5ppm.
EEC No: 601-024-00-X
Formula: C6H5CH (CH3)2
MEASUREMENT
Synonyms: Isopropylbenzene, 1-methyl
Cumene vapour in air can be determined by pumped
ethylbenzene; 2-phenyl
sampling through a Chromosorb 106 tube with
propane;
thermal desorption or through a charcoal tube with
Saturated vapour solvent desorption1, or using a diffusive Tenax or
concentration: 3900 ppm at 20°C Chromosorb sampler with thermal desorption2;
Boiling point: 152°C analysis is by gas chromatography. Colorimetric
detector tubes may be used to estimate cumene
Conversion factor: 1 ppm = 5.00 mg.m-3 at 20°C
concentrations, but they are not specific.]
R10: Flammable
HEALTH EFFECTS
R65: Harmful: may cause lung damage if
Animal studies
swallowed
Cumene has a low to moderate acute toxicity to
R37: Irritating to respiratory system
animals, with lethal concentrations in excess of 1000
R51/53: Toxic to aquatic organisms, may cause
ppm (5000 mg.m-3) (Smyth et al, 1951). The critical
longterm adverse effects in the aquatic
effect is irritation of the respiratory tract and CNS
environment
effects. RD50 values of 2000 - 2500 ppm (10,000 -
60
REVISED OES PROPOSAL
-3
12,500 mg.m ) have been reported in mice this difference is not considered to be significant and
(Kristiansen et al, 1986; Nielsen and Alarie, 1982). so the domestic limit has been retained.]
Increased activity and gait abnormalities were
reported in rats exposed to 500 ppm (2500 mg.m-3)
REFERENCES
cumene for 6 hours, with no effects observed at 100
ppm (500 mg.m-3 )(Bushy Run Research Center, 1. Methods for the determination of hazardous
1989). substances MDHS 36 (Rev) Toluene in air -
Laboratory method using pumped charcoal
Depression of the CNS and increases in liver, kidney
adsorption tubes, solvent desorption and gas
and adrenal weights were observed following
chromatography ISBN 0 11 885960 9 HSE Books
exposure of rats to 500 and 1200 ppm (2500 and 6000
(1990).
mg.m-3) for 90 days (Bushy Run Research Center,
1989). An increased incidence of cataracts was also 2. Methods for the determination of hazardous
noted in this study at 100, 500 and 1200 ppm (500, substances MDHS 66 (Rev) Mixed hydrocarbons (C5
2500 and 6000 mg.m-3), but due to the genetic to C10) in air - Laboratory method using porous
disposition of the animals for this lesion, this polymer diffusion samplers, thermal desorption and
observation is not suitable as basis for standard gas chromatography
setting. Following repeated administration of 244 ISBN 0 7176 0867 0 HSE Books (1995)
ppm (1220 mg.m-3) for 6 weeks or continuous
exposure to 30 ppm (150 mg.m-3) for 90 days, to rats
KEY BIBLIOGRAPHY
dogs or monkeys, no toxic effects were observed
(Jenkins et al, 1970). WATCH (1992) Cumene: Criteria Document for an
occupational exposure limit
There are no data available on the carcinogenicity of
cumene. From the data available, there is no ISBN 0-7176-0767-4 HSE Books (1994)
evidence that cumene is genotoxic (Florin et al, 1980; Bushy Run Research Centre (1989). Cumene
Simmon et al, 1977) or teratogenic (Bushy Run (isopropylbenzene) fourteen-week vapor inhalation
Research Center, 1989). study in rats with neurotoxicity evaluation. Project
No human toxicity data are available. report 52-628.
Florin, I., Rutberg, L., Curvall, M and Enzell, CR
(1980). Screening of tobacco smoke constinuents for
BASIS FOR SETTING THE LIMIT
mutagenicity using the Ames test. Toxicology 15,
The study conducted at the Bushy Run Research 219-232.
Center (1989), establishing a NOAEL of 100 ppm
Jenkins, L J, Jones, R A and Siegel, J (1970). Long
(500 mg.m-3) for CNS effects in a 90d study in rats,
term inhalation screening studies of benzene, toluene,
was considered to be the best available basis for
p-xylene and cumene on experimental animals.
proposing occupational exposure limits. A STEL (15
Toxicol. Appl. Pharmacol. 16, 818-823.
mins) of 50 ppm (250 mg.m-3) was proposed to limit
peaks of exposure which could result in irritation. A Kristiansen, U, Hansen, L, Nielsen, G D and Holst E
“skin” notation was recommended as dermal skin’ (1986). Sensory irritation and pulmonary irritation of
notation was recommended as dermal absorption cumene and n-propanol: mechanisms of receptor
could contribute substantially to the total body burden. activation and desensitization. Acts Pharmacol. et
Toxicol. 59, 60-72.
[WATCH had previously considered that, in the
absence of human data, it was appropriate to apply an Nielsen, G D and Alarie Y (1982). Sensory irritation,
uncertainty factor of 4 to the NOAEL of 100 ppm. pulmonary irritation and respiratory stimulation by
Consequently WATCH recommended an 8-hour airborne benzene and alkylbenzenes: prediction of
TWA of 25 ppm (125 mg.m-3). Although SCOEL safe industrial exposure levels and correlation with
have now recommended an 8-hour TWA of 20 ppm their thermodynamic properties. Toxicol. Appl.
