Distillates (petroleum), cracked stripped steam-cracked petroleum distillates, C8-10 fraction

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

192 mg/m³

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 toluene

Value:

192 mg/m³

Explanation for the modification of the dose descriptor starting point:

None applied

AF for dose response relationship:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for differences in duration of exposure:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for interspecies differences (allometric scaling):

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for other interspecies differences:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for intraspecies differences:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for the quality of the whole database:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for remaining uncertainties:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

384 mg/m³

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-STEL for toluene

Value:

384 mg/m³

Explanation for the modification of the dose descriptor starting point:

None applied

AF for dose response relationship:

1

Justification:

IOELV (STEL) used without modification (ECHA Guidance, Appendix R.8-13)

AF for interspecies differences (allometric scaling):

1

Justification:

IOELV (STEL) used without modification (ECHA Guidance, Appendix R.8-13)

AF for other interspecies differences:

1

Justification:

IOELV (STEL) used without modification (ECHA Guidance, Appendix R.8-13)

AF for intraspecies differences:

1

Justification:

IOELV (STEL) used without modification (ECHA Guidance, Appendix R.8-13)

AF for the quality of the whole database:

1

Justification:

IOELV (STEL) used without modification (ECHA Guidance, Appendix R.8-13)

AF for remaining uncertainties:

1

Justification:

IOELV (STEL) used without modification (ECHA Guidance, Appendix R.8-13)

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

192 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Dose descriptor:

other: IOELV for toluene

AF for dose response relationship:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for differences in duration of exposure:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for interspecies differences (allometric scaling):

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for other interspecies differences:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for intraspecies differences:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for the quality of the whole database:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for remaining uncertainties:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

384 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Dose descriptor starting point:

other: IOELV-STEL for toluene

AF for dose response relationship:

1

Justification:

IOELV (STEL) used without modification (ECHA Guidance, Appendix R.8-13)

AF for interspecies differences (allometric scaling):

1

Justification:

IOELV (STEL) used without modification (ECHA Guidance, Appendix R.8-13)

AF for other interspecies differences:

1

Justification:

IOELV (STEL) used without modification (ECHA Guidance, Appendix R.8-13)

AF for intraspecies differences:

1

Justification:

IOELV (STEL) used without modification (ECHA Guidance, Appendix R.8-13)

AF for the quality of the whole database:

1

Justification:

IOELV (STEL) used without modification (ECHA Guidance, Appendix R.8-13)

AF for remaining uncertainties:

1

Justification:

IOELV (STEL) used without modification (ECHA Guidance, Appendix R.8-13)

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

384 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 toluene

Value:

384 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 IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for differences in duration of exposure:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for interspecies differences (allometric scaling):

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for other interspecies differences:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for intraspecies differences:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for the quality of the whole database:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

AF for remaining uncertainties:

1

Justification:

The IOELV (8-hr) was used without modification (ECHA Guidance, Appendix R.8-13)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

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 (appended to IUCLID section 13), which lists the chemical marker substances present along with an indicative concentration range for each e.g.

Benzene < 0.1%

Toluene ≤ 50%

Dicyclopentadiene ≤ 2%

Xylenes ≤ 40%

Naphthalene ≤ 15 %

Ethylbenzene ≤ 50%

Styrene ≤ 5%

The approach developed by the ExWG on the selection of category constituents for use in human health exposure assessments was implemented for Category J. The primary constituents used are Toluene and DCPD. A full description of this approach is available in Section 13.

Uses:

Low benzene naphtha streams are used as intermediates and in manufacturing processes as well as in fuels sold to consumers. These DNELs address concerns linked to the CMR properties of the marker substances or their potential to cause other long-term health effects leading to an equivalent level of concern.

Substance selection for risk characterization:

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/mg^3)	Source/Rationale
Benzene	71-43-2	200-753-7	1.9	Interim value proposed by LOA, August 2018. Current EU value is 3.25. Benzene is only considered in the exposure assessment for streams where it is found in concentrations greater than 0.1%.
DCPD	77-73-6	201-052-9	2.31	Value from LOA REACH registration dossier. DCPD is the main driver for exposure assessment when benzene concentrations are less than 0.1%.
Naphthalene	91-20-3	202-049-5	25	Non-LOA substance. Derived from repeated dose toxicity.
Ethylbenzene	100-41-4	202-849-4	77	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.
Xylenes	1330-20-7	215-535-7	221	Value from LOA REACH registration dossier. Derived from neurotoxicity.

