Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
3.25 mg/m³
Most sensitive endpoint:
carcinogenicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
other: BOELV for benzene
Value:
3.25 mg/m³
Explanation for the modification of the dose descriptor starting point:
None applied
AF for dose response relationship:
1
Justification:
The BOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)
AF for differences in duration of exposure:
1
Justification:
The BOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)
AF for interspecies differences (allometric scaling):
1
Justification:
The BOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)
AF for other interspecies differences:
1
Justification:
The BOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)
AF for intraspecies differences:
1
Justification:
The BOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)
AF for the quality of the whole database:
1
Justification:
The BOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)
AF for remaining uncertainties:
1
Justification:
The BOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
23.4 mg/kg bw/day
Most sensitive endpoint:
carcinogenicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
other: BOELV for benzene
Value:
23.4 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The BOELV (mg/m3) was converted into a human dermal DNEL (mg/kg bwt/d) by adjusting for differences in uptake between the two routes of exposure (REACH Guidance, Appendix R.8-2, Example B.4).
AF for dose response relationship:
1
Justification:
The BOELV (8-hr) was used as the starting point
AF for differences in duration of exposure:
1
Justification:
The BOELV (8-hr) was used as the starting point
AF for interspecies differences (allometric scaling):
1
Justification:
The BOELV (8-hr) was used as the starting point
AF for other interspecies differences:
1
Justification:
The BOELV (8-hr) was used as the starting point
AF for intraspecies differences:
1
Justification:
The BOELV (8-hr) was used as the starting point
AF for the quality of the whole database:
1
Justification:
The BOELV (8-hr) was used as the starting point
AF for remaining uncertainties:
1
Justification:
The BOELV (8-hr) was used as the starting point
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Compositional information:

These hydrocarbon streams meet the regulatory definition of UVCB substances, with inherent variations in composition present due to differences in manufacturing history. This variability is documented in the Category Justification, which lists the chemical marker substances present along with an indicative concentration range for each e.g.

·        Benzene: up to 30%

·        Toluene: up to 20%

·        Ethylbenzene: up to 15%

·        Styrene: up to 15%

·        Naphthalene: up to 60%

·        Anthracene: up to 5%

Uses:

These hydrocarbon streams are used as intermediates, in manufacture and as fuels and hence exposure includes both workers and the general population. These DNELs address concerns linked to the CMR properties of the marker substances or their potential to cause other long-term health effects leading to an equivalent level of concern.

Substance selection for risk characterization:

Risk characterization will be based on the premise that a marker substance with a low DN(M)EL present at high concentration in a stream will possess a greater relative hazard potential than a marker substance with a higher DN(M)EL present at the same or lower concentration. It will also focus on the potential of the markers to cause serious long-term health effects rather than on short-term or irritation-related changes.

Against this background, the most hazardous marker substances present are highlighted in the following table (details of DN(M)EL calculations follow the table):

Marker substance

Indicative concentration

 

(%)

Inhalation

Dermal

DN(M)EL

 

mg/m3

Relative hazard potential

(max % ÷ DN(M)EL)

DN(M)EL

 

mg/kg bw/d

Relative hazard potential

(max % ÷ DN(M)EL)

benzene

<30

3.25

9.23

23.4

1.28

toluene

<20

192

0.10

384

0.05

ethylbenzene

<15

77

0.19

180

0.08

styrene

<15

85

0.18

406

0.04

naphthalene

<60

25

2.40

3.57

16.81

anthracene

<5

low systemic toxicity, no DNELs required

Based on this analysis, demonstration of “safe use” for hazards associated with inhalation exposure to benzene and dermal exposure to naphthalene would also provide adequate protection for workers against hazards arising from other marker substances present. However since benzene is a proven human carcinogen, it is concluded that it would be more prudent to conduct risk characterisation using this substance alone.

Intrinsic hazards of marker substances and associated DN(M)ELs:

The following hazard information and DNELs are available for marker substances present in this Category.

Benzene

Benzene causes adverse effects on the haematopoietic system of animals and in humans after repeated dose exposure via oral or inhalation routes. Long term experimental carcinogenicity bioassays have shown that it is a carcinogen producing a variety of tumours in animals (including lymphomas and leukaemia). Human epidemiological studies provide clear and consistent evidence of a causal association between benzene exposure and acute myelogenous (non-lymphocytic) leukaemia (AML or ANLL). An effect on bone marrow leading to subsequent changes in human blood cell populations is believed to underpin this response.

