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EC number: 271-260-2 | CAS number: 68527-18-4 A complex combination of hydrocarbons produced by distillation of the products from a steam cracking process. It consists of hydrocarbons having carbon numbers predominantly greater than C9 and boiling in the range of from approximately 205°C to 400°C (400°F to 752°F)
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://chesar.echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Toxicological Summary
- Administrative data
- Workers - Hazard via inhalation route
- Workers - Hazard via dermal route
- Workers - Hazard for the eyes
- Additional information - workers
- General Population - Hazard via inhalation route
- General Population - Hazard via dermal route
- General Population - Hazard via oral route
- General Population - Hazard for the eyes
- Additional information - General Population
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DMEL (Derived Minimum Effect Level)
- Value:
- 3.25 mg/m³
- 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:
- DMEL (Derived Minimum 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 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 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:
- low hazard (no threshold derived)
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- low 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 (appended to IUCLID secrion 13), which lists the chemical marker substances present along with an indicative concentration range for each e.g.
· Benzene: up to 19%
· Toluene: up to 2%
· Styrene: up to 2%
· Naphthalene: up to 60%
· Anthracene: up to 3%
The approach developed by the ExWG on the selection of category constituents for use in human health exposure assessments was implemented for Category G. The primary constituent used is benzene and naphthalene. A full description of this approach is available in Section 13.
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.
In general, 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.
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 Constituent |
CAS Number |
EC Number |
DNEL Value (mg/mg3) |
Source/Rationale |
Benzene |
71-43-2 |
200-753-7 |
3.25 |
To be revised in Q1 2020. |
DCPD |
77-73-6 |
201-052-9 |
2.31 |
Value from LOA REACH registration dossier. |
Naphthalene |
91-20-3 |
202-049-5 |
25 |
Non-LOA substance. Derived from repeated dose toxicity. |
Styrene |
100-42-5 |
202-851-5 |
85 |
Non-LOA substance. Derived from repeated dose toxicity. |
Toluene |
108-88-3 |
203-625-9 |
192 |
Value from LOA REACH registration dossier. Derived from neurotoxicity. |
Anthracene |
120-12-7 |
204 -371 -1 |
- |
Non-LOA substance. Low systemic toxicity, no DNELs required |
Based on this analysis, demonstration of “safe use” for hazards associated with inhalation exposure to benzene and dermal exposure to naphthalene would also provide adequate protection for workers against hazards arising from other marker substances present. However since benzene is a proven human carcinogen, it is concluded that it would be more prudent to conduct risk characterisation using this substance alone.
Intrinsic hazards of marker substances and associated DN(M)ELs:
The following hazard information and DNELs are available for marker substances present in this Category.
Benzene
Benzene causes adverse effects on the haematopoietic system of animals and in humans after repeated dose exposure via oral or inhalation routes. Long term experimental carcinogenicity bioassays have shown that it is a carcinogen producing a variety of tumours in animals (including lymphomas and leukaemia). Human epidemiological studies provide clear and consistent evidence of a causal association between benzene exposure and acute myelogenous (non-lymphocytic) leukaemia (AML or ANLL). An effect on bone marrow leading to subsequent changes in human blood cell populations is believed to underpin this response.
In accordance with REACH guidance, a science-based Binding Occupational Exposure Limit value (BOELV) can be used in place of a formal DN(M)EL providing no new scientific information exists which challenges the validity of the BOELV. While some information regarding a NOAEC for effects of benzene on human bone marrow (Schnatter et al, 2010; NOAEC = 11.18 mg/m3) post-date the BOELV, a DNEL based on these bone marrow findings would be higher than the BOELV. The BOELV (EU, 1999) will therefore be used as the basis of the DN(M)EL for long-term systemic effects associated with benzene, including carcinogenicity.
