Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
221 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: SEG/SUM/19B; Directive 2000/39/EC
Explanation for the modification of the dose descriptor starting point:
None applied
AF for dose response relationship:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for differences in duration of exposure:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for interspecies differences (allometric scaling):
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for other interspecies differences:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for intraspecies differences:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for the quality of the whole database:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for remaining uncertainties:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
442 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: SEG/SUM/19B; Directive 2000/39/EC
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:
221 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: SEG/SUM/19B; Directive 2000/39/EC
AF for dose response relationship:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for differences in duration of exposure:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for interspecies differences (allometric scaling):
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for other interspecies differences:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for intraspecies differences:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for the quality of the whole database:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for remaining uncertainties:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
442 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: SEG/SUM/19B; Directive 2000/39/EC
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:
212 mg/kg bw/day
Most sensitive endpoint:
neurotoxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
other: SEG/SUM/19B; Directive 2000/39/EC
Value:
212 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The IOELV (mg/m3) was converted into a human dermal NOAEL (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 without modification (ECHA Guidance, Appendix R.8-13)
AF for differences in duration of exposure:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for interspecies differences (allometric scaling):
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for other interspecies differences:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for intraspecies differences:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for the quality of the whole database:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for remaining uncertainties:
1
Justification:
IOELV (8-hr) 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:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Introduction

Mixed xylene (CAS 1330-20-7) comprises individual xylene isomers (m-xylene, o-xylene, p-xylene) and <10% ethyl benzene.

A comparison of toxicological data available for xylenes (including mixed xylenes and the individual isomers) demonstrates that the effects seen are generally similar and that the effect levels are of the same order of magnitude. The presence of up to 10% ethyl benzene is not expected to significantly alter this hazard profile, with overall effects on human health influenced primarily by xylenes.

Isomers of xylene have comparable toxicokinetic properties and toxicological profiles with the exception of ototoxicity, which seems to be specific to mixed xylenes (where ototoxic potency appears related to the level of ethyl benzene present) and p-xylene. For other endpoints, slight differences in effect levels are apparently related more closely to dose selection (and potentially other factors such as vehicle, gavage procedures) rather than to intrinsic hazard. This is consistent with a single classification for xylenes under CLP, and also with the views of the Scientific Expert Group on occupational exposure limits (SEG), which established a single IOELV (8 hr TWA) of 50 ppm (221 mg/m3) and STEL of 100 ppm (442 mg/m3) for all xylenes (isomers and mixed xylene) (SEG, 1992; European Commission, 2000).

While some new hazard data (addressing for example ototoxicity and developmental effects) have emerged subsequent to publication of the IOELV, it is not considered that this information undermines the reliability of this value. Hence Appendix R. 8-13 of REACH Guidance applies, allowing the IOELV to be used as a starting point for the derivation of DNELs.

Acute toxicity

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. C&L) has been identified and there is a potential for high peak exposures. These “peaks” are normally associated with inhalation exposure but are less common for skin contact and ingestion (Appendix R.8-8). The available data indicate that xylene isomers do not present an acute hazard following ingestion or skin contact hence a DNEL will be proposed for the inhalation route only.

Dose descriptor

The lowest acute LC50 for lethality is of p-xylene in the rat (4 hr exposure) is 16,694 mg/m3 with a LOAEC of 2,518 mg/m3 for CNS depression in rats (4 hours). The NOAEC for acute CNS effects of p-xylene in humans is 300 mg/m3 (4 hr exposure, equivalent to 69 ppm) (Anshelm Olson et al, 1985). As reported by SCOEL when establishing the IOELV, 100 ppm (442 mg/mg3) is the LOAEC for mild irritation effects and possible CNS effects in humans. Since the effects reported were mild, 442 mg/m3 was considered appropriate by SCOEL to derive a STEL. There is no new data which affects this position and therefore it is proposed that the IOELV (STEL) is the appropriate value to establish the DNEL acute inhalation.

Irritation

Corrosive and irritant effects on the skin and eye are local, concentration-dependent phenomena. No dose/response information can be derived from data available for liquid xylenes and DNELs cannot therefore be determined. The IOELV (STEL) of 100 ppm (442 mg/m3) was considered sufficiently protective for irritant effects by SCOEL. However past decisions from the C&L work group (as confirmed by classification detailed in the 25th ATP of Dir. 67/548/EEC) indicate that liquid xylenes are irritating to the skin and re-evaluation of effects on eye and respiratory tract by the registrant indicates a potential for irritation of these tissues also.

Long-term systemic effects

The potential of a substance to cause systemic effects after long-term exposure can be derived from the results of repeated dose (neuro)toxicity and reproductive (fertility, developmental) testing.

For xylenes, the following rodent inhalation NOAECs are presented in the IUCLID dossier:

Sub-chronic effects – ototoxicity (deficits in brainstem auditory evoked response)

m-xylene and o-xylene = 1800 ppm (7817 mg/m3)

mixed xylene (2 samples) = 500 ppm (2171 mg/m3) or 1000 (4342 mg/m3)

p-xylene = 450 ppm (1954 mg/m3)

The lowest overall NOAEC for repeated dose effects after inhalation is 450 ppm (1954 mg/m3; ototoxicity, p-xylene). It is noted that (relative to other xylene isomers) this is a conservative no-effect concentration.

