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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
1.91 mg/m³
DNEL related information
Overall assessment factor (AF):
1
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.34 mg/kg bw/day
DNEL related information
Overall assessment factor (AF):
42
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Compositional information:

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

·        Dicyclopentadiene:<80%

·        Benzene: <0 - 3%

·        n-Hexane: <0 – 0.2%

·        Toluene: up to 20%

·        Styrene: up to 25%

·        C8 Aromatics (xylene, ethylbenzene) up to 20%

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

Uses:

These hydrocarbon streams are used as intermediates, in manufacture and hence no exposure to the general population is likely. 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/mg3) 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.
n-Hexane 110-54-3 203-777-6 75 Non-LOA substance. Derived from neurotoxicity.
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 dicyclopentadiene / methylcyclopentadiene should also provide adequate protection against hazards arising from other marker substances present. However this conclusion does not consider the relative volatilities of the substances present, and overlooks the fact that benzene is a human carcinogen requiring an appropriate level of control.

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 benzene as the marker substance (based on its relatively high volatility and carcinogenicity), 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.

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 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 onworkerintraspecies 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 42is used based on interspecies differences for themouse (7), workerintraspecies 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

Benzene

Benzene causes adverse effects on the haematopoietic system of animals and in humans after repeated dose exposure via oral or inhalation routes. Long term experimental carcinogenicity bioassays have shown that it is a carcinogen producing a variety of tumours in animals (including lymphomas and leukaemia). Human epidemiological studiesprovide clear and consistent evidence of a causal association between benzene exposure and acute myelogenous (non-lymphocytic) 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)[2]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= 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 xwRV8-hour[3] x [ABSinhal-human/ ABSdermal-human] = 1.91 x 0.144 x [50 / 1] = 13.75

DN(M)ELl-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) 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)[4]– 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= IOELV = 192 mg/m3

Worker – long-term systemic dermal DNEL

The dermal DNEL for toluene is based on the internal dose achieved by a worker undertaking light work and exposed to the IOELV for 8 hr, assuming50% uptake by the lung and 3.6% uptake by skin(ten Berge, 2009).

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

Dermal NOAEL = IOELV x wRV8-hourx [50 / 3.6] = 192 x 0.144 x 13.8]

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(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 DNELl-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 wRVhuman-8hrx [ABSinhal-human/ ABSdermal-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:

DNELl-t inhalation= 500 mg/m3x [6.7 / 10] x [ABSinhal-rat/ ABSinhal-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)ELl-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 = NOAECl-t inhalationx sRVrat-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)ELl-t dermal= 2150 mg/kg bw/d / 12 = 180 mg/kg bw/d

References

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

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.

ECHA (2008b). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for for human health.

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 (2000).Council Directive 2000/39/EC of 8 June 2000 establishing a first list of indicative occupational exposure limit values (IOELV) in implementation of Council Directive 98/24/EC on the protection of the health and safety of workers from the risks related to chemical agents at work.Official Journal of the European Communities, L142, 47-50.

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.

MAK (2009) MAK Commission. MAK, 46 Lieferung

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 Interact184: 174-181.

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, 369–3

[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

 

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

 

[3] 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

 

[4] 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

  

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

Local effects

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

General Population - Hazard via dermal route

Systemic effects

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

Local effects

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

General Population - Hazard via oral route

Systemic effects

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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

These hydrocarbon streams are used as intermediates, in manufacture and hence no exposure to the general population is likely and no general population DNELs have been developed.