Worker – long-term systemic inhalation DNEL
The BOELV will be used with no further modification
DN(M)ELl-t inhalation= 3.25 mg/m3
Worker - long-term systemic dermal DNEL
The dermal DNEL for benzene is based on the internal dose achieved by a worker undertaking light work and exposed to the BOELV for 8 hr, assuming 50% uptake by the lung and 1% by skin for benzene uptake from petroleum streams. The value of 1% is based on experiments with compromised skin and with repeated exposure (Blank and McAuliffe, 1985; Maibach and Anjo, 1981) as well as the general observation that vehicle effects may alter the dermal penetration of aromatic compounds through the skin (Tsuruta et al, 1996). As the BOELV is based on worker life-time cancer risk estimates no assessment factor is needed.
Dermal NOAEL = BOELV x wRV8-hourx [ABSinhal-human/ ABSdermal-human] = 3.25 x 0.144 x [50 / 1]
DN(M)ELl-t dermal= 23.4 mg/kg bw/d
Dicyclopentadiene
The potential of dicyclopentadiene to cause long-term systemic effects can judged based on the results of repeated dose toxicity and reproductive (fertility, developmental) testing.
For DCPD, the following NOAEL/NOAECs are available:
Oral:
sub-chronic effects: male rat NOAEL = 4 mg/kg bw/d
reproductive effects: rat NOAEL = 50 mg/kg bw/d
developmental toxicity: rat NOAEL = 60 mg/kg bw/d
Inhalation:
sub-chronic effects: mouse NOAEC = 27.6 mg/m3
sub-chronic effects: rat NOAEC = 276 mg/m3
Worker – long-term systemic inhalation DNEL
Dose descriptor
A mouse inhalation NOAEC of 27.6 mg/m3 will be used to derive the DNELl-t inhalation.
Modification of dose descriptor
Correct the NOAEC to adjust for differences in duration in the animal study (6 h) and the worker (8 h) and light work following the TGD Figure R.8-2:
27.6 mg/m3x [6 h / 8 h] x [6.7 m3/ 10 m3] = 13.9 mg/m3
It is assumed that DCPD is similarly and efficiently (100%) absorbed after inhalation by mice and humans.
Assessment factors
An assessment factor of 6is used based on worker intraspecies differences (3)and correction for duration of exposure (sub-chronic to chronic = 2).
DNELl-t inhal= 13.9 mg/m3/ 6 = 2.3 mg/m3
Worker - long-term systemic dermal DNEL
Dose descriptor
A mouse inhalation NOAEC of 27.6 mg/m3will be used to derive the DNELl-t dermal.
Modification of dose descriptor
Correct the NOAEC to adjust for differences in duration of exposure; then convert the corrected mouse inhalation NOAEC (mg/m3) into a human dermal NOAEL (mg/kg bwt/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 DCPD after inhalation is 100% and, in the absence of data, dermal absorption is assumed to be the default of 100%.
correctedDermal NOAEL = NOAECinhalationx sRVmouse[1]x [ABSinhal-mouse/ABSdermal-human]
correctedDermal NOAEL = 27.6 x 0.514 x [100/100] = 14.19 mg/kg bwt/d
Assessment factors
An assessment factor of 42 is used based on interspecies differences for the mouse (7), worker intraspecies differences (3) and correction for duration of exposure (sub-chronic to chronic = 2).
DNELl-t dermal= 14.19 mg/kg bwt/d / 42 = 0.34 mg/kg bw/d
Toluene
Toluene exposure can produce central nervous system pathology in animals after high oral doses. Repeated inhalation exposure can produce ototoxicity in the rat and high concentrations are associated with local toxicity (nasal erosion). In humans neurophysiological effects and disturbances of auditory function and colour vision have been reported, particularly when exposures are not well controlled and/or associated with noisy environments.
Documentation supporting the IOELV (SCOEL, 2001) concluded that an exposure limit of 50 ppm (192 mg/m3) would protect against chronic effects. Hence, in accordance with REACH guidance and since no new scientific information has been obtained under REACH which contradicts use of the IOELV for this purpose, the established IOELV of 50 ppm (192 mg/m3) – 8 hr TWA (EU, 2006) will be used as the starting point for calculating the chronic dermal DNEL for workers.
