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
DNEL related information
Overall assessment factor (AF):
1
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
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
DNEL related information
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

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 10%

·        Styrene: up to 15%

·        Naphthalene: up to 70%

·        Anthracene: up to 5%

·        Biphenyl: up to 15%

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). No general population risk characterisation will be conducted for streams containing >0.1% benzene since their supply is prohibited under REACH. Equally, no risk characterisation will be performed for streams containing <0.1% benzene since their use is permitted under REACH. The use of benzene-containing streams in motor fuels is outside the scope of REACH and will not be addressed in this registration.

Anthracene exhibits low systemic toxicity and therefore no DNELs will be proposed. Biphenyl is irritating to eyes, respiratory tract and skin but is not classified for systemic effects and no DNEL will be developed.

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

Up to 30

3.25

9.23

23.4

1.28

toluene

Up to 20

192

0.10

384

0.05

ethylbenzene

Up to 10

77

0.13

180

0.06

styrene

Up to 15

85

0.18

406

0.04

naphthalene

Up to 70

50

1.4

72

0.97

anthracene

Up to 5

low systemic toxicity, no DNELs required

biphenyl

Up to 15

low systemic toxicity, no DNELs required

Based on this analysis, demonstration of “safe use” for hazards associated with inhalation and dermal exposure to benzene will also provide adequate protection for workers against hazards arising from other marker substances present.

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 EU RAR (EU, 2003b) identified the key health effects from naphthalene as haemolytic anaemia, repeat dose toxicity and nasal tumours in the rat. The IOELV for naphthalene is 50 mg/m3and will be used as the basis for calculating DNELs.

Worker – long-term systemic inhalation DNEL

The long-term systemic DNEL for naphthalene will be based upon the IOELV with no further modification:

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

Worker – long-term systemic dermal DNEL

The dermal NOAEC is extrapolated from the IOELV. The IOELV (mg/m3) is converted 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).

The EU (EU, 2003b) and ATSDR (2005) indicate that naphthalene is well absorbed via inhalation and oral routes. Dermal exposure may also result in significant systemic absorption. However, data are insufficient as to the rate and extent of absorption via the different routes. Since no substance-specific data are available a conservative default of 100% uptake via inhalation and 10% via dermal routes will be used.

Dermal NOAEL = IOELV x wRV8-hourx [ABSinhal-human/ ABSdermal-human] = 50 x 0.144 x [100 / 10] = 72 mg/kg bw/d

As the IOELV is based on human data no assessment factor is needed.

DN(M)ELl-t dermal= 72 mg/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:
14.7 mg/m³
DNEL related information
Overall assessment factor (AF):
1.7
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
42.4 mg/kg bw/day
DNEL related information
Overall assessment factor (AF):
1.7
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
4.23 mg/kg bw/day
DNEL related information
Overall assessment factor (AF):
1.7
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

General Population - Hazard for the eyes

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 10%

·        Styrene: up to 15%

·        Naphthalene: up to 70%

·        Anthracene: up to 5%

·        Biphenyl: up to 15%

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). No general population risk characterisation will be conducted for streams containing >0.1% benzene since their supply is prohibited under REACH. Equally, no risk characterisation will be performed for streams containing <0.1% benzene since such uses are permitted under REACH. The use of benzene-containing streams in motor fuels is outside the scope of REACH and will not be addressed in this registration.

Anthracene exhibits low systemic toxicity and therefore no DNELs will be proposed. Biphenyl is irritating to eyes, respiratory tract and skin but it is not classified for systemic effects and no DNEL will be developed.

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

Up to 30

supply of streams containing>0.1% benzene prohibited

toluene

Up to 20

56.5

0.35

226

0.09

8.13

2.46

ethylbenzene

Up to 10

14.8

0.68

108

0.09

1.60

6.25

styrene

Up to 15

10.2

1.47

343

0.04

2.1

7.1

naphthalene

Up to 70

14.7

4.8

42.4

1.6

4.23

16.5

anthracene

Up to 5

low systemic toxicity, no DNELs required

biphenyl

Up to 15

low systemic toxicity, no DNELs required

For the general population the long term inhalation, dermal and oral DNELs for naphthalene will be used for risk characterization.

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

As noted above, use of benzene is restricted under REACH and no general population DNELs will therefore be developed.

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 EU RAR (EU, 2003b) identified the key health effects from naphthalene as haemolytic anaemia, repeat dose toxicity and nasal tumours in the rat. The IOELV for naphthalene is 50 mg/m3and will be used as the basis for calculating DNELs.

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

Inhalation NOAEL = IOELV x (wRV8-hour/ sRV24-hour) = 50 x (0.144 / 0.288) = 25 mg/m3

DN(M)ELl-t inhal= 25 mg/m3/ 1.7 = 14.7 mg/m3

General population – long term systemic dermal DNEL

The long term dermal DNEL is based on the IOELV of 50 mg/m3. Correct the IOELV to a dermal NOAEL (mg/kg/day) by converting the dose absorbed after inhalation into a systemic dose, assuming 100% uptake by the lung and 10% uptake by skin:

Dermal NOAEL = IOELV x wRV8-hourx 100 / 10 = 50 x 0.144 x 1 = 72 mg/kg bw

An assessment factor of 1.7 is used to reflect uncertainty when moving from the IOELV to the general population.

DN(M)ELl-t dermal= 7.2 mg/kg bw/d / 1.7 = 42.4 mg/kg bw

General population – long term systemic oral DNEL

The long term oral DNEL is based on the IOELV of 50 mg/m3. Correct the IOELV to an oral NOAEL (mg/kg/day) by converting the dose absorbed after inhalation into a systemic dose, assuming 100% uptake by the lung and 100% uptake by the gastrointestinal tract:

Oral NOAEL = IOELV x wRV8-hourx 100 / 100 = 50 x 0.144 x 1 = 7.2 mg/kg bw

An assessment factor of 1.7 is used to reflect uncertainty when moving from the IOELV to the general population.

DN(M)ELl-t oral= 7.2 mg/kg bw/d / 1.7 = 4.23 mg/kg bw

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.

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