Based on this analysis, management of inhalation and dermal hazards associated with the presence of toluene / dicyclopentadiene should also provide adequate protection against hazards arising from other marker substances present.

Hence, in order to demonstrate safe use in worker exposure scenarios computed by application of the ECETOC TRA, estimates of inhalation exposure and risk characterisation will use toluene as the marker substance (based on its relatively high volatility), while estimates of dermal exposure and risk characterisation will use DCPD as the marker substance (based on its lower volatility and very low dermal DNEL).

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

The following hazard information and DNELs are available for marker substances present in this Category.

Benzene

Benzene causes adverse effects on the haematopoietic system of animals and in humans after repeated dose exposure via oral or inhalation routes. Long term experimental carcinogenicity bioassays have shown that it is a carcinogen producing a variety of tumours in animals (including lymphomas and leukaemia). Human epidemiological studies provide clear and consistent evidence of a causal association between benzene exposure and acute myelogenous (non-lymphocytic) leukemia (AML or ANLL). An effect on bone marrow leading to subsequent changes in human blood cell populations is believed to underpin this response.

In accordance with REACH guidance, a science-based Binding Occupational Exposure Limit value (BOELV) can be used in place of a formal DN(M)EL providing no new scientific information exists which challenges the validity of the BOELV. While some information regarding a NOAEC for effects of benzene on human bone marrow (Schnatter et al, 2010; NOAEC = 11.18 mg/m^3[1]) post-date the BOELV for benzene, a DNEL based on these bone marrow findings would be higher (and hence offer less protection) than the BOELV. The BOELV (EU, 1999) will therefore be used as the basis of the DN(M)EL for long-term systemic effects associated with benzene, including carcinogenicity.

Worker – long-term systemic inhalation DNEL

The BOELV will be used with no further modification

DN(M)EL_{l-t inhalation} = 1.91 mg/m³ (0.6 ppm)

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 xwRV_8-hour[2] x [ABS_inhal-human/ABS_dermal-human] = 1.91 x 0.144 x [50 / 1] = 13.75

                           

DN(M)EL_{l-t dermal} = 13.75 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) included a large amount of human data which indicate that the LOAEC for subjective effects of toluene is about 60 ppm (230 mg/m³). Newer data (from Muttray et al., 2005) indicate that 50 ppm (188 mg/m³) is a NOAEC for acute subjective effects (i.e. effects on how the person feels), supporting the current IOELV. Consequently, in accordance with REACH guidance (Appendix R.8-13), the established short term IOELV-STEL of 100 ppm (384 mg/m³) 15-min will be proposed as the short-term systemic inhalation DNEL for workers.

DNEL_{acute systemic inhalation} = IOELV- STEL = 384 mg/m³

Toluene vapours in ambient air are reported to cause subjective sensations of eye irritation in humans, with a NOAEC of 50 ppm (188 mg/m3) established by Muttray et al. (2005). These data support the current IOELV-STEL. Consequently, in accordance with REACH guidance (Appendix R.8-13), the established IOELV-STEL will be used as the short-term local inhalation DNEL.

DNEL_{acute local inhalation} = IOELV- STEL = 384 mg/m³

(Note: 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.)

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 long-term worker DNELs.

Worker – long-term systemic inhalation DNEL

The IOELV will be used with no further modification

DNEL_{l-t inhalation} = IOELV = 192 mg/m³

Worker – long-term systemic dermal DNEL

The dermal DNEL for toluene is based on the internal dose achieved by a worker undertaking light work and exposed to the IOELV for 8 hr, assuming 50% uptake by the lung and 3.6% uptake by skin (ten Berge, 2009).

As the IOELV is based on worker life-time exposure no assessment factor is needed.

Dermal NOAEL = IOELV x wRV8-hour x [50/3.6] = [192 x 0.144 x 13.89]

DNEL_{l-t dermal} = 384 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/m³will be used to derive the DNEL_{l-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 onworkerintraspecies differences (3)and correction for duration of exposure (sub-chronic to chronic = 2).