The equivalent worker NOAEC (Example A.2, ECHA Guidance, Chapter R.8) is therefore:

Worker NOAEC = inhalatory NOAEC x [sRVhuman / wRV]

= 1954 mg/m3 x [6.7 m3 / 10 m3]

= 1309.2 mg/m3

Assessment factors:

 

Long-term DNEL Assessment Factors (Worker, inhalation)

AF for dose response relationship

1

NOAEC used as starting point

AF for differences in duration of exposure

2

Default (correction for sub-chronic to chronic exposure)

AF for interspecies differences (allometric scaling)

1

Default (none required inhalation route)

AF for other interspecies differences

1

An analysis of assessment factors conducted by ECETOC (2003, 2010) showed that a standard approach of applying a default AF for any remaining differences is not appropriate since, in the majority of cases, this is adequately covered by the inherent interdependence of the inter- and intra-species assessment factors and taken into account by allometric scaling (see, for instance, ECETOC analysis of information from Calabrese and Gilbert (1993) Reg. Tox. Pharmacol. 17: 44-51). Furthermore, data available for xylene isomers, together with information available for chemically-related structures do not raise concern for possible differences in effect within or between species. Overall, no factor for remaining differences will therefore be applied.

AF for intraspecies differences

3

There are no data to quantify variability in susceptibility to the effects of exposure to xylene isomers in the human population. However the population exposed in the workplace is highly homogeneous and the health of the work force is typically good (healthy worker effect) while metabolic differences due to genetic polymorphisms do not automatically require an increased assessment factor since compensating mechanisms (including alternative pathways of elimination) are often present (ECETOC, 2003, 2010). 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 3 (i.e. the 90th percentile of human toxicokinetic and toxicodynamic variability) to account for intra-species variability present within workers.

AF for quality of the whole data base

1

No issues with quality of the whole database identified

AF for remaining uncertainties

1

None identified (conservative NOAEC used as starting point)

Overall AF

6

 

The DNEL for long-term inhalation exposure is therefore:

DNEL l-t inhalation = Worker NOAEC / AF = 1309.2 mg/m3 / 6 = 218.2 mg/m3

As the magnitude of the DNEL l-t inhalation is essentially identical to the IOELV, the IOELV of 221 mg/m3 (50 ppm, 8h TWA) should provide adequate protection and is proposed as the worker DNELl-t inhalation.

Oral

Not required for workers (TGD Table R.8-1)

Dermal

Dose descriptor

The IOELV of 50 ppm (221 mg/m3, 8h TWA) will be used for derivation of the worker 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 wRVhuman-8hr x [ABSinhal-human/ABSdermal-human]

correctedDermal NOAEL = 221 x 0.144 x (100/15) = 212 mg/kg bwt/d

Note:

worker respiratory volume (wRV) is 50% greater than the resting standard respiratory volume of 0.2 L/min/kg bw (wRV8-hour = (0.2 L/min/kg bw x 1.5 x 60 x 8) / 1000 = 0.144 m3/kg bw)

No assessment factor is necessary.

Inhalation

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

Long-term local effects

Information on local effects associated with repeated exposure to xylenes is limited to results from a rat repeated dose inhalation study, where no adverse effects were reported. It is considered that the long term systemic effect DNEL of 50 ppm for inhalation is protective for local effects and therefore no specific DNEL for long-term local effects is derived here.

Dermal

No information is available to characterise the repeated local effects of xylene on the skin, while route-to-route extrapolation (respiratory tract to skin) is not appropriate. No conclusion can therefore be reached for this endpoint.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
65.3 mg/m³
Most sensitive endpoint:
neurotoxicity
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: SEG/SUM/19B; Directive 2000/39/EC
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 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 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:
260 mg/m³
Most sensitive endpoint:
neurotoxicity
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: SEG/SUM/19B; Directive 2000/39/EC
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 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 IOELV-STEL has therefore been taken as a human 15-min 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-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:
65.3 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: SEG/SUM/19B; Directive 2000/39/EC
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 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 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:
260 mg/m³
Most sensitive endpoint:
neurotoxicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance; ECETOC (2003, 2010)
Overall assessment factor (AF):
1.7
Dose descriptor starting point:
other: SEG/SUM/19B; Directive 2000/39/EC
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 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 IOELV-STEL has therefore been taken as a human 15-min 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-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:
125 mg/kg bw/day
Most sensitive endpoint:
neurotoxicity
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: SEG/SUM/19B; Directive 2000/39/EC
Explanation for the modification of the dose descriptor starting point:
The IOELV (mg/m3) was converted into a human dermal NOAEL (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 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 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

