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

Local effects

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

Workers - Hazard via dermal route

Systemic effects

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

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Compositional information:

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

Uses:

These hydrocarbon streams are used as intermediates.

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.

In the case of this stream, the most hazardous marker substances present 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)

benzene

0.1 to <25

3.25

7.69

23.4

1.07

toluene

<25

192

0.13

384

0.07

hexane

<30

72

0.42

25.9

1.16

pentane

<45

no systemic toxicity, no DNELs required

cyclohexane

<40

700

0.06

2016

0.02

heptane

<50

no systemic toxicity, no DNELs required

 

Although benzene has a slightly lower dermal DN(M)ELs n- hexane leads to a marginally greater relative hazard and has therefore been selected as the basis for the dermal DNEL. Based on this analysis, demonstration of “safe use” for hazards associated with the presence of 25% benzene and 30% hexane will also provide adequate protection against hazards arising from the other components that are present.

The long-term inhalation DMEL for benzene and long term dermal DNEL for hexane will therefore be used for worker risk characterization.

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

The following hazard information and DN(M)ELs are available for marker substances present in this Category. These DN(M)ELs 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.

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) 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[1]) post-date the BOELV, a DNEL based on these bone marrow findings would be higher 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 inhalation DMEL

The BOELV will be used with no further modification

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

Worker - long-term systemic dermal DMEL

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, assuming50% 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

Hexane

Background information supporting the SCOEL decision 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[4]) 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

DNELl-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[5] x [ABSinhal-human/ABSdermal-human]

= 72 x 0.144 x [25 / 10] = 25.9mg/kg bw/d

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

DNELl-t dermal= 25.9 mg/kg bw/d

Pentane

Pentane is a simple asphyxiant with an IOELV of 3000 mg/m3(EU, 2006). No DN(M)EL will therefore be derived.


Cyclohexane

Worker – long-term systemic inhalation DNEL

The IOELV will be used without any modification

DNELl-t inhalation = 700 mg/m3

 

Worker – long-term systemic dermal DNEL

The dermal NOAEC is extrapolated from the IOELV. The IOELV is adjusted for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.4). It is assumed that uptake of cyclohexane after inhalation is 100% while dermal absorption is only 5% (as concluded in the EU RAR (2004), as derived from Jeffcott, 1996).

 

corrected_Dermal NOAEL = IOELV x sRVhuman 8hr x [ABSinhal-human/ABSdermal-human]

 

corrected_Dermal NOAEL = 700 mg/m3x wRV8-hour x [100% / 5%]

 

corrected_Dermal NOAEL = 700 x 0.144 x 20 = 2016 mg/kg bw/d

 

Note: 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).

 

No assessment factor is necessary

 

DNELl-t dermal = 2016 mg/kg bwt/d

 

Heptane

Heptane is a simple asphyxiant with an IOELV of 2085 mg/m3(EU, 2000). No DN(M)EL will therefore be derived.

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

ATSDR (1999).Toxicological Profile forn-Hexanehttp://www.atsdr.cdc.gov/toxprofiles/tp113.html

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

EU (1993). Occupational exposure limits: Criteria document for benzene. Report EUR 14491 en, ISSN 1018-5593, Commission of the European Communities, pp126.

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) Directive 2000/39/EC of 8 June 2000 establishing a first list of indicative occupational exposure limit values 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 Union, L 142, 47-50.

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.

MAK Commission (2009). 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 fortoluene108-88-3 http://ec.europa.eu/social/BlobServlet?docId=3816&langId=en

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.

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


[1] Data reported as 3.5 ppm, and converted to mg/m3 using tool available fromhttp://www.cdc.gov/niosh/docs/2004-101/calc.htm

[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/m3 values 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] Dir 2006/15/EC of 7 February 2006 [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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
3.25 µg/m³
Most sensitive endpoint:
carcinogenicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: The value that is proposed is based on a modification of the approach used by WHO (2000) which combined estimates of excess risk for leukaemia calculated by Crump (1994) for four models into a geometric mean estimate.
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
other: The Crump (1994) estimate of excess risk for AMML was substituted by estmates from TCEQ (2007), giving a median risk estimate of 0.9 x 10-5 per 1 ppb (3 x 10-6 per 1 µg/m3)
Value:
3.25 µg/m³
AF for dose response relationship:
1
Justification:
Excess risk estimates were based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984). No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for differences in duration of exposure:
1
Justification:
Excess risk estimates were based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984). No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
Excess risk estimates were based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984). No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for other interspecies differences:
1
Justification:
Excess risk estimates were based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984). No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for intraspecies differences:
1
Justification:
Excess risk estimates were based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984). No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for the quality of the whole database:
1
Justification:
Excess risk estimates were based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984). No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
AF for remaining uncertainties:
1
Justification:
Excess risk estimates were based on a human multiplicative risk, linear in cumulative exposure model (Crump and Allen, 1984). No additional assessment factors have been applied given the conservative nature of model, which is based on human lifetime exposure.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

General Population - Hazard via dermal route

Systemic effects

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

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
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).
Value:
0.464 µg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The inhalatory DMEL (ug/m3) was converted into a human 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

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) and, therefore, outside the scope of REACH. Since these streams all contain at least 0.1% benzene, their supply to the general population is prohibited except for fuels where the limits of benzene in fuels is 1%. No DN(M)ELs are therefore strictly required for the members of this category as there is no direct exposure of the general population. However equivalent information is necessary to characterise risks to man exposed via the environment, and DMELs for benzene have therefore been developed for this purpose. This information is summarised below:

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

0.1 to <25

0.00325

7692

0.464

53.9

0.0464

539

Further background on derivation of these values follows.

Benzene

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

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

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

References:

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

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

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

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

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

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

General population - long-term systemic inhalation DNEL

Dose descriptor

The inhalation DMEL will be used with no further modification.

DN(M)ELl-t inhalation= 3.25 µg/m3

General population - long-term systemic dermal DNEL

Dose descriptor

The inhalation DMEL of 3.25 µg/m3will be used.

Modification of dose descriptor

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

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

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

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

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

Assessment factors

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

DN(M)ELl-t dermal = 464 µg/kg bw/d

General population - long-term systemic oral DNEL

Dose descriptor

The inhalation DMEL of 3.25 µg/m3will be used.

Modification of dose descriptor

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

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

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

Assessment factors

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

DN(M)ELl-t oral = 0.464 µg/kg bw/d