Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No 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:
DNEL (Derived No 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: 0.1 - 90%

·        Toluene: 0.1 - 98%

·        Hexane: up to 20%

·        Xylenes: up to 25%

·        1,3-butadiene: <0.1 -1%

·        Naphthalene: up to 30%

·        Isoprene: up to 6%

·        Anthracene: up to 1%

Uses:

These hydrocarbon streams are used as intermediates, in manufacture and as fuels. 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). Since these streams all contain at last 0.1% benzene their supply to the general population is prohibited under REACH and no DN(M)ELs or risk characterisation for consumers is required.

Anthracene exhibits low systemic toxicity and therefore no DNEL will be proposed.

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

Workers

benzene

0.1 to 90

3.25

27.7

23.4

3.85

toluene

0.1 to 98

192

0.51

384

0.26

hexane

Up to 20

72

0.27

25.9

0.772

xylenes

Up to 25

221

0.11

3182

0.008

1,3-butadiene

<0.1 to 1

2.21

0.45

na[a]

na

naphthalene

Up to 30

50

0.6

72

0.42

isoprene

Up to 6

8.4

0.71

23.7

0.25

anthracene

Up to 1

low systemic toxicity, no DNELs required

Based on this analysis, demonstration of “safe use” for worker inhalation and dermal hazards associated with the presence of benzene will also provide adequate protection against hazards arising from other marker substances present. The long term inhalation and long term dermal DNELs for benzene will therefore be used for workers.

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)[b]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 xwRV8-hour[b] x [ABSinhal-human/ABSdermal-human]  = 3.25 x 0.144 x [50 / 1]

DN(M)ELl-t dermal   = 23.4mg/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)[c]– 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  = IOELV = 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]

DNELl-t dermal    = 384 mg/kg bw/d

Hexane

Background information supporting the SCOEL decision on n-hexane is not available, however ACGIH (2001) and ATSDR (1999) identify peripheral polyneuropathy as the lead effect for n-hexane in humans. Since n-hexane is not a core LOA substance, it has been assumed that no significant new information has come available to challenge the SCOEL position, and that the IOELV (included in the 2ndlist of indicative occupational exposure limit values - EU, 2006) remains valid.

Worker – long-term systemic inhalation DNEL

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

DN(M)ELl-t inhalation  = IOELV = 72 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).

Information cited by ACGIH indicates that uptake of n-hexane after inhalation is in a range 5-28%, with pulmonary retention of 25% reported for volunteers involved in work. ACGIH briefly reports a human case report which described “severe intoxication” following percutaneous absorption. However, the UK HSE (1990) concluded that “there is limited absorption of liquid through the skin” although no quantitative information is provided. No substance-specific data are available, hence a conservative default of 10% uptake will be used.

Dermal NOAEL = IOELV xwRV8-hour[b] x [ABSinhal-human/ABSdermal-human]  = 72 x 0.144 x [25 / 10]  = 25.9 mg/kg bw/d

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

DN(M)ELl-t dermal  = 25.9 mg/kg bw/d

Xylene isomers

An IOELV (EU, 2000) is available for the xylenes isomers. Significant new hazard data (addressing for example ototoxicity and developmental effects) are available, but it is considered that these data do not impact the overall NOAEC values which would be used for derivation of DNELs and therefore Appendix R. 8-13 applies, allowing IOELVs to be considered as a starting point for derivation of DNELs.

ECETOC guidance for assessment factors and the IOELV are used as starting points for all DNELs.

Worker – long-term systemic inhalation DNEL

The IOELV of 50 ppm (221 mg/m3, 8h TWA) is proposed.

Worker – long-term systemic dermal DNEL

The IOELV of 50 ppm (221 mg/m3, 8h) will be used for derivation of the worker DNELl-t dermal.

The IOELV (mg/m3) 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 xylenes after inhalation is 100% with a value of 1% for dermal absorption (ten Berge, 2009):

correctedDermal NOAEL = IOELV x wRVhuman-8hr[b]x [ABSinhal-human/ABSdermal-human] = 221 x 0.144 x (100 / 1) = 3182 mg/kg bw/d

No assessment factor is necessary.

