Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

77 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Overall assessment factor (AF):

3

Modified dose descriptor starting point:

NOAEC

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Value:

289 mg/m³

Overall assessment factor (AF):

1

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Value:

870 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Overall assessment factor (AF):

3

Dose descriptor starting point:

NOAEC

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

180 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Overall assessment factor (AF):

12

Modified dose descriptor starting point:

NOAEL

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Hazard assessment conclusion:

no hazard identified

DNEL Derivation Proposals for Xylenes Category

DNEL Derivation Proposals for Xylenes Category

Compositional information:

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

· o-Xylene, m-xylene and p-xylene: ≥45%

· Ethylbenzene: ≤55%

· Styrene: ≤ 25% (dependent on manufacturer)

· Benzene: <0.1 - 1% (dependent on manufacturer)

· Toluene: <0.1 - 5% (dependent on manufacturer)

Uses:

These hydrocarbon streams are used as intermediates and in manufacture and hence exposure includes both workers and the general population. 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.

Benzene is a category 1A carcinogen and inclusion in formulations supplied to the general population should be restricted to a maximum of <0.1%. No classification is required for such formulations, and therefore no general population DNELs will be developed for benzene.

In the case of this stream, the most hazardous marker substances present are highlighted in the following table:

Workers

Marker substance	Indicative concentration (%)	Short-term inhalation
Marker substance	Indicative concentration (%)	DN(M)EL mg/m3	Relative hazard potential (max % ÷ DN(M)EL)
xylene isomers	>45	442	0.10
ethylbenzene	<55	289	0.19
benzene+	<0.1 - 1%	€	€
toluene+	<0.1 - 5%	384	0.01
styrene+	≤ 25%	289 - 306	0.08 - 0.09

Marker substance	Indicative concentration (%)	Inhalation		Dermal
Marker substance	Indicative concentration (%)	DN(M)EL mg/m³	Relative hazard potential (max % ÷ DN(M)EL)	DN(M)EL mg/kg bwt/d	Relative hazard potential (max % ÷ DN(M)EL)
xylene isomers	>45	221	0.20	3182	0.014
ethylbenzene	<55	77	0.71	180	0.31
benzene+	<0.1 - 1%	3.25	0.31	23.4	0.043
toluene+	<0.1 - 5%	192	0.026	384	0.013
styrene+	≤ 25%	0.29	406	0.06	85

+ Streams from some manufactures may contain toluene, benzene, styrene

€ There is no short-term BOELV for benzene

Conclusions:

Risk characterisation for short and long-term inhalation and dermal exposure for workers handling streams containing xylene isomers and ethylbenzene is driven by ethylbenzene. The appropriate long-term DNEL for ethylbenzene will therefore be used for risk characterization in these circumstances.

Streams produced by some manufacturers contain, in addition, variable amounts of benzene, toluene and styrene. For workers, health risk characterization for inhalation and dermal exposure to such streams will also be influenced by by ethylbenzene.

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

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

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 – short-term local / systemic inhalation DNEL

The IOELV-STEL of 100 ppm (442 mg/m³, 15min) will be used as the basis of the worker short-term DNEL.

DNEL_{acute-local/systemic
inhalation}= 442 mg/m³

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 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 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[1]x (100/1) = 3182 mg/kg bwt/d

No assessment factor is necessary.

Ethylbenzene

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

Worker – short-term local inhalation DNEL
There is no short-term IOELV for ethylbenzene. The dose descriptor was taken from a human volunteer study which assessed subjective irritation and the presence of inflammatory biomarkers in nasal secretions following exposure to fluctuating concentrations of ethylbenzene in air, leading to a NOAEC of 200 ppm for short term exposures of 15 min (van Thriel et al., 2003). The NOAEC was the highest concentration investigated, and the “true” NOAEC is not known but certainly is higher.

Application of a 3-fold assessment factor (intra-species differences) gave an acute DNEL of 289 mg/m³(15-min TWA).