Pharmacol. 65, 459-477.
61
REVISED OES PROPOSAL
Simmon, V F, Kauhanen, K and Tardiff, R G (1977).
Mutagenic activity of chemicals identified in drinking
water. Progress in Genetic Toxicology. (Eds. Scott,
D, Bridges, B A and Sobels F H) Elsevier/North
Holland Biomedical Press. 249-258.
Smyth H F, Carpenter C P and Weil, C S (1951).
Range-finding toxicity data. List IV A M A Arch.
Ind. Hlth. 4, 119 - 122.
62
REVISED OES PROPOSAL
R67: Vapours may cause drowsiness and
ACETONE dizziness
Recommendation of the EC OCCURRENCE AND USE
Scientific Committee on Acetone is a normal body metabolite and may occur in
Occupational Exposure Limits small quantities in exhaled air of all mammals. It also
8-HOUR TWA: 500 ppm (1210 may be formed by various types of degradation or
mg.m-3) combustion of organic materials from agricultural and
industrial activities. It is widely used in industry as a
occupational exposure standard solvent for cellulose acetate and nitrocellulose, and for
15-minute STEL: 1500 ppm (3630 acrylic paints, varnishes, lacquers, adhesives, printing
mg.m-3) inks and other resin solutions. It is also used as a
degreasing agent and a raw material for chemical
subject to consultation
syntheses. The production rate in the EU is about 106
With the exception of [ ] this summary is prepared
tonnes per annum.
from the SCOEL SEG SUM
HEALTH SIGNIFICANCE
IDENTITY AND PROPERTIES
An average of 45% of inhaled acetone will be
Chemical Name: Acetone
absorbed (Wigaeus et al, 1981), but percutaneous
CAS No: 67-64-1 absorption is likely to be comparatively low. Most of
Einecs No: 200-662-2 the absorbed acetone is metabolised, becoming
EEC No: 606-001-00-8; incorporated into normal intermediary metabolism,
but an increasing proportion is exhaled at higher blood
Formula: CH3COCH3
concentrations (Owen et al, 1982).
Synonyms: 2-Propanone; dimethyl
The critical effects of acetone are considered to be
ketone; methyl ketone
irritation of mucous membranes and neurobehavioural
Vapour pressure: 24.7 kPa at 20 °C effects.
Saturated Vapour Exposure of volunteers to acetone for 6 hours per day
Concentration: ~ 231,000 ppm at 20 °C for 1 or 6 days resulted in mucous membrane irritation
Melting point: -95.4 °C at 500 and 1 000 ppm (1210 and 2420 mg.m-3), with
minimal effects of 250 ppm (605 mg.m-3) and none at
Boiling point: 56.2 °C
100 ppm (242 mg.m-3) (Matsushita et al, 1969 a and
Conversion factor: 2.42 mg/m3 = 1 ppm at b). No symptoms were reported in any of the groups
20oC, 101 kPa towards the end of the exposure sessions, indicating
Acetone is a clear colourless liquid with a sweetish sensory adaptation. Exposure at higher levels will
aromatic odour. The vapour density is 2.0 times that often be tolerable to workers, with complaints of
of air and it is explosive in the range 2.2 - 13.0% in irritation generally commencing at 8 hour time
air. The odour threshold is about 13 ppm (31 mg/m3). weighted exposures above 1 000 ppm (2420 mg.m-3)
Acetone is listed in the current Approved Supply List (Raleigh and McGee, 1972). More recently, irritation
under the Chemical (Hazard Information and of the eyes, mouth and throat in volunteers exposed to
Packaging for supply) Regulations 1994 (CHIP) as 1000 ppm (2420 mg.m-3) acetone for 4 or 8 hours was
flammable and irritant, to be labelled with risk (R) confirmed by Seeber et al (1992a).
phrases: The neurotoxicity of acetone has been documented in
R11: Highly flammable a number of experimental studies. In juvenile
R36: Irritating to the eyes baboons exposed continuously to 500 ppm (1210
mg.m-3) acetone for 7 days, an increase in response
R66: Repeated exposure may cause skin
time was seen for a complex operant discrimination
dryness or cracking task (Geller, et al, 1979). When mice were exposed to
63
REVISED OES PROPOSAL
a continuous series of 30 min acetone exposure which is also found in humans (Pattern et al, 1986).
sessions at six levels increasing from 100 to 56 000 Experimental studies suggest that some induction and
ppm (242 to 135 520 mg.m-3), a schedule-controlled resultant potentiation of toxicity due to other solvents
type of operant behaviour showed decreased response may occur at acute and doses of 0.05 ml.kg-1
rates at 1 000 ppm (2 420 mg.m-3) and above (Glowa (Charbonneau et al, 1988), corresponding to a
and Dews, 1987). blood-acetone concentration of 100 mg.l-1 and above
Increases in simple visual reaction time were seen in (Charbonneau et al, 1986). Blood concentrations at
six subjects exposed to 250 or 500 ppm (605 or 1210 that magnitude can be achieved in volunteers after an
mg.m-3) for 6 hours per day in an exposure chamber 8 hour exposure to acetone at 1000 ppm (2420
for six consecutive days (Matsushita et al, 1969b). mg.m-3) (Blaszkewicz et al, 1992). However, no
potentation could be detected in rats exposed to 1 000
In a more extensive study, 22 volunteers exposed to
ppm (2420 mg.m-3) acetone (Charbonneau et al,
250 ppm (605 mg.m-3) acetone for 4 hours in an
1986).
