Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
2.21 mg/m³
Most sensitive endpoint:
carcinogenicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: Cox regression (see endpoint summary for details)
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
other: A Cox regression model for leukaemia, reported by Cheng et al (2007).
Explanation for the modification of the dose descriptor starting point:
no route-to-route extrapolation necessary
AF for dose response relationship:
1
Justification:
accounted for in the model
AF for differences in duration of exposure:
1
Justification:
accounted for in the model
AF for interspecies differences (allometric scaling):
1
Justification:
model derived from human epidemiology studies
AF for other interspecies differences:
1
Justification:
model derived from human epidemiology studies
AF for intraspecies differences:
1
Justification:
accounted for in the model
AF for the quality of the whole database:
1
Justification:
database is robust
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
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:
DNEL (Derived No 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 benzene 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 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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

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.

Propene 0 – 75%

1,3-Butadiene 0.1 - <1%

Benzene 0.1 - <1%

Carbon monoxide 0.1 - <1%

Ethane<40%

Ethylene<50%

Propane<80%

Methane<80%

Butenes<60%

Butane<80%

Carbon dioxide<4%

 

Uses:

These hydrocarbon streams are used as intermediates and monomers, hence risk characterization will focus on workers only. (The presence of >0.1% butadiene and >0.1% benzene precludes their supply to the general population.)

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 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)

1,3-butadiene

0.1 - <1

2.21

0.452

na

na

benzene

0.1 - <1

3.25

0.308

23.4

0.043

carbon monoxide

0.1 - <1

10

0.10

na

na

propene

0 - 75

low systemic toxicity, no DNEL required

na

na

ethane

<40

low systemic toxicity, no DNEL required

na

na

ethylene

<50

low systemic toxicity, no DNEL required

na

na

propane

<80

low systemic toxicity, no DNEL required

na

na

methane

<80

low systemic toxicity, no DNEL required

na

na

butenes

<60

low systemic toxicity, no DNEL required

na

na

butane

<80

low systemic toxicity, no DNEL required

na

na

carbon dioxide

<4

low systemic toxicity, no DNEL required

na

na

na = substance is a gas

Demonstration of “safe use” for inhalation hazards associated with the presence of<1% butadiene, and dermal hazards linked to the presence of<1% benzene, will provide adequate protection against any hazards arising the use of these streams.

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

Dermal and oral studies are not technically feasible for many of the component substances present in these streams as they are gases at room temperature. Furthermore, the majority of the substances present show very low toxicity via the inhalation route. However, some streams may contain small quantities of benzene (0.1 - <1%), 1,3 butadiene (0.1 - <1%) and carbon monoxide (<4%), which therefore define the DN(M)ELs for this category. Benzene is the only marker substance that contributes dermal hazard to the stream (remaining markers are gases).

 

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 studiesprovide clear and consistent evidence of a causal association between benzene exposure and acute myelogenous (non-lymphocytic) leukemia (or ANLL). An effect on bone marrow leading to subsequent changes in human blood cell populations is believed 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 (NOAEC = 11.18 mg/m3) post-date the BOELV, a DNEL based on these bone marrow findings would be higher (and hence offer less protection) than the BOELV. The BOELV 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 dermal DN(M)EL
The dermal DN(M)EL 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 x [ABSinhal-human/ABSdermal-human]

                                   = 3.25 x 0.144 x [50 / 1]

DN(M)ELl-t dermal          = 23.4mg/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.

 

Worker – long-term systemic inhalation DN(M)EL

The association between 1,3-butadiene exposure and leukemia has been extensively modeled 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 (, 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 (Committee on Hazardous Substances, 2008).

 

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

 

Carbon monoxide

 

Worker – long-term systemic inhalation DN(M)EL

An IOELV has not been established for carbon monoxide, however, the toxicology and human health hazard has been comprehensively assessed by WHO (1999). The WHO air quality guidance value of 10 mg/m3, intended to ensure that a carboxy-haemoglobin (COHb) level of 2.5% is not exceeded when a normal subject engages in light or moderate exercise, has been considered as equivalent to the long-term systemic inhalation DNEL required by REACH

 

Carbon monoxide is a gas at room temperature and therefore exposure by the dermal route is not relevant.