DNEL_{acute-local
inhalation}= 289 mg/m³

Worker – short-term systemic inhalation DNEL

There is no short-term IOELV for ethylbenzene. No short-term systemic inhalation DNEL was developed by the Styrenics Steering Committee for ethylbenzene, hence the short-term local inhalation will be used instead. This value (289 mg/m3, 15-min TWA) compares favourably with the rat 4-hr LC50 of 17,600 mg/m3.

DNEL_{acute-systemic
inhalation}= 289 mg/m³

Worker – long-term systemic inhalation DNEL

There is no IOELV for ethylbenzene, therefore 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 activity driven and absorption percentage differences following ECHA TGD (2008) guidance:

DNEL_{l-t
inhalation}= 500 mg/m³x [6.7/10] x[ABS_inhal-rat/ABS_{inhalation-human}]

= 500 mg/m³x [6.7/10] x [45/65] = 232 mg/m³

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

DNEL_{l-t
inhalation}=232 mg/m³/ 3 = 77mg/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 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%.

_correctedDermal NOAEL = NOAEC_{l-t inhalation}x sRV_rat-8hrx 0.45

= 500 x 0.38[2]mg/kg bwt/d = 86 mg/kg bwt/d

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

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

DNEL_{l-t
dermal}= 2150 mg/kg bwt/d / 12 = 180 mg/kg bwt/d

Some UVCB streams in the xylenes category may also contain benzene, styrene and toluene (dependent on manufacturer).

DNELs for these are proposed as follows:

Styrene

DN(M) EL information was obtained from the Styrenics Steering Committee as requested by LOA membership. Documentation supporting these is to follow.

Worker– short-term local and systemic inhalation DNEL

DNEL DN(M) EL_{s-t inhalation}= 289 – 306 mg/m³

(short-term systemic DNEL = 289 mg/m³;short-term local DNEL = 306 mg/m³)

Worker – long-term systemic inhalation

DNEL DN(M) EL_{l-t inhalation}= 85mg/m³

Worker – long-term systemic dermal

DNEL DN(M) EL l_{-t dermal}= 406 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 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/m³[3])post-date the BOELV, a DNEL based on these bone marrow findings would be higher (and hence offer less protection) than the BOELV. The BOELV will therefore be used as the basis of the DN(M) EL for long-term systemic effects associated with benzene, including carcinogenicity.

Worker – long-term systemic inhalation DNEL

The BOELV will be used with no further modification

DN(M) EL_{l-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 wRV_8-hour[4]x [ABS_inhal-human/ABS_dermal-human]

= 3.25 x 0.144[5]x [50 / 1]

DN(M) EL_{l-t
dermal}= 23.4mg/kg bw/d

Toluene

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

Documentation supporting the IOELV (SCOEL, 2001) concluded that an exposure limit of 50 ppm (192 mg/m³) would protect against chronic effects hence, in accordance with REACH guidance and since no new scientific information has been obtained under REACH which contradicts use of the IOELV for this purpose, the established IOELV of 50 ppm (192 mg/m³) – 8 hr(EU, 2006) will be used as the starting point for calculating the chronic dermal DNEL for workers.

Worker – short-term local and systemic inhalation DNEL

Acute inhalation exposures are associated with signs of drowsiness and dizziness at concentrations lower than those which cause lethality and may cause respiratory tarct irritation, hence a DNEL will be proposed for the inhalation route. The acute LC₅₀for toluene in the rat (4 hour exposure) is > 20000 mg/m³. The NOAEC for acute CNS effects is 1131 mg/m³in the rat (from repeat dose study) and 188 mg/m³in humans (4.5 hour exposure). The current Indicative Occupational Exposure Limit Value (IOELV) and Short Term Exposure Limit (STEL) are based on a large amount of human data which indicate that the LOAEC for subjective effects of toluene is about 60 ppm (230 mg/m³). New data by Muttrayet 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^[6]. Consequently, in accordance with REACH guidance (Appendix R.8-13), the established short term IOELV of 100 ppm (384^[7]mg/m³) 15-min STEL will be proposed for the acute inhalation DNEL for workers.