DNEL_{l-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 DNEL_{l-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 = NOAEC_inhalationx sRV_mouse^[4]x [ABS_inhal-mouse/ABS_dermal-human]

_correctedDermal NOAEL = 27.6 x 0.514 x [100/100] = 14.19 mg/kg bwt/d

Assessment factors

An assessment factor of 42is used based on interspecies differences for themouse (7), workerintraspecies differences (3)and correction for duration of exposure (sub-chronic to chronic = 2).

DNEL_{l-t dermal}= 14.19 mg/kg bwt/d / 42 = 0.34 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) EL_{l-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) EL_{l-t dermal}= 3.57mg/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(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, 2008b) 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, 2008c). 

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

Xylene isomers

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

ECETOC guidance for assessment factors and used and the IOELV as starting point for all DNELs (worker and general population).

Worker – long-term systemic inhalation DNEL

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

Worker – long-term systemic dermal DNEL

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

The IOELV (mg/m³) is corrected into a human dermal NOAEL (mg/kg bw/d) by adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.4).

It is assumed that uptake of xylenes after inhalation is 100% with a value of 1% for dermal absorption (ten Berge, 2009):

_correctedDermal NOAEL = IOELV x wRV_human-8hrx [ABS_inhal-human/ ABS_dermal-human]

_correctedDermal NOAEL = 221 x 0.144 x (100 / 1) = 3182 mg/kg bw/d

No assessment factor is necessary.

Ethylbenzene

The cooperation of the Styrenics Steering Committee in providing DNELs for ethylbenzene is acknowledged.Documentation supporting these values is in the Styrenics REACH consortium dossier for ethylbenzene.

Worker – long-term systemic inhalation DNEL

There is no IOELV for ethylbenzene, therefore theDNEL is based on sub-chronic effects (ototoxicity) in the rat following inhalation exposure: extrapolated NOAEC = 500 mg/m³(114 ppm). Correct the NOAEC to adjust for activity driven and absorption percentage differences following ECHA TGD (2008b) guidance:

DNEL_{l-t inhalation}= 500 mg/m³x [6.7 / 10] x [ABS_inhal-rat/ ABS_inhal-human] = 500 mg/m³x 0.67 x [45 / 65] = 232 mg/m³

An assessment factor of 3 is used forintraspecies differences within worker population:

DN(M)EL_{l-t inhalation}= 232 mg/m³/ 3 = 77 mg/m³

Worker – long-term systemic dermal DNEL

The DNEL is based on sub-chronic effects (ototoxicity) in the rat following inhalation exposure: extrapolated NOAEC = 500 mg/m³(114 ppm). The NOAEC is corrected into a human dermal NOAEL (mg/kg bw/d) by adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.4). It is assumed that uptake of ethylbenzene after inhalation in rats is 45%.

_correctedDermal NOAEL = NOAEC_{l-t inhalation}x sRV_rat-8hr^[5]x 0.45 = 500 x 0.38 mg/kg bw/d = 86 mg/kg bw/d

A value of 4% used for dermal absorption in humans (Susten et al, 1990):

_correctedDermal NOAEL = 86 mg/kg bw/d x [100 /4 ] = 2150 mg/kg bw/d

An assessment factor of 12 is used based on interspecies differences for the rat (4) and intraspecies differences within worker populations (3).

The DNEL for long-term dermal exposure is derived as follows:

DN(M)EL_{l-t dermal}= 2150 mg/kg bw/d / 12 = 180 mg/kg bw/d

References

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

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

Engstrom K, Harkonen H, Pekari K and Rantanen J. (1978). Evaluation of occupational styrene exposure by ambient air and urine analysis. Scand. J. Work Environ. Health, 4 (Suppl. 2):121-123.

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 (2003). 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.

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

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

Susten, AS et al (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.

Triebig G, Bruckner T and Seeber A (2009). Occupational styrene exposure and hearing loss: a cohort study with repeated measurements. Int Arch Occup Environ Health, 82 (4), 463-481.

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

 

[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] 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

[5] Standard respiratory volume (sRV) of a 250 g rat = 0.38 m³/kg bw (TGDTable R.8-2)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

56.5 mg/m³

Most sensitive endpoint:

neurotoxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance; ECETOC (2003, 2010).