Worker – long-term systemic inhalation DNEL
The IOELV will be used with no further modification
DN(M)ELl-t inhalation= 192 mg/m3
Worker – long-term systemic dermal DNEL
The dermal DNEL for toluene is based on the internal dose achieved by a worker undertaking light work and exposed to the IOELV for 8 hr, assuming 50% uptake by the lung and 3.6% uptake by skin (ten Berge, 2009).
As the IOELV is based on worker life-time exposure no assessment factor is needed.
Dermal NOAEL = IOELV x wRV8-hourx [50 / 3.6] = [192 x 0.144 x 13.89]
DN(M)ELl-t dermal= 384 mg/kg bw/d
Styrene
The cooperation of the Styrenics REACH consortia in providing DN(M)ELs for styrene is acknowledged. Documentation supporting these values is in the Styrenics REACH consortium dossier for styrene.
The EU transitional RAR (EU, 2008c) identified the following end-points as of concern for human health: acute toxicity (CNS depression), skin, eye and respiratory tract irritation, effects on colour vision discrimination following repeated exposure, effects on hearing (ototoxicity) following repeated exposure, developmental toxicity.
Worker – long-term systemic inhalation DNEL
The DN(M)EL is based on ototoxicity in humans(Triebig et al, 2009). A NOAEC for humans of 20 ppm (85 mg/m3) can be derived as starting point from this study. As the DNEL is derived from studies on exposed workers an assessment factor is not necessary.
DN(M)ELl-t inhalation= 85 mg/m3
Worker – long-term systemic dermal DNEL
The DN(M)EL is based on long term inhalation NOAEC of 20 ppm (86 mg/m3) for ototoxicity in workers. The dose descriptor is corrected into a human dermal NOAEL. Using a respiratory volume for workers under light physical activity of 10 m3/person/day and a body weight of 70 kg (ECHA, 2008) the external exposure would be 86 x 10/70 = 12.3 mg/kg bw/d.
This is then converted to a dermal dose by adjusting for differences in exposure. Absorption of styrene from the respiratory tract is considered to be 66% based on a study in 7 volunteers at 50 ppm under light physical activity (50 Watt) (Engström et al, 1978). In humans only 2% of a dermal dose of liquid styrene is likely to be absorbed (EU, 2008).
Dermal NOAEL = 12.3 x [ABSinhal-human/ ABSdermal-human]
= 12.3 x [66/2]
= 406 mg/kg/d.
Since the worker-DNEL long-term for dermal exposure was directly derived from that for inhalation exposure no further assessment factors are necessary.
DN(M)ELl-t dermal= 406 mg/kg bw/d
Naphthalene
The cooperation of the REACH for Coal Chemicals (R4CC) consortium in permitting access to DNEL information present on the ECHA Dissemination pages for naphthalene is acknowledged.
Worker – long-term systemic inhalation DNEL
The long-term systemic DNEL for naphthalene is based upon (EU and USA) OEL values of generally 50 mg/m3, with an assessment factor of 2:
DN(M)ELl-t inhalation= 50 mg/m3/ 2 = 25 mg/m3
Worker – long-term systemic dermal DNEL
The long-term dermal DNEL is based upon the systemic dose achieved following 8 hr exposure at the DNEL of 25 mg/m3.
DN(M)ELl-t dermal= 3.57mg/kg bw/d
Anthracene
The toxicological properties of anthracene have been reviewed (EU RAR, 2009), with a conclusion that it is of low toxicity following repeated exposure (NOAEC of 1000 mg/kg/day in mouse oral toxicity study) and is not of concern for mutagenicity or carcinogenicity. Although data are lacking with respect to reproductive and developmental toxicity no detectable toxic effects on the reproductive system of mice were seen during a 90-day feeding study and it was concluded that anthracene may possess weak, if any, developmental toxicity. However, extensive studies in animals and humans demonstrate that anthracene possess phototoxic potential following exposure in combination with UV light.