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

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 wRV_8-hourx [50/3.6]

= [192 x 0.144 x 13.89]

DNEL_{l-t
dermal}= 384 mg/kg bw/d

[1]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)

[2]standard respiratory volume (sRV) of a 250 g rat = 0.38 m³/kg bw (TGD Table R.8-2)

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

[4]mg/m³values 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]worker respiratory volume (wRV) is 50% greater than the resting standard respiratory volume of 0.2 L/min/kg bw (wRV_{8 hour}= (0.2 L/min/kg bw x 1.5 x 60 x 8) / 1000 = 0.144 m³/kg bw

[6] The IOELV was published in 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.

[7] mg/m³values 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.

References

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

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

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

EU (2004) Directive 2004/37/EC of 29 April 2004 on the protection of workers from risks related to exposure to carcinogens or mutagens at work. Official Journal of the European Union, L229, 23-34.

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 (2008). Annex XV Transitional Dossier: Styrene.echa.europa.eu/doc/trd_substances/styrene/RAR/trd_rar_uk_styrene.rtf

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

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.

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

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14.8 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Overall assessment factor (AF):

5

Modified dose descriptor starting point:

NOAEC

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Value:

174 mg/m³

Overall assessment factor (AF):

1

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Value:

870 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Overall assessment factor (AF):

5

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

108 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

NOAEL

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.6 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Hazard assessment conclusion:

no hazard identified

DNEL Derivation Proposals for Xylenes Category

Compositional information:

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

· o-Xylene, m-xylene and p-xylene: ≥45%

· Ethylbenzene: ≤55%

· Styrene: ≤ 25% (dependent on manufacturer)

· Benzene: <0.1 - 1% (dependent on manufacturer)

· Toluene: <0.1 - 5% (dependent on manufacturer)

Uses:

These hydrocarbon streams are used as intermediates and in manufacture and hence exposure includes both workers and the general population. 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.

Benzene is a category 1A carcinogen and inclusion in formulations supplied to the general population should be restricted to a maximum of <0.1%. No classification is required for such formulations, and therefore no general population DNELs will be developed for benzene.

In the case of this stream, the most hazardous marker substances present are highlighted in the following table:

General Population

Marker substance	Indicative concentration (%)	Short-term inhalation
Marker substance	Indicative concentration (%)	DN(M)EL mg/m³	Relative hazard potential (max % ÷ DN(M)EL)
xylene isomers	>45	260	0.17
ethylbenzene	<55	174	0.32
benzene+	<0.1 – 1	&	&
toluene+	<0.1 – 5	226	0.02
styrene+	≤ 25	174 - 183	0.14

Marker substance	Indicative concentration (%)	Inhalation		Dermal		Oral
Marker substance	Indicative concentration (%)	DN(M)EL mg/m³	Relative hazard potential (max % ÷ DN(M)EL)	DN(M)EL mg/kg bwt/d	Relative hazard potential (max % ÷ DN(M)EL)	DN(M)EL mg/kg bwt/d	Relative hazard potential (max % ÷ DN(M)EL)
xylene isomers	>45	65.3	0.69	1872	0.024	12.5	3.6
ethylbenzene	<55	14.8	3.72	108	0.51	1.60	34.4
benzene+	<0.1 - 1%	&	&	&	&	&	&
toluene+	<0.1 - 5%	56.5	0.088	226	0.022	8.13	0.61
styrene+	≤ 25%	10.2	2.45	343	0.07	2.1	11.9

&marketing of steams containing >0.1% benzene prohibited

+ streams from some manufacturers may contain toluene, benzene, styrene

Conclusions:

Risk characterisation for inhalation, dermal and oral exposure for the general population handling streams containing xylene isomers and ethylbenzene is driven by ethylbenzene. The appropriate long-term DNEL for ethylbenzene will therefore be used for risk characterization in these circumstances.

