Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
192 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:
384 mg/kg bw/day
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

Workers - Hazard for the eyes

Additional information - workers

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%
  • Toluene: up to 50%
  • 1,3-butadiene: <0.1%
  • Anthracene : up to 0.2%

Uses:

Low benzene naphtha streams are used as intermediates and in manufacturing processes as well as in fuels sold to consumers. 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.

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 bwt/d

Relative hazard potential
(max % ÷ DN(M)EL)

benzene

< 0.1

3.25

<0.031

23.4

0.004

toluene

<50

192

0.260

384

0.13

1,3-butadiene

< 0.1

2.21

<0.045

na1

na1

anthracene

<0.2

low systemic toxicity, no DNELs required

na11,3-Butadiene is a gas at room temperature and therefore exposure by the dermal route is not relevant Based on this analysis, demonstration of ?safe use? for inhalation and dermal hazards associated with the presence of up to 50% toluene will also provide adequate protection against inhalation hazards arising from the other marker substance present.

The long term inhalation and dermal DNELs for toluene will therefore be used for worker 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

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) leukemia (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[1]) post-date the BOELV for benzene, a DNEL based on these bone marrow findings would be higher (and hence offer less protection) 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[2] 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[3]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

DNELl-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-hour x [50/3.6] 

= [192 x 0.144 x 13.89]

DNELl-t dermal              = 384 mg/kg bw/d

 

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 (leukemia). 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.

Since butadiene is a category 1A carcinogen, its inclusion in formulations supplied to the general population is restricted to a maximum of <0.1%. No classification is required for such formulations, and no general population DMELs will therefore be developed.

Worker ? long-term systemic inhalation DNEL

The association between 1,3-butadiene exposure and leukemia has been extensively modelled using Cox and Poisson regression models and the excess risk of leukemia 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 leukemia 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).

 

Worker ? long-term systemic dermal DNEL

1,3-Butadiene is a gas at room temperature and therefore exposure by the dermal route is not relevant.

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 nodetectable toxic effects on the reproductive system of mice were seen during a 90-day feeding studyit was concluded thatanthracene 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.

 

Explanatory notes

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

[2]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

[3]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

[4] this formula gives the internal (absorbed) dose achieved during a full-shift exposure at the IOEL

[5]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

References

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. Availablehttp://www.baua.de/nn_21712/en/Publications/Expert-Papers/Gd34,xv=vt.pdf

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

Bond JA, Dahl AR, Henderson RF, Dutcher JS, Mauderly JL and Birnbaum LS (1986) Species differences in the disposition of inhaled butadiene.Toxicol Appl Pharmacol, 84, 617-627.

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.

Dahl AR, Sun JD, Birnbaum LS, Bond JA, Griffith WC Jr, Mauderly JL, Muggenburg BA, Sabourin PJ and Henderson RF (1991) Toxicokinetics of inhaled 1,3-butadiene in monkeys: comparison to toxicokinetics in rats and mice.Toxicol Appl Pharmacol. 110, 9-19.

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 (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 RAR (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 fortoluene108-88-3 http://ec.europa.eu/social/BlobServlet?docId=3816&langId=en

Sielken RL, Valdez-Flores C, Gargas ML, Kirman CR, Teta MJ, Delzell E (2007). Cancer risk assessment for 1,3-butadiene: dose-response modeling from an epidemiological perspective. Chem Biol Interact 166, 140-149.

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

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

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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
56.5 mg/m³
DNEL related information
Overall assessment factor (AF):
1.7
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:
DNEL (Derived No Effect Level)
Value:
226 mg/kg bw/day
DNEL related information
Overall assessment factor (AF):
1.7
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:
DNEL (Derived No Effect Level)
Value:
8.13 mg/kg bw/day
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: <0.1%
  • Toluene: up to 50%
  • 1,3-butadiene: <0.1%
  • Anthracene : up to 0.2%

Uses:

Low benzene naphtha streams are used as intermediates and in manufacturing processes as well as in fuels sold to consumers. 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.

Benzene and butadiene are category 1A carcinogens and their inclusion in formulations supplied to the general population should be restricted to a maximum of <0.1%. No classification is required for such formulations, and therefore no general population DNELs will be developed for these substances.

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

Oral

DN(M)EL

mg/m3

Relative hazard potential
(max % ÷ DN(M)EL)

DN(M)EL

mg/kg bwt/d

Relative hazard potential
(max % ÷ DN(M)EL)

DN(M)EL

mg/kg bwt/d

Relative hazard potential
(max % ÷ DN(M)EL)

benzene

< 0.1

supply of steams containing>0.1% benzene prohibited

toluene

<50

56.5

0.88

226

0.22

8.13

6.15

1,3-butadiene

< 0.1

supply of steams containing>0.1% butadiene prohibited

anthracene

<0.2

low systemic toxicity, no DNELs required

Demonstration of ?safe use? for inhalation, dermal and oral hazards associated with the presence of 50% toluene will also provide adequate protection against any hazards arising from other components also present.

The long term inhalation, dermal and oral DNELs for toluene will therefore be used for general population 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 REACHand 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[1]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 [4]

Inhalation NOAEL        = IOELV x (wRV8-hour/ sRV24-hour)

= 192 x (0.144 / 0.288[2]) = 96 mg/m3

DNELl-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

Dermal NOAEL = 192 x 0.144 x 13.89 = 384 mg/kg bw

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

DNELl-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 form the basis of the oral DNEL for toluene.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][3]

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.DNELl-t oral  = 13.8 mg/kg bw/d / 1.7

= 8.13 mg/kg bw

 

1,3-Butadiene

Since butadiene is a category 1A carcinogen, its inclusion in formulations supplied to the general population is restricted to a maximum of <0.1%. No classification is required for such formulations, and no general population DNELs will therefore be developed.

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 nodetectable toxic effects on the reproductive system of mice were seen during a 90-day feeding studyit was concluded thatanthracene 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.

 

Explanatory notes

1]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

[2]standard respiratory volume of 0.2 L/min/kg bw (sRV24-hour= (0.2 L/min/kg bw x 60 x 24) / 1000 = 0.288 m3/kg bw

[3] this formula gives the internal (absorbed) dose achieved during a full-shift exposure at the IOELV

[4] based on the ratio of intra-species differences for worker (AF = 3) and general population (AF = 5) groups reported in ECETOC (2003) Derivation of assessment factors for human health risk assessment. Technical report no. 86, ECETOC, Brussels, February 2003.

References

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 RAR (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 fortoluene108-88-3 http://ec.europa.eu/social/BlobServlet?docId=3816&langId=en


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