Based on the lack of systemic toxicity no substance-specific DNELs will therefore be developed for this marker substance. It is considered that the low concentration of anthracene present in this stream would not impact on the overall toxicity assessment and that risk management measures and occupational controls intended to minimise human exposure to the other toxicologically-active marker substances also present would limit exposure to anthracene.
References
ASTDR (2005). Toxicological profile for naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. http://www.atsdr.cdc.gov/toxprofiles/tp67.pdf
Blank IH, McAuliffe DJ (1985). Penetration of benzene through human skin. J. Invest. Dermatol, 85, 522–526.
EU (1999). Council Directive 1999/38/EC of 29 April 1999 amending for the second time Directive 90/394/EEC on the protection of workers from the risks related to exposure to carcinogens at work and extending it to mutagens. Official Journal of the European Communities, L138, 66-69, 1 June 1999.
EU (2003b). Risk assessment report for naphthalene. http://ecb.jrc.ec.europa.eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/naphthalenereport020.pdf
EU (2006). Directive 2006/15/EC of 7 February 2006 establishing a second list of indicative occupational exposure limit values in implementation of Council Directive 98/24/EC and amending Directives 91/322/EEC and 2000/39/EC. Official Journal of the European Union, l 38, 36-39.
EU (2009). Anthracene (CAS No 120-1207; EINECS No 204-371-1): Summary risk assessment report, October 2009. Available from: http://ecb.jrc.ec.europa.eu/risk-assessment/
Maibach HI, Anjo DM (1981). Percutaneous penetration of benzene and benzene contained in solvents used in the rubber industry. Arch. Environ. Health 36, 256–260
Schnatter AR, Kerzic P, Zhou Y, Chen M, Nicolich M, Lavelle K, Armstrong T, Bird M, Lin l, Hua F and Irons R (2010). Peripheral blood effects in benzene-exposed workers. Chem Biol Interact (2009) doi:10.1016/j. cbi.2009.12.020.
SCOEL (2001). Recommendation from the Scientific Committee on Occupational Exposure Limits for toluene 108-88-3 http://ec.europa.eu/social/BlobServlet?docId=3816&langId=en
Susten AS,Niemeier RW and Simon SD (1990). In vivo percutaneous absorption studies of volatile organic solvents in hairless mice II; Toluene, ethylbenzene and aniline. J. Appl. Toxicol. 10: 217-225.
Tsuruta, H (1996). Skin absorption of solvent mixtures-effect of vehicle on skin absorption of toluene. Ind. Health, 34, 369–378.
ten Berge, W (2009). A simple dermal absorption model: Derivation and application. Chemosphere, 75, 1440-1445.
[1] 6 hour value calculated from TGD Table R.8-17 values (as per guidance Appx R.8-2, example B.4) – sRV for mouse (mean male/female) is 1.43 L/min/kg bw = 0.514 m3/kg bw for 6 hours.
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
- Explanation for the modification of the dose descriptor starting point:
- None applied
- 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:
- low hazard (no threshold derived)
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DMEL (Derived Minimum Effect Level)
- Value:
- 0.464 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: 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 mg/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:
- low hazard (no threshold derived)
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 are expected to contain 0.1% of benzene, their supply to the general population is prohibited and no formal risk characterisation is therefore required. General population DN(M)ELs for benzene have been developed, however, to support risk assessment of man exposed via the environment with the background discussed below.
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
Toluene
Toluene exposure can produce central nervous system pathology in animals after high oral doses. Repeated inhalation exposure can produce ototoxicity in the rat and high concentrations are associated with local toxicity (nasal erosion). In humans neurophysiological effects and disturbances of auditory function and colour vision have been reported, particularly when exposures are not well controlled and/or associated with noisy environments.
Documentation supporting the IOELV (SCOEL, 2001) concluded that an exposure limit of 50 ppm (192 mg/m3) would protect against chronic effects. Hence, in accordance with REACH guidance and since no new scientific information has been obtained under REACH which contradicts use of the IOELV for this purpose, the established IOELV of 50 ppm (192 mg/m3) – 8 hr TWA (EU, 2006) will be used as the starting point for calculating the chronic dermal DNEL for workers.