In accordance with REACH guidance, a science-based Binding Occupational Exposure Limit value (BOELV) can be used in place of a formal DN(M)EL providing no new scientific information exists which challenges the validity of the BOELV. While some information regarding a NOAEC for effects of benzene on human bone marrow (Schnatter et al, 2010; NOAEC = 11.18 mg/m3) post-date the BOELV, a DNEL based on these bone marrow findings would be higher than the BOELV. The BOELV (EU, 1999) will therefore be used as the basis of the DN(M)EL for long-term systemic effects associated with benzene, including carcinogenicity.

Worker – long-term systemic inhalation DNEL

The BOELV will be used with no further modification

DN(M)ELl-t inhalation= 3.25 mg/m3

Worker - long-term systemic dermal DNEL

The dermal DNEL for benzene is based on the internal dose achieved by a worker undertaking light work and exposed to the BOELV for 8 hr, assuming 50% uptake by the lung and 1% by skin for benzene uptake from petroleum streams. The value of 1% is based on experiments with compromised skin and with repeated exposure (Blank and McAuliffe, 1985; Maibach and Anjo, 1981) as well as the general observation that vehicle effects may alter the dermal penetration of aromatic compounds through the skin (Tsuruta et al, 1996). As the BOELV is based on worker life-time cancer risk estimates no assessment factor is needed.

Dermal NOAEL = BOELV x wRV8-hourx [ABSinhal-human/ ABSdermal-human] = 3.25 x 0.144 x [50 / 1]

DN(M)ELl-t dermal= 23.4 mg/kg bw/d

Toluene

Toluene exposure can produce central nervous system pathology in animals after high oral doses. Repeated inhalation exposure can produce ototoxicity in the rat and high concentrations are associated with local toxicity (nasal erosion). In humans neurophysiological effects and disturbances of auditory function and colour vision have been reported, particularly when exposures are not well controlled and/or associated with noisy environments.

Documentation supporting the IOELV (SCOEL, 2001) concluded that an exposure limit of 50 ppm (192 mg/m3) would protect against chronic effects. Hence, in accordance with REACH guidance and since no new scientific information has been obtained under REACH which contradicts use of the IOELV for this purpose, the established IOELV of 50 ppm (192 mg/m3) – 8 hr TWA (EU, 2006) will be used as the starting point for calculating the chronic dermal DNEL for workers.

Worker – long-term systemic inhalation DNEL

The IOELV will be used with no further modification

DN(M)ELl-t inhalation= 192 mg/m3

Worker – long-term systemic dermal DNEL

The dermal DNEL for toluene is based on the internal dose achieved by a worker undertaking light work and exposed to the IOELV for 8 hr, assuming 50% uptake by the lung and 3.6% uptake by skin (ten Berge, 2009).

As the IOELV is based on worker life-time exposure no assessment factor is needed.

Dermal NOAEL = IOELV x wRV8-hourx [50 / 3.6] = [192 x 0.144 x 13.89]

DN(M)ELl-t dermal= 384 mg/kg bw/d

Ethylbenzene

The cooperation of the Styrenics Steering Committee in providing DNELs for ethylbenzene is acknowledged. Documentation supporting these values is in the Styrenics REACH consortium dossier for ethylbenzene.

Worker – long-term systemic inhalation DNEL

There is no IOELV for ethylbenzene, therefore the DNEL is based on sub-chronic effects (ototoxicity) in the rat following inhalation exposure: extrapolated NOAEC = 500 mg/m3(114 ppm). Correct the NOAEC to adjust for activity driven and absorption percentage differences following ECHA TGD (2008) guidance:

DN(M)ELl-t inhalation= 500 mg/m3x [6.7 / 10] x [ABSinhal-rat/ ABSinhal-human] = 500 mg/m3x [6.7 / 10] x [45 / 65] = 232 mg/m3

An assessment factor of 3 is used for intraspecies differences within worker population:

DN(M)ELl-t inhalation= 232 mg/m3/ 3 = 77 mg/m3

Worker – long-term systemic dermal DNEL

The DNEL is based on sub-chronic effects (ototoxicity) in the rat following inhalation exposure: extrapolated NOAEC = 500 mg/m3 (114 ppm). The NOAEC is corrected into a human dermal NOAEL (mg/kg bw/d) by adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.4). It is assumed that uptake of ethylbenzene after inhalation in rats is 45%.

correctedDermal NOAEL = NOAECl-t inhalationx sRVrat-8hrx 0.45 = 500 x 0.38 mg/kg bw/d = 86 mg/kg bw/d

A value of 4% used for dermal absorption in humans (Susten et al, 1990):

correctedDermal NOAEL = 86 mg/kg bw/d x [100 / 4] = 2150 mg/kg bw/d

An assessment factor of 12 is used based on interspecies differences for the rat (4) and intraspecies differences within worker populations (3).