exposure chamber, small but statistically significant
decreases were found in two measures of a dual task
test (Dick et al, 1989). Choice reaction time, visual RECOMMENDATION
vigilance, memory scanning and postural sway Taking into account the reports noted above of
showed no changes, whilst minimal differences were irritation and neurobehavioural effects in volunteers
seen in the profile of moods test. However, this study and workers, it is considered that symptoms may
is not considered suitable to use as a basis is occur at acetone exposures of 1 000 ppm ( 2420
proposing occupational exposure limits. Exposure of mg.m-3) or greater. In view of the mild nature of the
16 volunteers to about 1000 ppm (2420 mg.m-3) symptoms, and because tolerance develops in workers,
acetone for 4 or 8 hours, simple and choice reaction an uncertainty factor of 2 was considered adequate.
time, memory scanning by the Sternberg paradigm and The recommended 8-hour TWA is 500 ppm (1210
spontaneous motor activity failed to show any clear mg.m-3). No 'skin' notation was considered to be
relationship to exposure (Seeber et al, 1992b; 1994). necessary.
Information on the chronic effects of acetone is not [Account was taken of the rapid response to exposure,
available. the uncertainties of dose-response data and the need
Acetone has generally been shown to be negative in to provide protection for workers across the whole
mutagenicity assays (Maron et al, 1981). Data on range of industries handling acetone, including those
carcinogenicity are lacking. only occasionally exposed and unacclimatised. A
A development study conducted with rats and mice STEL (15 mins) was set to limit peaks in exposure at
exposed to acetone intermittently during gestation 1500 ppm (3630 mg.m-3) which is not expected to lead
produced evidence of embryotoxicity but no to lead to adverse health effects, although some
significant increase in malformations. A NOAEL of 2 workers may consider it unpleasant.]
200 ppm (5 324 mg.m-3) was reported (NTP, 1988). At the levels recommended, no measurement
Administration of acetone to rats in the drinking water difficulties are foreseen.
for 13 weeks of approximately 3400 mg.kg-1.day-1
resulted in decreased motility and increased
KEY BIBLIOGRAPHY
abnormalities of the sperm, but no histopathological
lesions, (NTP, 1991). No effects were seen in male Blaszkewicz, M., Golka, K., Vangala, R.R,
mice treated similarly at doses up to 4858 Kiesswetter, E., Seeber, A. and Bolt, H.M. (1992),
mg.kg-1.day-1 (NTP, 1991) or in male rats given 'Biologische Uberwaching bei Aceton-und
acetone in the drinking water at a dose of 1071 Ethylacetatexposition unter simulierten
mg.kg-1.day-1 for 6 weeks (Larsen et al, 1991). MAK-Bedingungen'. Verh. Dtsch. Ges. Arbeitsmed.,
31, pp. 141-144.
Acetone exposure to rats causes induction of
cytochrome P450 enzymes particularly P450 2E1, Charbonneau, M., Brodeur, J., du Souich, P. and Plaa,
G.L (1986). 'Correlaton between acetone-potentiated
64
REVISED OES PROPOSAL
CC14-induced liver injury and blood concentrations
or oral administration'. Toxicol. Appl. Pharmacol., NTP (1988). Report No PNL-6768.
84, pp 286-294.
NTP (1991) NIH Publ. 31-3122.
65
REVISED OES PROPOSAL
67
REVISED OES PROPOSAL
repeated exposure studies animals exposed to showed no effects on weight gain or histopathological
cyclohexane vapour showed lacrimation. findings in a range of tissues. At 25000 ppm, males
Cyclohexanone has the potential to irritate the showed a 19% decrease in weight gain. At 34000
respiratory tract following a single exposure to ppm, males and females, respectively, showed
relatively high airborne exposure concentrations. decreases in weight gain of 24% and 15 %
Studies in guinea pigs and mice showed no evidence respectively. At 47000 ppm, increased mortality
of skin sensitisation potential. There are no data (9/20) and incidences of focal liver necrosis and
relating to respiratory sensitisation. However, the lack hyperplasia of the thymus were observed. Only very
of chemical reactivity of cyclohexanone and its limited data are available concerning the effects of
metabolites towards nucleophilic groups suggests that repeated contact with the skin. No effects on growth,
it lacks the potential to behave as a hapten. This and behaviour or structure of the eyes were observed when
the absence of skin sensitisation potential suggests that cyclohexanone was applied to the skin of rabbits or
cyclohexanone does not have respiratory sensitisation guinea pigs at up to ~160 and ~1400 mg.kg-1.day-1,
potential. respectively, for 3 days/week for 3 weeks.