Overall assessment factor (AF):

1.7

Modified dose descriptor starting point:

other: IOELV for toluene

Value:

192 mg/m³

Explanation for the modification of the dose descriptor starting point:

None applied

AF for dose response relationship:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for differences in duration of exposure:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for interspecies differences (allometric scaling):

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for other interspecies differences:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for intraspecies differences:

1.7

Justification:

The worker IOELV has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV has been examined for consistency and biological plausibility by the Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The magnitude of the IOELV was further modified to take into account differences in duration of exposure experienced by workers and the general population. The IOELV has therefore been taken as a human 8-hr NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.

AF for the quality of the whole database:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for remaining uncertainties:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

226 mg/m³

Most sensitive endpoint:

neurotoxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance; ECETOC (2003, 2010).

Overall assessment factor (AF):

1.7

Modified dose descriptor starting point:

other: IOELV-STEL for toluene

Value:

384 mg/m³

Explanation for the modification of the dose descriptor starting point:

None applied

AF for dose response relationship:

1

Justification:

IOELV-STEL (15-min) used as starting point (human NAEL)

AF for interspecies differences (allometric scaling):

1

Justification:

IOELV-STEL (15-min) used as starting point (human NAEL)

AF for other interspecies differences:

1

Justification:

IOELV-STEL (15-min) used as starting point (human NAEL)

AF for intraspecies differences:

1.7

Justification:

The worker IOELV-STEL has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV-STEL has been examined for consistency and biological plausibility by the Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV-STEL to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.

AF for the quality of the whole database:

1

Justification:

IOELV-STEL (15-min) used as starting point (human NAEL)

AF for remaining uncertainties:

1

Justification:

IOELV-STEL (15-min) used as starting point (human NAEL)

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

56.5 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance; ECETOC (2003, 2010).

Overall assessment factor (AF):

1.7

Dose descriptor:

other: IOELV for toluene

AF for dose response relationship:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for differences in duration of exposure:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for interspecies differences (allometric scaling):

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for other interspecies differences:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for intraspecies differences:

1.7

Justification:

The worker IOELV has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV has been examined for consistency and biological plausibility by the Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The magnitude of the IOELV was further modified to take into account differences in duration of exposure experienced by workers and the general population. The IOELV has therefore been taken as a human 8-hr NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.

AF for the quality of the whole database:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for remaining uncertainties:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

226 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance; ECETOC (2003, 2010).

Overall assessment factor (AF):

1.7

Dose descriptor starting point:

other: IOELV-STEL for toluene

AF for dose response relationship:

1

Justification:

IOELV-STEL (15-min) used as starting point (human NAEL)

AF for interspecies differences (allometric scaling):

1

Justification:

IOELV-STEL (15-min) used as starting point (human NAEL)

AF for other interspecies differences:

1

Justification:

IOELV-STEL (15-min) used as starting point (human NAEL)

AF for intraspecies differences:

1.7

Justification:

The worker IOELV-STEL has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV-STEL has been examined for consistency and biological plausibility by the Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV-STEL to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.

AF for the quality of the whole database:

1

Justification:

IOELV-STEL (15-min) used as starting point (human NAEL)

AF for remaining uncertainties:

1

Justification:

IOELV-STEL (15-min) used as starting point (human NAEL)

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

226 mg/kg bw/day

Most sensitive endpoint:

neurotoxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance; ECETOC (2003, 2010).

Overall assessment factor (AF):

1.7

Modified dose descriptor starting point:

other: IOELV for toluene

Value:

384 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:

IOELV (8-hr) used as starting point (human NAEL)

AF for differences in duration of exposure:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for interspecies differences (allometric scaling):

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for other interspecies differences:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for intraspecies differences:

1.7

Justification:

The worker IOELV has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV has been examined for consistency and biological plausibility by the Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The magnitude of the IOELV was further modified to take into account differences in duration of exposure experienced by workers and the general population. The IOELV has therefore been taken as a human 8-hr NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.

AF for the quality of the whole database:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for remaining uncertainties:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

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:

DNEL (Derived No Effect Level)

Value:

8.13 mg/kg bw/day

Most sensitive endpoint:

neurotoxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance; ECETOC (2003, 2010).

Overall assessment factor (AF):

1.7

Modified dose descriptor starting point:

other: IOELV for toluene

Value:

13.8 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The IOELV (mg/m3) was converted into a human oral 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:

IOELV (8-hr) used as starting point (human NAEL)

AF for differences in duration of exposure:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for interspecies differences (allometric scaling):

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for other interspecies differences:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for intraspecies differences:

1.7

Justification:

The worker IOELV has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV has been examined for consistency and biological plausibility by the Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The magnitude of the IOELV was further modified to take into account differences in duration of exposure experienced by workers and the general population. The IOELV has therefore been taken as a human 8-hr NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.