The DNEL for long-term dermal exposure is derived as follows:

DN(M)ELl-t dermal= 2150 mg/kg bw/d / 12 = 180 mg/kg bw/d

Styrene

The cooperation of the Styrenics REACH consortia in providing DN(M)ELs for styrene is acknowledged. Documentation supporting these values is in the Styrenics REACH consortium dossier for styrene.

The EU transitional RAR (EU, 2008c) identified the following end-points as of concern for human health: acute toxicity (CNS depression), skin, eye and respiratory tract irritation, effects on colour vision discrimination following repeated exposure, effects on hearing (ototoxicity) following repeated exposure, developmental toxicity. 

Worker – long-term systemic inhalation DNEL

The DN(M)EL is based on ototoxicity in humans(Triebig et al, 2009). A NOAEC for humans of 20 ppm (85 mg/m3) can be derived as starting point from this study. As the DNEL is derived from studies on exposed workers an assessment factor is not necessary.

DN(M)ELl-t inhalation= 85 mg/m3

Worker – long-term systemic dermal DNEL

The DN(M)EL is based on long term inhalation NOAEC of 20 ppm (86 mg/m3) for ototoxicity in workers. The dose descriptor is corrected into a human dermal NOAEL. Using a respiratory volume for workers under light physical activity of 10 m3/person/day and a body weight of 70 kg (ECHA, 2008) the external exposure would be 86 x 10/70 = 12.3 mg/kg bw/d.

This is then converted to a dermal dose by adjusting for differences in exposure. Absorption of styrene from the respiratory tract is considered to be 66% based on a study in 7 volunteers at 50 ppm under light physical activity (50 Watt) (Engström et al, 1978). In humans only 2% of a dermal dose of liquid styrene is likely to be absorbed (EU, 2008). 

Dermal NOAEL = 12.3 x [ABSinhal-human/ ABSdermal-human]

= 12.3 x [66/2]

= 406 mg/kg/d.

Since the worker-DNEL long-term for dermal exposure was directly derived from that for inhalation exposure no further assessment factors are necessary.

DN(M)ELl-t dermal= 406 mg/kg bw/d

Naphthalene

The cooperation of the REACH for Coal Chemicals (R4CC) consortium in permitting access to DNEL information present on the ECHA Dissemination pages for naphthalene is acknowledged.

 

Worker – long-term systemic inhalation DNEL

The long-term systemic DNEL for naphthalene is based upon (EU and USA) OEL values of generally 50 mg/m3, with an assessment factor of 2:

 

DN(M)ELl-t inhalation= 50 mg/m3/ 2 = 25 mg/m3

 

Worker – long-term systemic dermal DNEL

The long-term dermal DNEL is based upon the systemic dose achieved following 8 hr exposure at the DNEL of 25 mg/m3.

 

DN(M)ELl-t dermal= 3.57mg/kg bw/d

Anthracene

The toxicological properties of anthracene have been reviewed (EU RAR, 2009), with a conclusion that it is of low toxicity following repeated exposure (NOAEC of 1000 mg/kg/day in mouse oral toxicity study) and is not of concern for mutagenicity or carcinogenicity. Although data are lacking with respect to reproductive and developmental toxicity no detectable toxic effects on the reproductive system of mice were seen during a 90-day feeding study and it was concluded that anthracene may possess weak, if any, developmental toxicity. However, extensive studies in animals and humans demonstrate that anthracene possess phototoxic potential following exposure in combination with UV light.

Based on the lack of systemic toxicity no substance-specific DNELs will therefore be developed for this marker substance. It is considered that the low concentration of anthracene present in this stream would not impact on the overall toxicity assessment and that risk management measures and occupational controls intended to minimise human exposure to the other toxicologically-active marker substances also present would limit exposure to anthracene.

References

ASTDR (2005). Toxicological profile for naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. http://www.atsdr.cdc.gov/toxprofiles/tp67.pdf

Blank IH, McAuliffe DJ (1985). Penetration of benzene through human skin. J. Invest. Dermatol, 85, 522–526.

EU (1999). Council Directive 1999/38/EC of 29 April 1999 amending for the second time Directive 90/394/EEC on the protection of workers from the risks related to exposure to carcinogens at work and extending it to mutagens. Official Journal of the European Communities, L138, 66-69, 1 June 1999.

EU (2003b). Risk assessment report for naphthalene. http://ecb.jrc.ec.europa.eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/naphthalenereport020.pdf

EU (2006). Directive 2006/15/EC of 7 February 2006 establishing a second list of indicative occupational exposure limit values in implementation of Council Directive 98/24/EC and amending Directives 91/322/EEC and 2000/39/EC. Official Journal of the European Union, l 38, 36-39.