Taken together, the findings of repeated exposure
The toxicity of cyclohexanone following repeated studies in experimental animals suggest that the liver
exposure using occupationally relevant routes of is a target organ for toxicity following long term
exposure has not been well investigated. Many of the repeated daily exposure to relatively high
available studies are of uncertain or poor quality with concentrations of cyclohexanone.
inadequate reporting. In relation to genotoxicity, studies in bacteria gave
A poorly reported 10-week inhalation study in rabbits negative results in the presence and absence of
revealed “barely demonstrable degenerative changes exogenous metabolic activation. There are a number
in the liver and kidneys” at the lowest exposure of in vitro studies in mammalian cells available. The
concentration of 190 ppm7. Histopathology was not data from these studies are mixed, although it is
performed on tissues/organs at the higher possible that the apparently positive findings arose
concentrations tested. However, between 309 ppm to indirectly from excessive toxicity. Reassuringly, the
773 ppm conjunctival irritation was observed. All better quality studies are generally negative.
animals exposed to 1414 ppm survived, showing Negative results were obtained from an in vivo study
lethargy in addition to conjunctival irritation. After 3 of bone marrow chromosomal aberrations and a
weeks exposure to 3082 ppm, narcosis, laboured dominant lethal test. Overall, the results of tests
breathing, weight loss and deaths were observed. No conducted in vivo gives reassurance that
haematological findings were observed at any cyclohexanone is not mutagenic to somatic or germ
exposure level. The toxicological significance of the cells .
effects seen in the liver and kidneys is uncertain. No treatment-related tumours were observed in F344
However, effects on the liver were seen at rats exposed for 2 years to cyclohexanone
comparatively high exposure concentrations in other administered with the drinking water at a
repeated exposure studies, and therefore, this finding concentration of 3300 ppm (~500 mg.kg-1.day-1)8. At
cannot be considered as irrelevant to human health 6500 ppm (~1000 mg.kg-1.day-1) there was an
and 190 ppm is regarded as the LOAEL. A further increased incidence of benign and/or malignant
inhalation study in rats established a NOAEL of 100 tumours of the thyroid in male rats only. There is no
mg.kg-1.day-1 for intravenous injection of information to indicate the underlying mechanism of
cyclohexanone12. tumour formation in these rats, hence the relevance to
Data on effects via ingestion are available from human health is uncertain. However, the relevance of
studies with limited reporting in which cyclohexanone this finding to the health of exposed workers is likely
was administered via the drinking water to rats and to be low, particularly as the potency of
mice. The studies reported only investigations of cyclohexanone to cause tumours in rats is low i.e. the
bodyweight and histopathology. increase in tumours in rats was seen only at 1000
Rats administered up to 4700 ppm cyclohexanone in mg.kg-1.day-1 with no toxicologically significant
their drinking water for 25 weeks showed no effects on the thyroid or other tissues at 500
treatment-related effects on bodyweight gain or mg.kg-1.day-1
histopathological findings. At a concentration of 6500
ppm, a 10% decrease in bodyweight gain was In B6C3F1 mice exposed to cyclohexanone via the
observed. Following administration to rats for 104 drinking water for 2 years, a slight increase in the
incidence of liver tumours was observed in males only
weeks at ~500 to ~1000 mg.kg-1.day-1 via the drinking
at the lowest concentration tested (6500 ppm). In
water there was a statistically significant decrease in view of the high background spontaneous incidence of
body weight gain (~15 % and ~30 %, respectively); this lesion, and in the absence of a dose-response
no effects on the organs were reported. relationship, it can be concluded that this study
Groups of mice administered drinking water produced no evidence of carcinogenic potential for
containing cyclohexanone at 13000 ppm for 13 weeks cyclohexanone in mice.
68
REVISED OES PROPOSAL
In relation to the potential effects of cyclohexanone Ill characterised, self-reported “irritation” to the eyes,
on reproduction, a 2-generation inhalation study in nose and throat at a calculated exposure level of 75
rats is available. In this study, Fo generation rats were ppm (exposure duration 3 - 5 minutes) was perceived
exposed to 0, 250, 500 or 1000 ppm, whereas the F1 in a group of about 10 volunteers, while the majority
generation rats were exposed to 0, 250, 500 or 1400 of subjects did not “object” to 25 ppm(11). There have
ppm, 6 hours/day, 5 days/week. Histopathological been no reports of skin or respiratory sensitisation due
examination revealed no effects on the testes at any to exposure cyclohexanone.
exposure level. No effect on fertility was There are no useful data describing the effects of
demonstrated at up to 500 ppm in both generations. cyclohexanone in humans in relation to repeated
Rats exposed to 1000 ppm (first generation) or 1400 exposure or mutagenicity, carcinogenicity or
ppm (second generation) showed transient reductions reproductive toxicity.