AF for the quality of the whole database:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

AF for remaining uncertainties:

1

Justification:

IOELV (8-hr) used as starting point (human NAEL)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Compositional information:

These hydrocarbon streams meet the regulatory definition of UVCB substances, with inherent variations in composition present due to differences in manufacturing history. This variability is documented in the Category Justification (appended to IUCLID section 13),which lists the chemical marker substances present along with an indicative concentration range for each e.g.

Benzene < 0.1%

Toluene ≤ 50%

Dicyclopentadiene ≤ 2%

Xylenes ≤ 40%

Naphthalene ≤ 15 %

Ethylbenzene ≤ 50%

Styrene ≤ 5%

The approach developed by the ExWG on the selection of category constituents for use in human health exposure assessments was implemented for Category J. The primary constituents used are Toluene and DCPD. A full description of this approach is available in Section 13.

Uses:

Low benzene naphtha streams are used as intermediates and in manufacturing processes as well as in fuels sold to consumers. These DNELs address concerns linked to the CMR properties of the marker substances or their potential to cause other long-term health effects leading to an equivalent level of concern.

Substance selection for risk characterization:

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.

 

 

Based on this analysis, management of inhalation and dermal hazards associated with the presence of toluene / dicyclopentadiene should also provide adequate protection against hazards arising from other marker substances present.

 

Hence, in order to demonstrate safe use in general population exposure scenarios computed by application of the ECETOC TRA, estimates of inhalation exposure and risk characterisation will use toluene as the marker substance (based on its relatively high volatility), while estimates of dermal exposure and risk characterisation will use DCPD as the marker substance (based on its lower volatility and very low dermal DNEL).

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

The following hazard information and DNELs are available for marker substances present in this Category.

Benzene

As noted above, use of benzene is restricted under REACH and no general population DNELs will therefore be developed.

Toluene

Toluene exposure can produce central nervous system pathology in animals after high oral doses. Repeated inhalation exposure can produce ototoxicity in the rat and high concentrations are associated with local toxicity (nasal erosion). In humans neurophysiological effects and disturbances of auditory function and colour vision have been reported, particularly when exposures are not well controlled and/or associated with noisy environments.

General population DNELs for toluene have used the worker IOELV as their starting point. This is considered scientifically justifiable since information supporting the IOELV has been examined for consistency and biological plausibility by SCOEL, with only robust data used in the limit setting process. Importantly, results from human investigations played a key part in this process. It was also considered that the use of a common starting point (the IOELV) for both population groups would result in greater consistency in hazard (dose-response) identification than would be the case if different methods of assessment had been used for workers and the general population. The IOELV has therefore been taken as a human no adverse effect level (NAEL) which, after modification (though use of an assessment factor), would be more broadly applicable to the general population. Similar considerations apply to the IOELV-STEL, which has been taken as a surrogate human 15-minute NAEL.

Documentation supporting the IOELV (SCOEL, 2001) included a large amount of human data which was used by SCOEL to established an IOELV-STEL of 100 ppm (384 mg/m³) 15-min for systemic and local effects. This forms the basis of the short-term systemic and local DNELs presented here.

While assessment factors are not required when a worker DNEL is based upon an IOELV, one is included here to reflect uncertainty when moving from the IOELV to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV-STEL to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.

DNEL_{short-term inhalation} = 384 mg/m³ / 1.7 = 226 mg/m³

Documentation supporting the IOELV (SCOEL, 2001) concluded that an exposure limit of 50 ppm (192 mg/m3) would protect against long-term effects.

For long-term inhalation exposure, the dose descriptor has been modified to take into account the different duration of exposure experienced by workers (8-hours) versus the chronic exposure experienced by the general population (24-hours).

Inhalation NOAEL = IOELV x (wRV8-hour / sRV24-hour) = 192 x (0.144 / 0.288 2) = 96 mg/m³

An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), has been used to reflect uncertainty when moving from the IOELV to the general population.