General population – long term systemic inhalation DNEL
Long-term inhalation systemic DNEL is based on the IOELV after adjusting for differences in respiratory volume between workers (light exercise) and the general population (at rest), with an assessment factor of 1.7 used to account for intraspecies differences. The assessment factor of 1.7 is based on the ratio of intra-species differences for worker (AF = 3) and general population (AF = 5) groups reported in ECETOC (2003).
Inhalation NOAEL = IOELV x (wRV8-hour/ sRV24-hour) = 192 x (0.144 / 0.288) = 96 mg/m3
DN(M)ELl-t inhal= 96 mg/m3/ 1.7 = 56.5 mg/m3
General population – long-term systemic dermal DNEL
The long-term dermal systemic DNEL is based on the IOELV using route-to-route extrapolation after adjusting for differences in respiratory volume between workers (light exercise) and the general population (at rest).
Dermal NOAEL = IOELV x wRV8-hourx 50 / 3.6 = 192 x 0.144 x 13.89 = 384 mg/kg bw
An assessment factor of 1.7 is used to account for intraspecies differences.
DN(M)ELl-t dermal=384 mg/kg bw/d / 1.7 = 226 mg/kg bw
General population – long-term systemic oral DNEL
The IOELV of 192 mg/m3will be used. Correct the IOELV to an oral NOAEL (mg/kg/day) by converting the dose absorbed after inhalation into a systemic dose, assuming 50% uptake by the lung and 100% uptake from the GI tract:
Oral NOAEL = IOELV x wRV8-hourx [50 / 100] = 192 x 0.144 x 0.5 = 13.8 mg/kg bw/d
An assessment factor of 1.7 is used to account for intraspecies differences.
DN(M)ELl-t oral= 13.8 mg/kg bw/d / 1.7 = 8.13 mg/kg bw
Styrene
The cooperation of the Styrenics REACH consortia in providing DN(M)ELs for styrene is acknowledged.Documentation supporting these values is in the Styrenics REACH consortium dossier for styrene.
The EU transitional RAR (EU, 2008c) identified the following end-points as of concern for human health: acute toxicity (CNS depression), skin, eye and respiratory tract irritation, effects on colour vision discrimination following repeated exposure, effects on hearing (ototoxicity) following repeated exposure, developmental toxicity.
General population – long-term systemic inhalation DNEL
The DN(M)EL is based on ototoxicity in humans(Triebig et al, 2009). A NOAEC for humans of 20 ppm (85 mg/m3) can be derived as starting point from this study. A consumer DNEL is calculated by adjusting for differences in exposure (2 d/week for Do-It-Yourself (DIY) use of styrene containing products v 5 days /week i.e. 5/2 = 2.5) and adjusting for differences between the general population and workers (AF =3):
DN(M)ELl-t inhalation(DIY) = 20x 2.5 /3 = 17 ppm
For continuous exposure via the environment the (DIY) DNEL is adjusted for differences in exposure:
DIY vs. 24 h/d for exposure via the environment: 8/24
2 d/week for DIY vs. 7 d/week for exposure via the environment: 2/7
In addition, the worker DNEL is derived for light physical activity at the workplace. This does not apply to the continuous exposure via the environment leading to a correction factor of 1/0.67.
DN(M)ELl-t inhalation = 17x 2/7 x 8/24 x 1/0.67
= 17 x 0.286 x 0.33 x 1.5
=2.4 ppm = 10.2 mg/m3.