EU (2009). Anthracene (CAS No 120-1207; EINECS No 204-371-1): Summary risk assessment report, October 2009. Available from: http://ecb.jrc.ec.europa.eu/risk-assessment/

Maibach HI, Anjo DM (1981). Percutaneous penetration of benzene and benzene contained in solvents used in the rubber industry. Arch. Environ. Health 36, 256–260

Schnatter AR, Kerzic P, Zhou Y, Chen M, Nicolich M, Lavelle K, Armstrong T, Bird M, Lin l, Hua F and Irons R (2010). Peripheral blood effects in benzene-exposed workers. Chem Biol Interact (2009) doi:10.1016/j. cbi.2009.12.020.

SCOEL (2001). Recommendation from the Scientific Committee on Occupational Exposure Limits for toluene 108-88-3 http://ec.europa.eu/social/BlobServlet?docId=3816&langId=en

Susten AS,Niemeier RW and Simon SD (1990). In vivo percutaneous absorption studies of volatile organic solvents in hairless mice II; Toluene, ethylbenzene and aniline. J. Appl. Toxicol. 10: 217-225.

Tsuruta, H (1996). Skin absorption of solvent mixtures-effect of vehicle on skin absorption of toluene. Ind. Health, 34, 369–378.

ten Berge, W (2009). A simple dermal absorption model: Derivation and application. Chemosphere, 75, 1440-1445.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
3.25 µg/m³
Most sensitive endpoint:
carcinogenicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: The value that is proposed is based on a modification of the approach used by WHO (2000) which combined estimates of excess risk for leukaemia calculated by Crump (1994) for four models into a geometric mean estimate.
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
other: The Crump (1994) estimate of excess risk for AMML was substituted by estmates from TCEQ (2007), giving a median risk estimate of 0.9 x 10-5 per 1 ppb (3 x 10-6 per 1 µg/m3).
Value:
3.25 µg/m³
Explanation for the modification of the dose descriptor starting point:
None applied
AF for dose response relationship:
1
Justification:
Excess risk estimates were based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984). No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for differences in duration of exposure:
1
Justification:
Excess risk estimates were based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984). No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
Excess risk estimates were based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984). No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for other interspecies differences:
1
Justification:
Excess risk estimates were based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984). No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for intraspecies differences:
1
Justification:
Excess risk estimates were based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984). No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for the quality of the whole database:
1
Justification:
Excess risk estimates were based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984). No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for remaining uncertainties:
1
Justification:
Excess risk estimates were based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984). No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
464 µg/kg bw/day
Most sensitive endpoint:
carcinogenicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
other: The inhalatory DMEL (ug/m3) was converted into a human dermal DMEL (ug/kg bwt/d) by adjusting for differences in uptake between the two routes of exposure (REACH Guidance, Appendix R.8-2, Example B.4).
Value:
464 µg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The inhalatory DMEL (ug/m3) was converted into a human dermal DMEL (ug/kg bwt/d) by adjusting for differences in uptake between the two routes of exposure (REACH Guidance, Appendix R.8-2, Example B.4).
AF for dose response relationship:
1
Justification:
Excess risk estimates based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984), were used as the starting point. No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for differences in duration of exposure:
1
Justification:
Excess risk estimates based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984), were used as the starting point. No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
Excess risk estimates based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984), were used as the starting point. No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for other interspecies differences:
1
Justification:
Excess risk estimates based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984), were used as the starting point. No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for intraspecies differences:
1
Justification:
Excess risk estimates based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984), were used as the starting point. No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for the quality of the whole database:
1
Justification:
Excess risk estimates based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984), were used as the starting point. No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for remaining uncertainties:
1
Justification:
Excess risk estimates based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984), were used as the starting point. No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.464 mg/kg bw/day
Most sensitive endpoint:
carcinogenicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
other: The inhalatory DMEL (ug/m3) was converted into a human oral DMEL (ug/kg bwt/d) by adjusting for differences in uptake between the two routes of exposure (REACH Guidance, Appendix R.8-2, Example B.4).
Value:
0.464 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The inhalatory DMEL (ug/m3) was converted into a human oral DMEL (ug/kg bwt/d) by adjusting for differences in uptake between the two routes of exposure (REACH Guidance, Appendix R.8-2, Example B.4).
AF for dose response relationship:
1
Justification:
Excess risk estimates based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984), were used as the starting point. No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure
AF for differences in duration of exposure:
1
Justification:
Excess risk estimates based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984), were used as the starting point. No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure
AF for interspecies differences (allometric scaling):
1
Justification:
Excess risk estimates based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984), were used as the starting point. No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure
AF for other interspecies differences:
1
Justification:
Excess risk estimates based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984), were used as the starting point. No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure
AF for intraspecies differences:
1
Justification:
Excess risk estimates based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984), were used as the starting point. No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure
AF for the quality of the whole database:
1
Justification:
Excess risk estimates based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984), were used as the starting point. No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure
AF for remaining uncertainties:
1
Justification:
Excess risk estimates based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984), were used as the starting point. No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Compositional information:

These hydrocarbon streams meet the regulatory definition of UVCB substances, with inherent variations in composition present due to differences in manufacturing history. This variability is documented in the Category Justification, which lists the chemical marker substances present along with an indicative concentration range for each e.g.