 

Propene

Worker – long-term systemic inhalation DN(M)EL

As no adverse systemic effects were reported at the highest dose level tested in a chronic toxicity study, no DNELs have been derived for propene.

The weight of evidence indicates that local nasal effects recorded in rodents, which unlike man are obligate nasal breathers, superimposed on a high background of spontaneous nasal pathology and with no obvious dose-response relationships, are likely to be of little relevance in extrapolation of risk to humans and considered an inappropriate finding from which to derive a DNEL. In addition, the concentrations at which these effects were reported in the animal experiments are very high compared to the actual human exposure levels in practice.

Dermal and oral studies with propene are not technically feasible as this substance is a gas at room temperature.

Methane, ethane, butane and propane

No long term systemic DNELs are available for these simple alkanes, while Annex VI of the CLP Regulation records no potential to cause harm following repeated exposure. These component substances are therefore considered to possess low systemic toxicity, and no DNELs are therefore required.

 

Ethylene

Ethylene has been shown to cause subtle nasal effects (rhinitis) in rats in repeated high-exposure inhalation studies. These (and similar) effects have not been reported in humans. The relevance of the rat findings for humans is therefore questionable. Based upon the current animal data, a health-based reference concentration of approximately 50-75 ppm is suggested, i.e., significantly greater than current worker exposure levels. In the circumstances, a DNEL for ethylene is not being proposed. Whilst ethylene has been shown to have anaesthetic properties (at concentrations of 80%, equivalent dose 800,000 ppm or 917,857 mg/m3), the effect is at concentrations which far exceed occupational exposure levels and a clear NOAEC of 10,000ppm has been identified in studies in rats, therefore this should not drive DNEL derivation.

 

Butenes

Repeat dosing studies via inhalation exposure are available for but-1-ene, 2-butene and 2-methylpropene. All studies have shown minimal systemic or target organ toxicity.

 

Exposure of rats to but-1-ene at concentrations of 500, 2000, 8000 ppm (1147, 4589, 18,359 mg/m3) did not induce systemic toxicity in males or females exposed for a minimum of 28 days or in pregnant female rats exposed for 14 days pre-mating, through mating and gestation to day 19. No treatment-related effects on body weight, clinical chemistry, organ weights or histopathology were found. Neurotoxicity screening also showed no effects on motor activity or functional observation battery. A NOAEC of 8000 ppm (18,359 mg/m3) (the highest dose level) was established (Huntingdon, 2003). 

 

Exposure of rats to 2-butene at target concentrations of 2500 or 5000 ppm (5737 or 11,474 mg/m3) did not induce significant systemic toxicity in males and females exposed for 28 days, or in pregnant female rats exposed for 14 days pre-mating, through mating and gestation to day 19 (TNO 1992b). Mean absolute organ weights and relative weights were comparable in all groups. No abnormal, treatment-related macroscopic changes (all groups) or pathological changes (only determined in control and 5000 ppm groups) were observed. The only treatment-related changes were some small decreases in body weights and body weight gains in both sexes at both dose levels and decreased food consumption at 5000 ppm during the first week (premating). Although the authors (TNO 1992b) interpreted the NOAEC as 2500 ppm based on these findings, a reanalysis by RIVM (2007) concluded that as these effects were not dose-related and not consistently present during the study the NOAEC for 2-butene should be 5000 ppm (11,474 mg/m3) (RIVM 2007 and amended SIDS report 2007).