General population – long-term systemic dermal DNEL
The DN(M)EL is based on long term general population inhalation (DIY) DNEL of 17 ppm (73 mg/m3). The dose descriptor is corrected into a human dermal NOAEL by adjusting for differences in uptake between the two routes of exposure. Using a respiratory volume for workers under light physical activity of 10 m3/person/day and a body weight of 70 kg (ECHA, 2008) the external exposure would be 73 x 1/70 =10.4 mg/kg bw/day
This is then converted to a dermal dose by adjusting for differences in exposure. Absorption of styrene from the respiratory tract is considered to be 66% based on a study in 7 volunteers at 50 ppm under light physical activity (50 Watt) (Engström et al, 1978). In humans only 2% of a dermal dose of liquid styrene is likely to be absorbed (EU, 2008c).
Dermal NOAEL = 10.4 x [ABSinhal-human/ ABSdermal-human]
= 10.4 x [66/2]
= 343 mg/kg/d
Since the consumer-DNEL long-term for dermal exposure was directly derived from that for inhalation exposure no further assessment factors are necessary.
DN(M)ELl-t dermal= 343 mg/kg bw/d
General population – long-term systemic oral DNEL
The DNEL is based on the long term inhalation route via environment of 10.2 mg/m³. A respiratory volume of 20 m³/person/d is used for humans exposed via environment (ECHA, 2008) and an uptake by inhalation of 70% according to Engström (1978a). This leads to an internal body burden of
10.1 x 20 x 0.7 = 144 mg/person/d, corresponding to 2.1 mg/kg/d.
The oral absorption in rats is 90% and therefore 100% absorption by oral exposure is taken for humans.
Thus, the DNEL long-term oral is 2.1 mg/kg/d for humans exposed via environment.
Naphthalene
The cooperation of the REACH for Coal Chemicals (R4CC) consortium in permitting access to DNEL information present on the ECHA Dissemination pages for naphthalene is acknowledged.
No hazards were identified for consumers exposed via inhalation, skin contact or after ingestion, and hence no DNELs were proposed by R4CC.
Anthracene
The toxicological properties of anthracene have been reviewed (EU, 2009), with a conclusion that it is of low toxicity following repeated exposure (NOAEC of 1000 mg/kg/day in mouse oral toxicity study) and is not of concern for mutagenicity or carcinogenicity. Although data are lacking with respect to reproductive and developmental toxicity no detectable toxic effects on the reproductive system of mice were seen during a 90-day feeding study and it was concluded that anthracene may possess weak, if any, developmental toxicity. However, extensive studies in animals and humans demonstrate that anthracene possess phototoxic potential following exposure in combination with UV light.
Based on the lack of systemic toxicity no substance-specific DNELs will therefore be developed for this marker substance. It is considered that the low concentration of anthracene present in this stream would not impact on the overall toxicity assessment and that risk management measures and occupational controls intended to minimise human exposure to the other toxicologically-active marker substances also present would limit exposure to anthracene.
References
ASTDR (2005). Toxicological profile for naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. http://www.atsdr.cdc.gov/toxprofiles/tp67.pdf
ECETOC (2003). Derivation of assessment factors for human health risk assessment. Technical report No. 86, ECETOC, Brussels, February 2003.
EU (2003b). Risk assessment report for naphthalene. http://ecb.jrc.ec.europa.eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/naphthalenereport020.pdf
EU (2006). Directive 2006/15/EC of 7 February 2006 establishing a second list of indicative occupational exposure limit values in implementation of Council Directive 98/24/EC and amending Directives 91/322/EEC and 2000/39/EC. Official Journal of the European Union, l 38, 36-39.
EU (2009). Anthracene (CAS No 120-1207; EINECS No 204-371-1): Summary risk assessment report, October 2009. Available from: http://ecb.jrc.ec.europa.eu/risk-assessment/
SCOEL (2001). Recommendation from the Scientific Committee on Occupational Exposure Limits for toluene 108-88-3 http://ec.europa.eu/social/BlobServlet?docId=3816&langId=en
Susten AS,Niemeier RW and Simon SD (1990). In vivo percutaneous absorption studies of volatile organic solvents in hairless mice II; Toluene, ethylbenzene and aniline. J. Appl. Toxicol. 10: 217-225.
ten Berge, W (2009). A simple dermal absorption model: Derivation and application. Chemosphere, 75, 1440-1445.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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