·        Benzene: up to 30%

·        Toluene: up to 20%

·        Ethylbenzene: up to 15%

·        Styrene: up to 15%

·        Naphthalene: up to 60%

·        Anthracene: up to 5%

Uses:

These hydrocarbon streams are used as intermediates, in manufacture and as fuels and hence exposure includes both workers and the general population. These DNELs address concerns linked to the CMR properties of the marker substances or their potential to cause other long-term health effects leading to an equivalent level of concern.

Substance selection for risk characterization:

Risk characterization will be based on the premise that a marker substance with a low DN(M)EL present at high concentration in a stream will possess a greater relative hazard potential than a marker substance with a higher DN(M)EL present at the same or lower concentration. It will also focus on the potential of the markers to cause serious long-term health effects rather than on short-term or irritation-related changes.

According to REACH Annex XVII, benzene shall not be placed on the market as a constituent of other substances, or in mixtures, in concentrations>0.1% by weight with the exception of motor fuels which are the subject of a separate directive (98/70/EC).

Against this background, the most hazardous marker substances present are highlighted in the following table (details of DN(M)EL calculations follow the table):

Marker substance

Indicative concentration

 

(%)

Inhalation

Dermal

Oral

DN(M)EL

 

mg/m3

Relative hazard potential

(max % ÷ DN(M)EL)

DN(M)EL

 

mg/kg bw/d

Relative hazard potential

(max % ÷ DN(M)EL)

DN(M)EL

 

mg/kg bw/d

Relative hazard potential

(max % ÷ DN(M)EL)

benzene

<30

0.00325

9231

0.464

64.6

0.0464

646

toluene

<20

56.5

0.35

226

0.09

8.13

2.46

ethylbenzene

<15

14.8

1.01

108

0.14

1.60

9.37

styrene

<15

10.2

1.47

343

0.04

2.1

7.1

naphthalene

<60

no hazard identified, no DNELs required

anthracene

<5

low systemic toxicity, no DNELs required

For the general population the long term inhalation, dermal and oral DMELs for benzene appear relevant for risk characterization. The DMEL for benzene will also be used for exposure of man via the environment.

Intrinsic hazards of marker substances and associated DN(M)ELs:

The following hazard information and DNELs are available for marker substances present in this Category.

Benzene

Epidemiology studies provide clear and consistent evidence of a causal association between benzene exposure and acute myelogenous (non-lymphocytic) leukaemia (AML or ANLL). IARC (Baan et al., 2009) has recently concluded that, although there is “sufficient” evidence for an increased risk of AML/ANLL in humans, there is only “limited” or “inadequate” evidence of carcinogenicity in humans for other types of leukaemia. An effect of benzene on bone marrow leading to subsequent changes in human blood cell populations is believed to underpin this response. The long-term systemic DN(M)EL for benzene will therefore be based upon the following information:

Human chronic toxicity (Schnatter et al., 2010): NOAEC = 11.18 mg/m3

Human carcinogenicity (Crump, 1994; WHO, 2000; TCEQ, 2007) = 3.25 µg/m3.

References:

Crump KS (1994). Risk of benzene-induced leukemia: a sensitivity analysis of the Pliofilm cohort with additional follow-up and new exposure estimates. J Toxicol Environ Health 42, 219-242.

WHO (2000) Air Quality Guidelines for Europe, Second Edition. WHO regional publications, European series; No. 91.

TCEQ (2007). Texas Commission on Environmental Quality. Development Support Document. Benzene. Chief Engineer’s Office. Available: http: //tceq. com/assets/public/implementation/tox/dsd/final/benzene_71-43-2_final_10-15-07.pdf

The value that is proposed is based on the approach used by WHO (2000) which combined estimates of excess risk for leukaemia calculated by Crump (1994) for four models into a geometric mean estimate. The same four models were used for the derivation of this DMEL but estimates of excess risk for acute myelogenous or acute monocytic leukaemia (AMML) calculated by Crump (1994) were used instead of those for leukaemia. For three of the four models, excess risk estimates calculated by Crump (1994) were used. A more recent estimate of excess risk was available for one model (TCEQ, 2007) and this was used instead of the estimate calculated by Crump (1994). The value of 3.25 µg/m3(1 ppb) is protective against haematotoxicity, genotoxicity and carcinogenicity and results in a geometric mean excess lifetime risk of AMLL of 0.9 x 10-5.