1,3-Butadiene

1,3-Butadiene is a multi-species carcinogen. In the mouse, it is a potent multi-organ carcinogen. Tumours develop after short durations of exposure, at low exposure concentrations and the carcinogenic response includes rare types of tumours. In the rat, fewer tumour types, mostly benign, develop at exposure concentrations of 100 to1000-times higher than in the mouse. In humans, 1,3-butadiene is a recognised carcinogen. A positive association was demonstrated between workplace exposure to butadiene for men employed in the styrene-butadiene rubber industry and lymphohaematopoietic cancer (leukaemia). Various models have established a dose response-relationship for cumulative exposure to 1,3-butadiene, especially concentrations above 100 ppm. The estimates for occupational and population human risk are based on these models.

Worker – long-term systemic inhalation DNEL

The association between 1,3-butadiene exposure and leukaemia has been extensively modeled using Cox and Poisson regression models and the excess risk of leukaemia determined. The preferred model for workers is the Cox continuous model (Cheng et al, 2007) as employed by Sielken et al (2008), using the exposure metric that excluded exposure that occurred more than 40 years ago or excluded the 5% of workers with the highest cumulative 1,3-butadiene exposures and included as covariate, the cumulative number of exposures to 1,3-butadiene concentrations > 100 ppm (the number of High Intensity Tasks [HITs]). This model incorporates dose descriptors and assessment factors and therefore further corrected dose descriptors and overall assessment factors are not required. The estimate of the excess risk of death from leukaemia as a result of exposure to a DMEL of 2.21 mg/m3(1 ppm) is 0.33 x 10-4(with an upper bound of 0.66 x 10-4based on a one-sided 95% upper confidence limit for the regression parameter).

This estimate is less than 0.4 x 10-4, which has been proposed as a future limit for acceptable occupational risk (AGS, 2008). Regression coefficients from other Cox regression models reported by Cheng et al (2007) and TCEQ (2008), and estimates from Poisson regression models, indicate that other risk estimates are generally close to 0.4 x 10-4, even if based on regression models that do not adjust for 1,3-butadiene HITs. All of the estimates are considerably lower than the current limit for acceptable occupational risk of 4 x 10-4that has recently been proposed (AGS, 2008).

DN(M)EL l-t inhalation = 2.21 mg/m3

Worker – long-term systemic dermal DNEL

As 1,3-butadiene is a gas a dermal DNEL is not quantifiable.

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. Naphthalene was included in the SCOEL (2010) consolidated list of IOELVs and the IOELV for naphthalene of 50 mg/m3 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 (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 xwRV8-hour[b] x [ABSinhal-human/ABSdermal-human]  = 50 x 0.144 x [100 / 10]  = 72mg/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

Isoprene

Isoprene has been shown to be carcinogenic to mice and rats. When inhaled in concentrations of 70 ppm and above, it was found to induce tumours in a range of tissues in male mice while tissue responses in females were more limited. No statistically significant increases in tumours were reported in either sex at a dose level of 10 ppm. Inhalation by rats of concentrations above 220 ppm caused a significantly increased incidence of mammary gland, testicular and kidney tumours in males, and mammary gland tumours in females. At the lowest dose tested, 220 ppm, a statistically significant increase in only mammary gland fibroadenoma was observed in females.

Worker – long-term systemic inhalation DNEL

In accordance with REACH guidance (Appendix R.8-13), the established MAK (2009) value of 3 ppm (equivalent to 8.4 mg/m3) - 8 hr TWA will form the basis of the inhalation DNEL for workers. It was concluded by the MAK Commission that a maximum admissible concentration can be established for humans and that the carcinogenic and genotoxic effects of isoprene is low. There would be no appreciable increase of carcinogenic risk in humans if this value is not exceeded.