Streams produced by some manufacturers contain, in addition, variable amounts of benzene, toluene and styrene. For the general population, health risk characterization for these streams is also driven by ethylbenzene.

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.

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).

General population – short-term local / systemic inhalation DNEL

The IOELV-STEL of 100 ppm (442 mg/m³, 15min) will be used as the basis of the general population short-term DNEL.

An assessment factor of 1.7 is used based on the ratio of intraspecies differences for workers and the general population identified by ECETOC (2003).

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

DNEL_{l-t
inhalation}= 442 mg/m³/ 1.7 = 260 mg/m³

General population – long-term systemic inhalation DNEL

The IOELV of 221 mg/m³will be used to derive the DNEL_{l-t
inhalation}.

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

Inhalation NOAEL = IOELV x (wRV_8-hour/ sRV_24-hour)

Inhalation NOAEL = 221 x (0.144 / 0.288[1]) = 111 mg/m³

An assessment factor of 1.7 is used based on intraspecies differences between worker and general populations.

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

DNEL_{l-t
inhalation} = 111 mg/m³/ 1.7 = 65.3 mg/m³

General population – long-term systemic dermal DNEL

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

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 1% for dermal absorption(ten Berge, 2009):

_correctedDermal NOAEL = IOELV x wRV_8-hourx 100/1

_correctedDermal NOAEL = 221 x 0.144[2]x 100 = 3182 mg/kg bw

An assessment factor of 1.7 is used based on between worker and general populations.

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

DNEL_{l-t
dermal}= 3182 mg/kg bwt/d / 1.7 = 1872 mg/kg bwt/d

General population – long-term systemic oral DNEL

For xylenes, the following overall NOAEC is presented in the IUCLID dossier: chronic effects: rat NOAEC (bodyweight) = 250 mg/kg/d

DNEL_{l-t
oral}= 250 mg/kg bwt/d / 20 = 12.5 mg/kg bwt/d

Ethylbenzene

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

General population – short-term local inhalation DNEL

The dose descriptor was taken from a human volunteer study which assessed subjective irritation and the presence of inflammatory biomarkers in nasal secretions following exposure to fluctuating concentrations of ethylbenzene in air, with a NOAEC of 200 ppm for short term exposures of 15 min (van Thriel et al., 2003). The NOAEC was the highest concentration investigated, and the “true” NOAEC is not known but certainly is higher.

Application of a 5-fold assessment factor (intra-species differences) gave an acute DNEL of 174 mg/m³(15-min TWA).

DNEL_{acute-local
inhalation}= 174 mg/m³

General population – short-term systemic inhalation DNEL

No short-term systemic inhalation DNEL was developed by the Styrenics Streeing Committee for ethylbenzene, hence the short-term local inhalation will be used instead. This value (174 mg/m³, 15-min TWA) compares favourably with the rat 4-hr LC50 of 17,600 mg/m³.

DNEL_{acute-systemic
inhalation}= 174 mg/m³

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[ABS_inhal-rat/ABS_{inhalationl-human}]

= 500 mg/m³x [6/24] x [6/7] x[45/65] = 74 mg/m³

An assessment factor of 5 is used based on intraspecies 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%.

_correctedDermal NOAEL = NOAEC_{l-t inhalation}x sRV_rat-8hrx 0.45

= 500 x 0.38[3]x 0.45 = 86 mg/kg bwt/d

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

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

= 2150 mg/kg bwt/d

An assessment factor of 20 is used (interspecies differences = 4; intraspecies differences = 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:

_correctedOral NOAEL = 75 mg/kg bwt/d x [ABS_oral-rat/ABS_oral-human]

= 75 mg/kg bwt/d x [84/100] = 63 mg/kg bwt/d

Assessment factors

An assessment factor of 40 was used (intraspecies differences =4; intraspecies differences = 5; differences in duration of exposure = 2).