While information regarding the NOAEC for effects on human bone marrow post-date WHO (2000), a DNEL based on these bone marrow (threshold) findings would be higher (and hence offer less protection) than one based on AMML. It is also the case that it is not possible to ascribe precise concentrations of benzene to the occurrence of human myelodysplastic syndrome, precluding use of this information for development of a DN(M)EL.

As a consequence, a DMEL for benzene of 1.0 ppb (3.25 µg/m3) is proposed. This value is lower than the air quality limits of 10 µg/m3and 5 µg/m3that were established for benzene in subsequent European Directives 2000/69/EC and 2008/50/EC, respectively.

General population - long-term systemic inhalation DNEL

Dose descriptor

The inhalation DMEL will be used with no further modification.

DN(M)ELl-t inhalation= 3.25 µg/m3

General population - long-term systemic dermal DNEL

Dose descriptor

The inhalation DMEL of 3.25 µg/m3will be used.

Modification of dose descriptor

Convert the inhalation DMEL into a human dermal NOAEL (mg/kg bw/d) after adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.4).

It is assumed that uptake of benzene after inhalation is approximately 50% while dermal absorption is only 0.1% (Modjtahedi and Maibach, 2008).

sRV24 -hour (20 m3) and body weight (70 kg) are based on REACH defaults.

Dermal LOAEL = [AQS x sRV24-hour x [ABSinhal-human/ABSdermal-human]] / body weight

= 3.25 x 20 x 500 / 70 = 464 µg/kg bw/d

Assessment factors

As the AQS is based on general population life-time exposure no assessment factor is needed.

DN(M)ELl-t dermal = 464 µg/kg bw/d

General population - long-term systemic oral DNEL

Dose descriptor

The inhalation DMEL of 3.25 µg/m3will be used.

Modification of dose descriptor

Correct the inhalation DMEL to an oral NOAEL (mg/kg/day) by converting the dose absorbed after inhalation into a systemic dose, assuming 50% uptake by the lung and 100% uptake from the GI tract, a sRV24 -hour of 20 m3and body weight of 70 kg (REACH TGD, Appendix R.8 -2):

Oral NOAEL = [AQS x sRV24 -hour x [50/100]] / body weight

= 3.25 x 20 x 0.5 / 70 = 0.464 µg/kg bw/d

Assessment factors

As the inhalation DMEL is based on general population life-time exposure no assessment factor is needed.

DN(M)ELl-t oral = 0.464 µg/kg bw/d

Toluene

Toluene exposure can produce central nervous system pathology in animals after high oral doses. Repeated inhalation exposure can produce ototoxicity in the rat and high concentrations are associated with local toxicity (nasal erosion). In humans neurophysiological effects and disturbances of auditory function and colour vision have been reported, particularly when exposures are not well controlled and/or associated with noisy environments.

Documentation supporting the IOELV (SCOEL, 2001) concluded that an exposure limit of 50 ppm (192 mg/m3) would protect against chronic effects. Hence, in accordance with REACH guidance and since no new scientific information has been obtained under REACH which contradicts use of the IOELV for this purpose, the established IOELV of 50 ppm (192 mg/m3) – 8 hr TWA (EU, 2006) will be used as the starting point for calculating the chronic dermal DNEL for workers.

General population – long term systemic inhalation DNEL

Long-term inhalation systemic DNEL is based on the IOELV after adjusting for differences in respiratory volume between workers (light exercise) and the general population (at rest), with an assessment factor of 1.7 used to account for intraspecies differences. The assessment factor of 1.7 is based on the ratio of intra-species differences for worker (AF = 3) and general population (AF = 5) groups reported in ECETOC (2003).

Inhalation NOAEL = IOELV x (wRV8-hour/ sRV24-hour) = 192 x (0.144 / 0.288) = 96 mg/m3

DN(M)ELl-t inhal= 96 mg/m3/ 1.7 = 56.5 mg/m3

General population – long-term systemic dermal DNEL

The long-term dermal systemic DNEL is based on the IOELV using route-to-route extrapolation after adjusting for differences in respiratory volume between workers (light exercise) and the general population (at rest).

Dermal NOAEL = IOELV x wRV8-hourx 50 / 3.6 = 192 x 0.144 x 13.89 = 384 mg/kg bw

An assessment factor of 1.7 is used to account for intraspecies differences.