DN(M)ELl-t inhalation  =8.4 mg/m3

Worker - long-term systemic dermal DNEL

The long-term dermal DN(M)EL is calculated from the inhalation DN(M)EL using route-to-route extrapolation, having determined the net inhalation uptake or dose.Filser et al (1996) determined the rates of isoprene metabolism (µmol/hr/kg bw) in humans, rats, and mice at steady-state over a range of atmospheric concentrations to validate a PT model for isoprene. Metabolism of isoprene is linear up to 50 ppm. At the isoprene exposure concentration of interest 8.4 mg/m3(3 ppm), the rate of metabolism (µmol/hr/kg bw) can be determined and subtracted from the rate of metabolism at 0 mg/m3(0 ppm). At an exposure concentration of 3 ppm, the rate of isoprene metabolism is 0.13 µmol/hr/kg bw and in an 8-hr workday, net inhalation uptake (or dose) is: 0.13 µmol/hr/kg bw x 8 hr i.e. 1.04 µmol/kg (equivalent to 71 µg/kg). This value is adjusted for the low absorption factor of 0.003% giving a DN(M)EL of 23.7 mg/kg bw/d.

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 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

ACGIH (2001). n-Hexane: TLV Documentation, 7th Edition, p1-16.

AGS (2008). Committee on Hazardous Substances. Guide for the quantification of cancer risk figures after exposure to carcinogenic hazardous substances for establishing limit values at the workplace. 1. Edition. Dortmund: Bundesanstalt für Arbeitsschutz und Arbeitsmedizin. Available from:http://www.baua.de/nn_21712/en/Publications/Expert-Papers/Gd34,xv=vt.pdf

ATSDR (1999).Toxicological Profile for n-Hexane. http://www.atsdr.cdc.gov/toxprofiles/tp113.html

ATSDR (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.

Cheng H, Sathiakumar N, Graff J, Matthews R, Delzell E (2007). 1,3-Butadiene and leukemia among synthetic rubber industry workers: exposure-response relationships. Chem Biol Interact, 166,15-24.

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 (2000). Council Directive 2000/39/EC of 8 June 2000 establishing a first list of indicative occupational exposure limit values (IOELV) 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.Official Journal of the European Communities, L142, 47-50.

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 (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/

Filser JG, Csanady GA, Denk B, Hartmann M, Kauffmann A, Kessler W, Kreuzer PE, Putz C, Shen JH, Stei P.(1996). Toxicokinetics of isoprene in rodents and humans. Toxicology 113:278-287.

MAK (2009). MAK Commission 46 Lieferung.

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 toluene108-88 -3. http://ec.europa.eu/social/BlobServlet?docId=3816&langId=en

SCOEL (2010) Consolidated Indicative Occupational Exposure Limits Values (IOELVs). Available from http://ec.europa.eu/social/main.jsp?catId=153&langId=en&intPageId=684

Sielken RL, Valdez-Flores C, Delzell E (2008). Quantitative Risk Assessment of Exposures to Butadiene in European Union Occupational Settings Based on the University of Alabama at Birmingham Epidemiological Study: All Leukemia, Acute Myelogenous Leukemia, Chronic Lymphocytic Leukemia, and Chronic Myelogenous Leukemia. Unpublished report to Lower Olefins Sector Group, Brussels, Belgium.

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

TCEQ (2008). Texas Commission on Environmental Quality. Development Support Document. 1,3-Butadiene. Chief Engineer’s Office. Available from:http://tceq.com/assets/public/implementation/tox/dsd/final/butadiene,_1-3-_106-99-0_final.pdf

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

UK HSE (1990). N-Hexane occupational exposure hazard. HSE Review 1990, D34-D35, Published 1993.


[a] 1,3-butadiene is a gas and a dermal DNELs is not quantifiable

[b] Data reported as 3.5 ppm, and converted to mg/m3using tool available from http://www.cdc.gov/niosh/docs/2004-101/calc.ht

[c] Worker respiratory volume (wRV) is 50% greater than the resting standard respiratory volume of 0.2 L/min/kg bw (wRV8-hour= (0.2 L/min/kg bw x 1.5 x 60 x 8) / 1000 = 0.144 m3/kg bw

[d] mg/m3values quoted in this document are as reported in the publication or calculated using a conversion at 25°C as used by ACGIH (http://www.cdc.gov/niosh/docs/2004-101/calc.htm).It is recognized that SCOEL used a different calculation

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

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). Since these streams all contain at least 0.1% benzene, their supply to the general population is prohibited and no DN(M)ELs or risk characterisation for consumers is required.