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance; ECETOC (2003, 2010)
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
None applied
AF for dose response relationship:
1
Justification:
NOAEL used as starting point
AF for differences in duration of exposure:
1
Justification:
Results taken from a chronic toxicity study
AF for interspecies differences (allometric scaling):
4
Justification:
Default for the rat
AF for other interspecies differences:
1
Justification:
An analysis of assessment factors conducted by ECETOC (2003, 2010) showed that a standard approach of applying a default AF for any remaining differences is not appropriate since, in the majority of cases, this is adequately covered by the inherent interdependence of the inter- and intra-species assessment factors and taken into account by allometric scaling (see, for instance, ECETOC analysis of information from Calabrese and Gilbert (1993) Reg. Tox. Pharmacol. 17: 44-51). Furthermore, data available for xylene isomers, together with information available for chemically-related structures, do not raise concern for possible differences in effect within or between species. Overall, no factor for remaining differences will therefore be applied.
AF for intraspecies differences:
5
Justification:
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.
AF for the quality of the whole database:
1
Justification:
No issues with quality of the whole database identified
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties 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:
low hazard (no threshold derived)

Additional information - General Population

Introduction

Mixed xylene (CAS 1330-20-7) comprises individual xylene isomers (m-xylene, o-xylene, p-xylene) and <10% ethyl benzene.

A comparison of toxicological data available for xylenes (including mixed xylenes and the individual isomers) demonstrates that the effects seen are generally similar and that the effect levels are of the same order of magnitude. The presence of up to 10% ethyl benzene is not expected to significantly alter this hazard profile, with overall effects on human health influenced primarily by xylenes.

Isomers of xylene have comparable toxicokinetic properties and toxicological profiles with the exception of ototoxicity, which seems to be specific to mixed xylenes (where ototoxic potency appears related to the level of ethyl benzene present) and p-xylene. For other endpoints, slight differences in effect levels are apparently related more closely to dose selection (and potentially other factors such as vehicle, gavage procedures) rather than to intrinsic hazard. This is consistent with a single classification for xylenes under CLP, and also with the views of the Scientific Expert Group on occupational exposure limits (SEG), which established a single IOELV (8 hr TWA) of 50 ppm (221 mg/m3) and STEL of 100 ppm (442 mg/m3) for all xylenes (isomers and mixed xylene) (SEG, 1992; European Commission, 2000).

While some new hazard data (addressing for example ototoxicity and developmental effects) have emerged subsequent to publication of the IOELV, it is not considered that this information undermines the reliability of this value. Hence Appendix R. 8-13 of REACH Guidance applies, allowing the IOELV to be used as a starting point for the derivation of DNELs.

This document uses ECETOC guidance for assessment factors and the IOELV as starting point for all General Population DNELs.

Acute and long-term inhalation DNELs were based on the IOELV, with the long-term DNELs adjusted to reflect differences in respiratory volume between workers and the general population. Following route-to-route extrapolation, the IOELV was also used as the basis of long-term systemic dermal DNEL. An assessment factor was applied in all instances to account for the intra-species variability present in workers and the general population.

Acute toxicity

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. C&L) has been identified and there is a potential for high peak exposures. These “peaks” are normally associated with inhalation exposure but are less common for skin contact and ingestion (Appendix R.8-8). The available data indicate that xylene isomers do not present an acute hazard following ingestion or skin contact hence a DNEL will be proposed for the inhalation route only. As for workers, the IOELV (STEL and 8-hour TWA) will be used to derive the general population DNELs.

Modification of dose descriptor

No modification necessary

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

 

The DNEL for acute inhalation exposure is derived as follows:

DNELacute inhalation = STEL / AF = 442 mg/m3 / 1.7 = 260 mg/m3

Irritation

Corrosive and irritant effects on the skin and eye are local, concentration-dependent phenomena. No dose/response information can be derived from data available for xylenes and DNELs cannot therefore be determined. However past decisions from the C&L work group indicate that liquid xylenes are irritating to the skin and while re-evaluation of effects on eye and respiratory tract by the registrant indicates a potential for irritation also. Appropriate RMM (personal protective equipments) should therefore be employed.

Long-term systemic effects

The potential of a substance to cause systemic effects after long-term exposure can judged based on the results of repeated dose (neuro)toxicity and reproductive (fertility, developmental) testing.

Inhalation:

For xylenes, the following rodent inhalation NOAECs are presented in the IUCLID dossier:

Sub-chronic effects – ototoxicity (deficits in brainstem auditory evoked response):

m-xylene and o-xylene = 1800 ppm (7817 mg/m3)

mixed xylene (2 samples) = 500 ppm (2171 mg/m3) or 1000 (4342 mg/m3)

p-xylene = 450 ppm (1954 mg/m3)

Oral:

For xylenes, 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

Dermal

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

Inhalation

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

Long-term local effects

Information on local effects associated with repeated exposure to xylene is limited to results from a rat repeated dose inhalation study, where no adverse were reported. It is considered that the long term systemic effect DNEL for inhalation (65.3 mg/m3) is protective for local effects and therefore no specific DNEL for long-term local effects is derived here.

Dermal

No information is available to characterise the repeated local effects of xylene on the skin, while route-to-route extrapolation (respiratory tract to skin) is not appropriate. No conclusion can therefore be reached for this endpoint.