DN(M)ELl-t dermal=384 mg/kg bw/d / 1.7 = 226 mg/kg bw

General population – long-term systemic oral DNEL

The IOELV of 192 mg/m3will be used. Correct the IOELV to an oral NOAEL (mg/kg/day) by converting the dose absorbed after inhalation into a systemic dose, assuming 50% uptake by the lung and 100% uptake from the GI tract:

Oral NOAEL = IOELV x wRV8-hourx [50 / 100] = 192 x 0.144 x 0.5 = 13.8 mg/kg bw/d

An assessment factor of 1.7 is used to account for intraspecies differences.

DN(M)ELl-t oral= 13.8 mg/kg bw/d / 1.7 = 8.13 mg/kg bw

Ethylbenzene

The cooperation of the Styrenics Steering Committee in providing DNELs for ethylbenzene is acknowledged. Documentation supporting these values is in the Styrenics REACH consortium dossier for ethylbenzene.

General population – long-term systemic inhalation DNEL

The DNEL is based on sub-chronic effects (ototoxicity) in the rat following inhalation exposure: extrapolated NOAEC = 500 mg/m3(114 ppm). Correct the NOAEC to adjust for absorption percentage differences following ECHA TGD (2008) guidance. Adjustment is also made for exposure duration with experimental conditions being 6 hours/day, 6 days/week.

DNELlt inhalation= 500 mg/m3x [6 / 24] x [6 / 7] x [ABSinhal-rat/ ABSinhal-human] = 500 mg/m3x 0.25 x 0.86 x [45 / 65] = 74 mg/m3

An assessment factor of 5 is used based on intraspecies differences between worker and general populations.

The DNEL for long-term inhalation exposure is derived as follows:

DN(M)ELl-t inhalation= 74 mg/m3/ 5 = 14.8 mg/m3

General population – long-term systemic dermal DNEL

The DNEL is based on sub-chronic effects (ototoxicity) in the rat following inhalation exposure: extrapolated NOAEC = 500 mg/m3(114 ppm). The dose descriptor is corrected into a human dermal NOAEL (mg/kg bw/d) by adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.4). It is assumed that uptake of ethylbenzene after inhalation in rats is 45%.

correctedDermal NOAEL = NOAECl-t inhalationx sRVrat-8hrx 0.45 = 500 x 0.38 x 0.45 = 86 mg/kg bw/d

A value of 4% used for dermal absorption in humans (Susten et al, 1990):

correctedDermal NOAEL = 86 mg/kg bw/d x [100 / 4] = 2150 mg/kg bw/d

An assessment factor of 20 is used based on interspecies differences for the rat (4) and intraspecies differences between worker and general populations (5).

The DNEL for long-term dermal exposure is derived as follows:

DN(M)ELl-t dermal= 2150 mg/kg bw/d / 20 = 108 mg/kg bw/d

General population – long-term systemic oral DNEL

The starting point is the NOAEL in a guideline oral 90 day study with rats was 75 mg/kg bw/d. An 84% oral absorption is used for rats and 100% for humans as conservative default leading to an internal dose:

correctedOral NOAEL = 75 mg/kg bw/d x [ABSoral-rat/ ABSoral-human] = 75 mg/kg bw/d x [84 / 100] = 63 mg/kg bw/d

An assessment factor of 40 is used based on interspecies differences for the rat (4), intraspecies differences between worker and general populations (5) and a correction for duration of exposure.

The DNEL for long-term oral exposure is derived as follows:

DN(M)ELl-t oral= 63 mg/kg bw/d / 40 = 1.6 mg/kg bw/d

Styrene

The cooperation of the Styrenics REACH consortia in providing DN(M)ELs for styrene is acknowledged.Documentation supporting these values is in the Styrenics REACH consortium dossier for styrene.

The EU transitional RAR (EU, 2008c) identified the following end-points as of concern for human health: acute toxicity (CNS depression), skin, eye and respiratory tract irritation, effects on colour vision discrimination following repeated exposure, effects on hearing (ototoxicity) following repeated exposure, developmental toxicity. 

General population – long-term systemic inhalation DNEL

The DN(M)EL is based on ototoxicity in humans(Triebig et al, 2009). A NOAEC for humans of 20 ppm (85 mg/m3) can be derived as starting point from this study. A consumer DNEL is calculated by adjusting for differences in exposure (2 d/week for Do-It-Yourself (DIY) use of styrene containing products v 5 days /week i.e. 5/2 = 2.5) and adjusting for differences between the general population and workers (AF =3):

DN(M)ELl-t inhalation(DIY) = 20x 2.5 /3 = 17 ppm

For continuous exposure via the environment the (DIY) DNEL is adjusted for differences in exposure:

DIY vs. 24 h/d for exposure via the environment: 8/24

2 d/week for DIY vs. 7 d/week for exposure via the environment: 2/7

In addition, the worker DNEL is derived for light physical activity at the workplace. This does not apply to the continuous exposure via the environment leading to a correction factor of 1/0.67.