in maternal bodyweight. At 1000 ppm there was no
effect on male fertility in the F0 generation. However, BASIS FOR SETTING THE LIMIT
at 1400 ppm in male rats of the F1 generation there Cyclohexanone is included in the 1st Consolidated
were reduced indices of male fertility [not further Indicative Limit Occupational Exposure Limit Values
described in the documentation available9,10]. Directive (2000/39/EC), with values of 10 ppm
However, there was a persistent reduction in body (8-hour TWA) and 20 ppm (STEL) and a skin
weight gain at this exposure level, and it is also noted notation. The following is an extract from the SCOEL
that at 1000 ppm there was ataxia, irregular breathing, SEG SUM:
lacrimation and irritation of mucous membranes with The studies indicating a LOAEL of 190 ppm
the first few exposures. Therefore at 1400 ppm such (775 mg.m-3) for systemic effects in rabbits7
effects may have been more severe. Hence it is and a NOAEL of 25 ppm (102 mg.m-3) for
possible that generalised toxicity (including CNS irritation to the throat and eyes of human
depression) may have influenced fertility outcome in volunteers11 , were considered to be the best
males at 1400 ppm rather than any direct effect on the available basis for proposing a limit. An
testes. Reduced survival and bodyweights in the uncertainty factor of 2 was applied to allow
offspring were observed at 1400 ppm. The NOAEL for the limitations of the Nelson study11. The
for effects on fertility is considered to be 500 ppm. recommended 8-hour TWA is 10 ppm (40.8
Studies of developmental toxicity in rats exposed via mg.m-3). This is not contradicted by the study
inhalation show no effects on development of the establishing a NOEL for systemic effects of
offspring with repeated daily exposures of 500 or 650 100 mg.kg-1.day-1 by intravenous injection. A
ppm during gestation. Decreases in maternal and fetal STEL (15 min) of 20 ppm (81.6 mg.m-3) is
bodyweights were observed at 1400 ppm (6 h/d, days proposed to limit peaks in exposure which
6-19 of gestation). In a limited study in mice exposed could result in irritation. A ‘skin’ notation is
to 1400 ppm (6h/d days 6-17 of gestation), decreased also recommended as dermal absorption could
maternal weight was accompanied by a reduction in contribute substantially to the total body
the number of corpora lutea and live fetuses. Studies burden.
of limited quality indicate that no effects on neonate Studies are required to determine whether the
body or organ weights occurred following maternal potential conversion of cyclohexanone to
dosing by oral gavage at 800 mg.kg-1.day-1 on days 8 - cyclohexanol is sufficient to result in testiclar
12 of gestation. At 2200 mg/kg/d, decreased neonatal toxicity.
body weight was observed in the presence of gross WATCH agreed that biological monitoring may be
maternal toxicity indicated by increased mortality and useful, in view of the potential for systemic toxicity,
decreased body weight gain. Overall, the results and that dermal exposure to cyclohexanone may
indicate that cyclohexanone produces no effect on the contribute to the overall body burden of
developing offspring at doses which are not cyclohexanone. Therefore, the establishment of a
maternally toxic and a NOAEL of 650 ppm is BMGV was proposed.
apparent from the developmental toxicity studies.
Where adverse consequences for development were REFERENCES
seen at higher maternally toxic doses, the contribution
made by toxicity towards the dam is unclear. 1. NIOSH Manual of Analytical Methods, 4th Ed.,
1994, US Dept of Health and Human Services
Human data (NIOSH) Publ No 94-113, Ketones 1, method 1300.
There is relatively little human data available. Case
reports of human poisonings indicate that a single 2. Occupational Health and Safety Administration, US
ingestion of cyclohexanone may cause Dept of Labour, Cyclohexanone in air, method #01,
unconsciousness or excitation and metabolic acidosis. April 1979.
69
REVISED OES PROPOSAL
3. Health and Safety Executive, Volatile compounds
in air...pumped solid sorbent tubes, thermal desorp-
tion, MDHS 72, HSE Books 1993, ISBN 0 11
885692 8.
70
REVISED OES PROPOSAL
OCCURRENCE, PRODUCTION AND USE
71
REVISED OES PROPOSAL
Draeger 100-4000 Petroleum Draeger tube Diethyl ether has a low acute toxicity and induces
hydrocarbons, diethyl ether anaesthesia at concentrations in excess of 15,000 ppm
alcohols, 100/a
aromatics and (46.2 mg.m-3). The critical effect is nasal irritation. In
esters human volunteers the first indication of irritation
occurred at a calculated level of 300 ppm (924
Dynamic Indirect Methods mg.m-3). Most individuals tested felt that a
concentration of 100 ppm (308 mg.m-3) would be
Solid sorbent acceptable over an 8 hour exposure period3.
Sorbent Range Desorption Analysi Ref. No animal inhalation studies are available. A 90 day
s gavage study in rats4 established a NOEL for systemic
Charcoal 0.3 - 11 Solvent GC/FID NIOSH toxicity of 500 mg.kg-1 bw.day-1. This may
mg per
sample. correspond to an inhalation exposure concentration of
0.3 mg = 1000 ppm (3080 mg.m-3).
10 ppm
for 3 litre Diethyl ether shows no evidence of mutagenicity,
sample
either in vitro or in vivo 5,6,7. No long term animal
studies or reproduction studies are available.
Instrumental Methods
BASIS FOR THE LIMIT
Instrument Principle Lower Ref. The information in this section is taken from the
detection SCOEL summary document SEG/CDO/5A (1991)2.
limit(ppm)
MIRAN Infra-red 0.1 Quantitech
monitor, Although the Nelson study has major limitations, it
various provides the only available basis for setting exposure
models limits. A NOAEL of 100 ppm (308 mg.m-3) for nasal
Servomex Infra-red 0.08 Servomex irritancy in human volunteers was indicated by this
P404
portable IR
study. A 90 day gavage study in rats was suggestive of
analyser a NOAEL of 1000 ppm (3080 mg.m-3) for systemic
B&K Type Photoacousti Not given Bruel & effects. The volatility of diethyl ether makes the
1302 c infra-red Kjaer calculation of the effective dose administered in the
multigas
experiment difficult. However, it seems that an 8 hour
monitor
TWA of 100 ppm (308 mg.m-3), derived from
TOXICOKINETICS Nelson’s study would also provide sufficient
protection against systemic effects. To prevent short
Few data are available. Its appreciable water and lipid term exposure to irritant levels a STEL (15 min) of
solubility and its anaesthetising properties indicate 200 ppm (616 mg.m-3) is recommended.