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

DNEL_{l-t
oral}= 63 mg/kg bwt/d / 40 = 1.6 mg/kg bwt/d

Some UVCB streams in the xylenes category may also contain benzene, styrene and toluene (dependent on manufacturer).

DNELs for these are proposed as follows:

Styrene

DN(M) EL information was obtained from the Styrenics Steering Committee as requested by LOA membership. Documentation supporting these is to follow.

General population– short-term local and systemic inhalation DNEL

DNEL DN(M) EL_{s-t inhalation}= 174 – 183 mg/m³

(short-term systemic DNEL = 174 mg/m³;short-term local DNEL = 183 mg/m³)

General population – long-term systemic inhalation DNEL

DNEL_{l-t
inhalation}= 10.2 mg/m³

General population – long-term systemic dermal DNEL

DNEL_{l-t
dermal}= 343 mg/kg bw/d

General population – long-term systemic oral DNEL

DNEL_{l-t
oral}= 2.1 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)[4]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 (EU, 2006) will be used as the starting point for calculating the chronic dermal DNEL for workers.

General population – short-term local and systemic inhalation DNEL

Acute inhalation exposures are associated with signs of drowsiness and dizziness at concentrations lower than those which cause lethality and may cause respiratory tarct irritation, hence a DNEL will be proposed for the inhalation route. The acute LC₅₀for toluene in the rat (4 hour exposure) is > 20000 mg/m³. The NOAEC for acute CNS effects is 1131 mg/m³in the rat (from repeat dose study) and 188 mg/m³in humans (4.5 hour exposure). The current Indicative Occupational Exposure Limit Value (IOELV) and Short Term Exposure Limit (STEL) are based on a large amount of human data which indicate that the LOAEC for subjective effects of toluene is about 60 ppm (230 mg/m³). New data by Muttrayet 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^[5]. Consequently, in accordance with REACH guidance (Appendix R.8-13), the established short term IOELV of 100 ppm (384^[6]mg/m³) 15-min STEL will be proposed for the acute inhalation DNEL for workers.

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

Dose descriptor – 15 min duration, short-term acute exposure

IOELV-STEL = 384 mg/m³

Modification of dose descriptor

None required (human inhalation exposure).

NOAEL_{acute
inhalation}= IOELV = 384 mg/m³

Assessment factors

Assessment factors are not required when a worker DNEL is based upon an IOELV, however one is included here to reflect uncertainty when moving from the IOELV to the general population. An assessment factor of 1.7 is used, this reflecting the ratio of the <><><> ect ect

DNEL_{acute
inhalation}= 384 mg/m³/ 1.7 = 226 mg/m³

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

Inhalation NOAEL = IOELV x (wRV_8-hour/ sRV_24-hour)

= 192 x (0.144 / 0.288[7]) = 96 mg/m³

DNEL_{l-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 wRV_8-hourx 50/3.6

Dermal NOAEL = 192 x 0.144 x 13.89 = 384 mg/kg bw

An assessment factor of 1.7 is used to account for intraspecies differences.

DNEL_{l-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 wRV_8-hourx [50/100][8]

Oral NOAEL = [IOELV x wRV_8-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.

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

[1]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.

[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]standard respiratory volume (sRV) of a 250 g rat = 0.38 m³/kg bw (TGD Table R.8-2)

[4]mg/m³values 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]The IOELV was published in 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.

[6]mg/m³values 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.

[7]standard respiratory volume of 0.2 L/min/kg bw (sRV_24-hour= (0.2 L/min/kg bw x 60 x 24) / 1000 = 0.288 m³/kg bw

[8]This formula gives the internal (absorbed) dose achieved during a full-shift exposure at the IOELV