DN(M)ELl-t inhalation                        = 17x 2/7 x 8/24 x 1/0.67

= 17 x 0.286 x 0.33 x 1.5

 =2.4 ppm = 10.2 mg/m3.

General population – long-term systemic dermal DNEL

The DN(M)EL is based on long term general population inhalation (DIY) DNEL of 17 ppm (73 mg/m3). The dose descriptor is corrected into a human dermal NOAEL by adjusting for differences in uptake between the two routes of exposure. Using a respiratory volume for workers under light physical activity of 10 m3/person/day and a body weight of 70 kg (ECHA, 2008) the external exposure would be 73 x 1/70 =10.4 mg/kg bw/day

This is then converted to a dermal dose by adjusting for differences in exposure. Absorption of styrene from the respiratory tract is considered to be 66% based on a study in 7 volunteers at 50 ppm under light physical activity (50 Watt) (Engström et al, 1978). In humans only 2% of a dermal dose of liquid styrene is likely to be absorbed (EU, 2008c). 

Dermal NOAEL = 10.4 x [ABSinhal-human/ ABSdermal-human]

= 10.4 x [66/2]

= 343 mg/kg/d

Since the consumer-DNEL long-term for dermal exposure was directly derived from that for inhalation exposure no further assessment factors are necessary.

DN(M)ELl-t dermal= 343 mg/kg bw/d

General population – long-term systemic oral DNEL

The DNEL is based on the long term inhalation route via environment of 10.2 mg/m³. A respiratory volume of 20 m³/person/d is used for humans exposed via environment (ECHA, 2008) and an uptake by inhalation of 70% according to Engström (1978a). This leads to an internal body burden of

10.1 x 20 x 0.7 = 144 mg/person/d, corresponding to 2.1 mg/kg/d.

The oral absorption in rats is 90% and therefore 100% absorption by oral exposure is taken for humans.

Thus, the DNEL long-term oral is 2.1 mg/kg/d for humans exposed via environment.

Naphthalene

The cooperation of the REACH for Coal Chemicals (R4CC) consortium in permitting access to DNEL information present on the ECHA Dissemination pages for naphthalene is acknowledged.

 

No hazards were identified for consumers exposed via inhalation, skin contact or after ingestion, and hence no DNELs were proposed by R4CC.

Anthracene

The toxicological properties of anthracene have been reviewed (EU, 2009), with a conclusion that it is of low toxicity following repeated exposure (NOAEC of 1000 mg/kg/day in mouse oral toxicity study) and is not of concern for mutagenicity or carcinogenicity. Although data are lacking with respect to reproductive and developmental toxicity no detectable toxic effects on the reproductive system of mice were seen during a 90-day feeding study and it was concluded that anthracene may possess weak, if any, developmental toxicity. However, extensive studies in animals and humans demonstrate that anthracene possess phototoxic potential following exposure in combination with UV light.

Based on the lack of systemic toxicity no substance-specific DNELs will therefore be developed for this marker substance. It is considered that the low concentration of anthracene present in this stream would not impact on the overall toxicity assessment and that risk management measures and occupational controls intended to minimise human exposure to the other toxicologically-active marker substances also present would limit exposure to anthracene.

References

ASTDR (2005). Toxicological profile for naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. http://www.atsdr.cdc.gov/toxprofiles/tp67.pdf

ECETOC (2003). Derivation of assessment factors for human health risk assessment. Technical report No. 86, ECETOC, Brussels, February 2003.

EU (2003b). Risk assessment report for naphthalene. http://ecb.jrc.ec.europa.eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/naphthalenereport020.pdf

EU (2006). Directive 2006/15/EC of 7 February 2006 establishing a second list of indicative occupational exposure limit values in implementation of Council Directive 98/24/EC and amending Directives 91/322/EEC and 2000/39/EC. Official Journal of the European Union, l 38, 36-39.

EU (2009). Anthracene (CAS No 120-1207; EINECS No 204-371-1): Summary risk assessment report, October 2009. Available from: http://ecb.jrc.ec.europa.eu/risk-assessment/

SCOEL (2001). Recommendation from the Scientific Committee on Occupational Exposure Limits for toluene 108-88-3 http://ec.europa.eu/social/BlobServlet?docId=3816&langId=en

Susten AS,Niemeier RW and Simon SD (1990). In vivo percutaneous absorption studies of volatile organic solvents in hairless mice II; Toluene, ethylbenzene and aniline. J. Appl. Toxicol. 10: 217-225.

ten Berge, W (2009). A simple dermal absorption model: Derivation and application. Chemosphere, 75, 1440-1445.