that the vapour is readily absorbed across the
REFERENCES
respiratory tract. Absorption from the gastro-intestinal
tract or following application to the skin would be 1 US National Institute of Occupational Safety and
complicated by the volatility of diethyl ether, and no Health NIOSH (1984) Manual of Analytical Methods
actual data are available. Tissue/air partition 3rd Edition Method (3) 1610 DHHS (NIOSH)
coefficients suggest that absorbed diethyl ether will be Publication
widely distributed around the body. and there are data
in animals to show that it can cross the placenta into 2 SEG/CDO/5A (1991). CEC Criteria document for
the foetus. Information on metabolism is limited, but occupational exposure limit values. Diethyl ether.
suggests that a small percentage of absorbed diethyl Prepared by the Dept. of Environmental Technology,
ether undergoes oxidative hydrolysis to ethanol, Danish Technological Institute.
ethanal and ethanoic acid, thereby entering the carbon
pool. However, most diethyl ether appears to be 3 Nelson KW, Ege JF, Ross M, Woodman LE, and
exhaled rapidly in an unchanged form. Silverman L (1943) Sensory response to certain
industrial solvent vapours J Ind Hyg Toxicol 25 (7)
HEALTH EFFECTS 282-285
Animal studies 4 American Biogenics Corporation (1988). Study
410-2343. Ninety day gavage study in albino rats
The information in this section is taken from the using diethyl ether. Submitted to US EPA, office of
SCOEL summary document SEG/CDO/5A (1991)2. Solid Waste, Washington, DC 20460
72
REVISED OES PROPOSAL
5 Baden, JM, and Simmon, VF, (1980). Mutagenic
activity of inhalational anaesthetics. Mutat. Res. 75,
169 - 189
73
REVISED OES PROPOSAL
Heptan-3-one is a medium-volume solvent with a
HEPTAN-3-ONE production rate less than 1000 tonnes per annum in the
Recommendation of EC Scientific European Community. It is used as a solvent for
Committee on Occupational nitrocellulose and polyvinyl resins.
Exposure Limits
8-hour TWA: 35 ppm (166 mg.m-3) [MEASUREMENT
KEY BIBLIOGRAPHY
[National Institute for Occupational Safety and Health
(1984) Manual of Analytical Methods (3rd Edition)
Method 1301
75
REVISED OES PROPOSAL
OCCURRENCE AND USE
5-METHYLHEXAN-2-ONE MIAK is a high-volume solvent with a production rate
Recommendation of the Scientific greater than 1 000 tonnes per annum in the European
Committee on Occupational Community. It is used as a solvent for
Exposure Limits cellulose-esters, acrylics and copolymers.
76
REVISED OES PROPOSAL
KEY BIBILOGRAPHY
With methyl isoamyl ketone only one subchronic [National Institute for Occupational Safety and Health
inhalation study on rats has been reported (200, 1000 (1984) Manual of Analytical Methods (3rd Edition)
and 2000 ppm; 950, 4750 and 9500 mg.m-3, six hours Method 1301
a day, five days a week for 90 days). Decrease in
aural response, lethargy and histological changes in Methods for the determination of hazardous
the liver and kidney were observed at 1000 ppm (4 substances (MDHS) 72 Volatile organic compounds
750 mg.m-3) and 2000 ppm (9500 mg.m-3). From this in air - Laboratory method using pumped solid
study (Katz et al., 1986) it may be deduced that the sorbent tubes, thermal desorption and gas
critical targets are the central nervous system, kidney chromatography ISBN 0 11 885692 8 HSE Books
and liver, and that the NOAEL is 200 ppm (950 (1992)]
mg.m-3).
De Ceaurriz, J., Micillino, J. C., Marignac, B.,
Bonnet, P., Muller, J. and Guenier, J.P. (1984)
The only observation in man is that MIAK showed no
‘Quantitative evaluation of sensory irritating and
positive reaction in a sensitization study on human
neurobehavioural properties of alphatic ketones in
volunteers.
mice’, Fd. Chem. Toxicol., 22, pp. 545-549.
77
REVISED OES PROPOSAL
R20: Harmful by inhalation
4-METHYLPENTAN-2-ONE R36/37: Irritating to eyes and the respiratory
Recommendation of the EC system
Scientific Committee on R66: Repeated exposure may cause skin
Occupational Exposure Limits
dryness or cracking
-3
8 hour TWA: 20 ppm (83 mg.m )
STEL (15 mins): 50 ppm (208 mg.m-3) OCCURRENCE AND USE
occupational exposure standard MIBK is a high volume industrial solvent with a
production rate in the European Community greater
Notation: Skin
than 1000 tonnes per annum. It is mainly used as a
Biological monitoring Health Guidance solvent in glues, paints, and cleaners, but also as a
Value: 20 µmol 4-methylpentan-2-one/l in solvent for some plastics and various fats, oils and
post urine shift samples waxes. Frequently, MIBK is used in combination with
subject to consultation other solvents such as toluene.