 

2-Methylpropene also caused no toxicologically significant changes when rats were exposed to 250, 1000 or 8000ppm (573, 2294 or 18,359 mg/m3) for 13 weeks. The only clinical change was an elevation in ketone bodies detected in urine at 1000 ppm and 8000 ppm (males), the toxicological significance of this is unknown. The NOAEC was 8000 ppm (18,359 mg/m3) the highest concentration level tested (Hazleton 1982). Similar results were obtained in 14 week inhalation studies conducted by the NTP (NTP, 1998). F344/N rats and B6C3F1 mice were exposed to 2-methylpropene at concentrations of 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm, (1147, 2294, 4589, 9179, 18,359 mg/m3) for 14 weeks. There were no significant exposure-related toxicologic effects in either species at any dose level. Increased kidney weights in mice; and increased liver and kidney weights and minimal hypertrophy of goblet cells lining the nasopharyngeal ducts in rats, were considered to be non-toxic adaptive responses. The NOAEL for both studies was 8000 ppm (18,359 mg/m3) the highest concentration level tested.

 

The absence of significant toxicological findings in these investigations indicates that no repeated dose systemic DNEL is necessary.

Carbon dioxide

No long term systemic DNEL is available for carbon dioxide, while classifications notified to the CLP inventory indicate no potential to cause long-term systemic effects.

 

 

References

 

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

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

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.

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

World Health Organisation (1999). Environmental Health Criteria 213 (Carbon Monoxide, second edition) 1999, updated 2004

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.265 mg/m³
Most sensitive endpoint:
carcinogenicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: Cox regression (see endpoint summary for details)
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
other: A Cox regression model for leukaemia, reported by Cheng et al (2007).
Explanation for the modification of the dose descriptor starting point:
no route-to-route extrapolation necessary
AF for dose response relationship:
1
Justification:
accounted for in the model
AF for differences in duration of exposure:
1
Justification:
accounted for in the model
AF for interspecies differences (allometric scaling):
1
Justification:
model derived from human epidemiology studies
AF for other interspecies differences:
1
Justification:
model derived from human epidemiology studies
AF for intraspecies differences:
1
Justification:
accounted for in the model
AF for the quality of the whole database:
1
Justification:
database is robust
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
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:
no hazard identified
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.464 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 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).
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:
no hazard identified

Additional information - General Population

The main use of hydrocarbon streams are as intermediates and monomers, hence no exposure of the general population is likely. The presence of >0.1% butadiene and >0.1% benzene precludes the supply of these streams to the general population, however general population DN(M)ELs for the inhalation (butadiene) and oral (benzene) routes have been developed for the assessment of risks to man exposed via the environment.

1,3-Butadiene: General Population – long-term systemic inhalation DN(M)EL

The association between 1,3-butadiene exposure and leukemia has been extensively modeled. The excess risk of leukemia as a result of exposure to 1,3-butadiene has then been determined from these models. The details of this approach can be found in the Summary and Discussion of Carcinogenicity Section. The preferred model for the general population is one used for occupational exposure calculations i.e. the Cox continuous model adjusted only for age (Cheng et al, 2007)based on all leukemias combined, using the exposure metric that excluded exposure that occurred more than 40 years ago. The model incorporates dose descriptors and assessment factors and therefore further corrected dose descriptors and overall assessment factors are not required. Instead, an estimate of the concentration of 1,3-butadiene giving an excess risk of death from leukemia (all cell types combined) of 1 in 105was determined and while a higher value could have been proposed by including BD HITS, a DMEL of 120 ppb (0.265 mg/m3) is proposed.

A long-term inhalation DN(M)EL for 1,3 butadiene of 0.265 mg/m3will therefore be used for an assessment of risks to man exposed via the environment.

References

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.

Benzene: General Population – long-term systemic oral DN(M)EL

Development of inhalation DN(M)EL

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.

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, an inhalation 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/m3 and 5 µg/m3 that were established for benzene in subsequent European Directives 2000/69/EC and 2008/50/EC, respectively.

Extrapolation from inhalation DN(M)EL to oral DN(M)EL

Dose descriptor: The inhalation DMEL of 3.25 µg/m3 will 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 m3 and 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

References

Baan R et al. (2009). A review of human carcinogens - Part F: Chemical agents and related occupations.The Lancet Oncology, 10(12):1143–1144.

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.

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

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