DNEL_{l-t inhal} = 96 mg/m³ / 1.7 = 56.5 mg/m³

For for long-term dermal exposure, route-to-route extrapolation was used to convert the IOELV into a dermal NOAEL (mg/kg/day) and was based upon the dose absorbed after inhalation exposure (8 hr) assuming 50% uptake by the lung and 3.6% uptake by skin (ten Berge, 2009):

Dermal NOAEL = IOELV x wRV8-hour x 50/3.6 = 192 x 0.144 x 13.89 = 384 mg/kg bw

An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), has been used to reflect uncertainty when moving from the IOELV to the general population.

DNEL_{l-t dermal} =384 mg/kg bw/d / 1.7 = 226 mg/kg bw, once per week

For long-term oral exposure, the IOELV was converted into a systemic dose (mg/kg/day) by assuming 50% uptake by the lung and 100% uptake from the GI tract:

Oral NOAEL = IOELV x wRV8-hour x [50/100] = [IOELV x wRV8-hour x 50/100] = 192 x 0.144 x 0.5 = 13.8 mg/kg bw/d

An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), has been used to reflect uncertainty when moving from the IOELV to the general population.

DNEL_{l-t oral} = 13.8 mg/kg bw/d / 1.7 = 8.13 mg/kg bw

 

Xylenes
General Population – long-term systemic inhalation DNEL

Dose descriptor

The IOELV of 221 mg/m3 will be used to derive the DNELl-t inhalation (see discussion under Workers).

Modification of dose descriptor

Correct the NOAEC to adjust for differences in duration for the IOELV (8 h TWA) and general population exposure (24 h) following the TGD Figure R.8-2:

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

Inhalation NOAEL = 221 x (0.144 / 0.288) = 111 mg/m3

Note:

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

It is assumed that xylene is similarly and efficiently (100%) absorbed after inhalation by rats and humans.

Assessment factors

Uncertainty	AF	Justification
Interspecies differences	1	Human data, not required
Intraspecies differences	1.7	The worker IOELV has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV has been examined for consistency and biological plausibility by Scientific Expert Group on Occupational Exposure Limits (now SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The magnitude of the IOELV was further modified to take into account differences in duration of exposure experienced by workers and the general population. The IOELV has therefore been taken as a human (worker) 8-hr NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.
Differences in duration of exposure	1	default AF
Dose response and endpoint specific/severity issues	1	default AF
Quality of database	1	default AF
Overall AF	1.7

DNELl-t inhalation = 111 mg/m3 / 1.7 = 65.3 mg/m3

 

General Population – long-term systemic dermal DNEL

Dose descriptor

The IOELV (8 h TWA) of 50 ppm (221 mg/m3) will be used to derive the DNELl-t dermal.

Modification of dose descriptor

The IOELV (mg/m3) is corrected into a human dermal NOAEL (mg/kg bwt/d) by adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.4).

It is assumed that uptake of xylenes after inhalation is 100% with a value of 15% for dermal absorption (ten Berge, 2009):

correctedDermal NOAEL = IOELV x wRV8-hour x 100/15

correctedDermal NOAEL = 221 x 0.144 x 100/15 = 212 mg/kg bw

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)

Assessment factors

Uncertainty	AF	Justification
Interspecies differences	1	Human data, not required
Intraspecies differences	1.7	The worker IOELV has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV has been examined for consistency and biological plausibility by Scientific Expert Group on Occupational Exposure Limits (now SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The magnitude of the IOELV was further modified to take into account differences in duration of exposure experienced by workers and the general population. The IOELV has therefore been taken as a human (worker) 8-hr NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.
Differences in duration of exposure	1	default AF
Dose response and endpoint specific/severity issues	1	default AF
Quality of database	1	default AF
Overall AF	1.7

 

DNELl-t dermal = 212 mg/kg bwt/d / 1.7 = 125 mg/kg bwt/d

 

General Population – long-term systemic oral DNEL

The following overall NOAEC is presented in the IUCLID dossier:

chronic effects: rat NOAEC (bodyweight) = 250 mg/kg/d

Dose descriptor

A rat oral NOAEL of 250 mg/kg bw/d (rat, 2 yr) will be used (NTP, 1986 – bodyweight) to derive the DNELl-t oral