78
REVISED OES PROPOSAL
MIBK shows a low acute toxicity by oral However, the SEG agreed that the symptoms were
administration to animals (rats, mice ; LD50 >2000M subjective and decided that, in the absence of a
mg.kg-1). A mouse LC50 value of 18100 ppm (75296 dose-related response, the evidence for effects at these
mg.m-3) for a 45 minute exposure period has been concentrations was not convincing. The Armali study
determined. was therefore used as the basis for setting the limits.
79
REVISED OES PROPOSAL
Hagberg M. (1988): Methylisobutyl Ketone.In:
Heimbürger G. and P.Lundberg (eds), Criteria
documents from the Nordic Expert Group. Arbete och
Hälsa, 33, 53-76.
80
REVISED OES PROPOSAL
1994 (CHIP) as Irritant, to be labelled with the
TETRAHYDROFURAN following risk (R) phrases:
81
REVISED OES PROPOSAL
Inhalation studies in animals indicate that the mucous required. Additional information on human effects
membranes of the eyes and respiratory tract, and the should be obtained.
central nervous system are the critical target tissues. At the levels recommended, no measurement
Liver and kidney damage have also been noted. difficulties are foreseen.
Although there are no controlled human studies,
comparable effects have been observed in reports on
workers exposed to THF vapour. BIBLIOGRAPHY
Concentration-related effects on nasal and tracheal Methods for the determination of hazardous
ciliary beating have been reported, with minimal, substances MDHS 72 Volatile organic compounds in
transient, effects of 100 and 250 ppm (300 and 750 air - Laboratory method using pumped solid sorbent
mg.m-3) (Ikeoka et al, 1984; Ohashi et al, 1983). tubes, thermal desorption and gas chromatography
Exposure of rats to 200 ppm (600 mg.m-3) for 3 hours ISBN 0 11 885692 8 HSE Books (1992)
also caused slight irritation of the nose and eyes
(Katahira et al, 1982a). CNS effects have been Ong CN, Chia SE et al (1991) Biological monitoring
observed following exposure of rats to 3000 ppm of occupational exposure to tetrahydrofuran Br J Ind
(9000 mg.m-3) 3 h/day, 5 days/week for 8 weeks Med 48, 616-621
(Kawata et al, 1986). Increases in serum enzymes,
indicative of liver damage, have been observed in rats
exposed to THF at 1000 ppm (3000 mg.m-3) 4h/day, 5 ACGIH (1989). Threshold Limit Values and
days/week for 12 weeks (Katahira et al, 1982b). Biological Exposure Indices for 1989-1990.
Similar indications have been seen in workers exposed American Conference of Government Industrial
to THF vapour at less than 1000 ppm (3000 mg.m-3) Hygienist, Cincinnati, Ohio.
(Horiushi et al, 1967). A 13 week inhalation study,
conducted by Chhabra et al (1990), identified Chhabra, R S, Elwell, M R, Chou, B, Miller, R A and
NOAELs for systemic effects (CNS and liver Renne, R A (1990). Sub chronic toxicity of
damage), of 1800 ppm (5400 mg.m-3) in rats and 600 tetrahydrofuran vapours in rats and mice. Fund.
ppm (1800 mg.m-3) in mice. Thus, 100 ppm (300 Appl. Toxicol 14, 338-345.
mg.m-3) may be considered as the minimal effect level.
THF may lower the threshold for epileptic seizures.
DFG (1989). Maximum concentrations at the
workplace and biological tolerance values for working
RECOMMENDATIONS materials 1989. Report XXV Commission for the
Studies showing reduction in ciliary beating (Ikeoka et investigation of health hazards of chemical
al, 1984; Ohashi et al, 1983) and irritation of the nose compounds in the work area. Deutsche
and eyes of the rat (Katahari et al, 1982a) established Forschungsgemeinschaft. VCH, Weinheim, Germany.
a lowest observed effect level of 100 ppm (300
Horiushi, K, Horigushi, S, Utsunomiya, T, Shinagawa,
mg.m-3) and were considered to be the best available
K, Nakagawa, T, Takada, F, Deguchi, T, Okada, H,
basis for setting exposure limits. An uncertainty
Kawasaki, N, Murakami, Y and Kuroda, Y. (1967).
factor of 2 was considered to be appropriate in view of
Toxicity of an organic solvent, tetrahydrofuran, on the
the transient nature of the minimal effects observed.
basis of industrial health studies at a certain factory.
The recommended 8-hour TWA is 50 ppm (150
Sumitomo Bulletin of Industrial Health, No 3m-49-56.
mg.m-3). To prevent short term exposure to irritant
levels an STEL (15 mins) of 100 pm (300 mg.m-3) is
Ikeoka, H, Ohashi, Y, Maruoka, K, Nataka, J,
recommended.
Masutani, H, Nakai, Y, Horigushi, S, and Teramoto,
Skin penetration may make a substantial contribution K (1984). Effects of tetrahydrofuran exposure on the
to the total body burden so a skin notation is also ciliary activity and morphology of tracheal epithelium
in rabbits. Osaka City Med, J, 30, 53-67.
82
REVISED OES PROPOSAL
83
APPENDIX 4
1. It is Government policy that the costs of all new or revised regulation must be
assessed. Since 1982 the Health and Safety Commission (HSC) has required cost benefit
assessments (CBAs) to be undertaken for all major proposals for health and safety
regulations unless the costs resulting from their introduction are negligible. This approach has
also been extended to the consultation period for Occupational Exposure Limits (OELs).
Since October 1998, costs and benefits are discussed in the regulatory impact assessment
(RIA) framework.
3. On the other side of the scale, quantifying the benefits of an OEL also poses some
particular problems. Quantification is normally based upon how far the OEL reduces the risk
to employees exposed using dose-effect information. However, for substances such as
carcinogens the dose-effect relationship is commonly not established, and alternative ways of
deriving a monetary value to represent the benefits of setting OELs have been developed.
4. In addition, there are a number of underlying benefits that can accrue from the
introduction of an OEL and lead to more general improvements in worker protection but
cannot easily be quantified. Such benefits are often less tangible, longer term, or relate to the
general principles of introducing an OEL rather than to its specific level. They may also lead
to consequential improvements in productivity, reduction in product loss and improvements
in employee recruitment and retention, some of which are difficult to quantify. These
potential benefits include factors such as:
84
w Defining a level playing field for all users.
w Defining adequate control.
w Providing clearer guidance on the level considered to be reasonably
practicable.
w Providing a standard for new users.
w Reducing/ limiting scope of 'discretion' by enforcing authority.
w Providing consistency with international developments.
w Reinforcing/ improving good practice.
w Encouraging/ stimulating proper reporting of ill-health.
w Promoting more effective health surveillance.
w Reducing ambient air contamination generally.
85
APPENDIX 4A
86
Phenol Phenol is not manufactured in Great Britain, but is used
extensively with some 70 - 80,000 people exposed in total.
The major applications (with best estimates of numbers
exposed) are: supply and transportation (250 exposed);
chemical synthesis, including resin manufacture (ca 12
companies, <200 exposed); paint stripping - aircraft (20
sites, 200 exposed); use of phenolic resins (large number of
sites, 40,000 exposed); foundry sand binders (900 foundries,
up to 33,000 exposed). Health benefits arising from a MEL
would be a reduction in the risk of mutagenic effects,
however, this is not quantifiable as there is no conclusive
evidence regarding dose and effects.
The cost to industry overall in complying with a MEL of 2
ppm (8 hr TWA) are estimated to lie in the range £606k to
£1622k (over ten-years in present value terms). The average
costs of around £15 per employee are considerably lower
than for many other substances with concerns about
genotoxicity. The foundries sector is the major contributor
to the estimated costs, however, the average cost is still
estimated to be less than £50 per employee.
1st Consolidated Indicative Costs are attributable to cyclohexanone and diethyl ether.
Occupational Exposure Limit Costs are also attributable to phenol and o-xylene, m-xylene,
Values (IOELV) Directive p-xylene, xylene mixed isomers, butoxyethanol, and
5-methylheptan-3. Total one-off costs, as a result of capital
expenditure, are estimated to be about £0.4 million
(1999/2000 prices), while the ten-year present value of the
recurring costs is £8.8 million (1999/2000 prices). Recurring
costs are incurred mainly as a result of increased use of
respiratory protective equipment and increased monitoring to
check compliance with the new limit. Thus, the total cost to
society of implementing the whole Directive is £9.2 million
(1999/2000 prices) over 10 years, in present value terms. The
RIA could not quantify any of the health benefits resulting
from the introduction of this Directive. However, it was
noted that there are negative health effects associated with
exposure to the substances covered by the Directive and that
reducing exposure may lead to health benefits.
87
APPENDIX 5
1. We would like you to tell us what you think about the proposals set out in this
consultative document. The proposals are summarised below in a questionnaire which you
may wish to copy or tear out and use. You may wish to attach a separate sheet if your
comments are extensive.
2. When replying, you may also wish to bear in mind the legal advise on implementation
of the IOELV Directive. This advice is outlined in paragraphs 4 and 5 of the consultation
document.
3. The Commission tries to make its consultation procedure as thorough and open as
possible. Responses to this consultative document will be lodged with HSE’s Information
Centres after the close of the consultation period where they can be inspected by members of
the public. Please note: All views will be placed in HSE Information Centres unless you
specifically state that this response, or a part of it, should be treated as confidential.
Carole Sullivan
Health Directorate, Chemicals Policy Division
Health and Safety Executive
6th Floor, South Wing, Rose Court
2 Southwark Bridge
London SE1 9HS
e mail: carole.sullivan@hse.gsi.gov.uk
88
Health and Safety Commission
Reply form
(Please type, or write in block capitals)
....................................................................................................................................................
Question Comment
1. Do you agree with the 8 hour TWA MEL
proposal for chlorobenzene?
89
2. Do you agree with the STEL MEL
proposal for chlorobenzene?
90
7. Do you agree that it is not necessary to
set a STEL MEL for phenol?
91
12. Do you agree with the proposal to
develop a BMGV for xylenes?
92
17. Do you agree with the Sk notation
proposal for 2-Methoxy-1-methylethyl
acetate?
93
21. Do you have any further information or
views that are relevant to this consultation?
94
CONSULTATIVE
DOCUMENT
The full text of this and other Consultative Documents can be viewed
and downloaded from the Health and Safety Executive web site on the internet:
www.hse.gov.uk/condocs/