Modification of dose descriptor

No modification required

Assessment factors

Uncertainty	AF	Justification
Interspecies differences	4	default AF
Intraspecies differences	5	There are no data to quantify variability in susceptibility to the effects of exposure to xylene isomers in the human population. However an analysis of assessment factors conducted by ECETOC (2003, 2010) showed that metabolic differences due to genetic polymorphisms do not to automatically require an increased assessment factor since alternative pathways of elimination are often present. Following a review of the distribution of variability in toxicokinetic and toxicodynamic parameters for populations of different ages, genders and disease states, ECETOC concluded that human data (Renwick and Lazarus (1998) Reg. Tox. Pharmacol. 27:3-20 ; Hattis et al. (1999) Risk Anal. 19: 421-431) support the use of an assessment factor of 5 (i.e. the 95th percentile of human toxicokinetic and toxicodynamic variability) to account for intra-species variability present within the general population.
Differences in duration of exposure	1	chronic study
Dose response and endpoint specific/severity issues	1	default AF; clear NOAEC
Quality of database	1	default AF
Overall AF	20

 

DNELl-t oral = 250 mg/kg bwt/d / 20 = 12.5 mg/kg bwt/d

 

Naphthalene 

The cooperation of the REACH for Coal Chemicals (R4CC) consortium in providing DNELs for naphthalene is acknowledged. Documentation supporting these values is in the R4CC consortium dossier for naphthalene.

No hazards were identified for consumers exposed via inhalation, skin contact or after ingestion, and hence no DNELs were proposed by R4CC.

 

Ethylbenzene

The cooperation of the Styrenics Steering Committee in providing DNELs for ethylbenzene is acknowledged.

General population – long-term systemic inhalation DNEL

The DNEL is based on sub-chronic effects (ototoxicity) in the rat following inhalation exposure: extrapolated NOAEC = 500 mg/m³(114 ppm). Correct the NOAEC to adjust for absorption percentage differences following ECHA TGD (2008) guidance. Adjustment is also made for exposure duration with experimental conditions being 6 hours/day, 6 days/week.

DNEL_{lt inhalation} = 500 mg/m³x [6/24] x [6/7] x[ABSinhal-rat/ABSinhalationl-human] = 500 mg/m³x [6/24] x [6/7] x[45/65] = 74 mg/m³

An assessment factor of 5 is used based on intaspecies differences between worker and general populations.

The DNEL for long-term inhalation exposure is derived as follows:

DNEL_{l-t inhalation} =74 mg/m³/ 5 = 14.8mg/m³

General population – long-term systemic dermal DNEL

The DNEL is based on sub-chronic effects (ototoxicity) in the rat following inhalation exposure: extrapolated NOAEC = 500 mg/m³(114 ppm). The dose descriptor is corrected into a human dermal NOAEL (mg/kg bwt/d) by adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.4). It is assumed that uptake of ethylbenzene after inhalation in rats is 45%.

Corrected Dermal NOAEL = NOAEC_{l-t inhalation} x sRVrat-8hrx 0.45 = 500 x 0.38 x 0.45 = 86 mg/kg bwt/d

A value of 4% used for dermal absorption in humans (Susten et al, 1990):

Corrected Dermal NOAEL = 86 mg/kg bwt/d x [100/4] = 2150 mg/kg bwt/d

An assessment factor of 20 is used based on interspecies differences for the rat (4) and intraspecies differences between worker and general populations (5).

The DNEL for long-term dermal exposure is derived as follows:

DNEL_{l-t dermal} = 2150 mg/kg bwt/d / 20 = 108 mg/kg bwt/d 

General population – long-term systemic oral DNEL

The starting point is the NOAEL in a guideline oral 90 day study with rats was 75 mg/kg bw/d. An 84% oral absorption is used for rats and 100% for humans as conservative default leading to an internal dose:

Corrected Oral NOAEL = 75 mg/kg bwt/d x [ABSoral-rat/ABSoral-human] = 75 mg/kg bwt/d x [84/100] = 63 mg/kg bwt/d

References

EU (2006) Directive 2006/15/EC of 7 February 2006 establishing a second list of indicative occupational exposure limit values in implementation of Council Directive 98/24/EC and amending Directives 91/322/EEC and 2000/39/EC. Official Journal of the European Union, l 38, 36-39.

SCOEL (2001).Recommendation from the Scientific Committee on Occupational Exposure Limits fortoluene108-88-3 http://ec.europa.eu/social/BlobServlet?docId=3816&langId=en