Mesitylene

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 mg/m³

Most sensitive endpoint:

repeated dose toxicity

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/34, 1999; Dir 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:

100 mg/m³

Most sensitive endpoint:

acute toxicity

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/34, 1999; Dir 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 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)

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 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/34, 1999; Dir 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:

100 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/34, 1999; Dir 2000/39/EC

AF for dose response relationship:

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)

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

16 171 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

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/34, 1999; Dir 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 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:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

A comparison of toxicological data available for the individual isomers of trimethylbenzene demonstrates that effects reported and the corresponding effect and no effect levels obtained are generally similar. This is consistent with the current EU position on trimethylbenzenes for which SEG established a single IOELV (8 hr TWA) of 20 ppm (100 mg/m3) (SEG, 1994; European Commission, 2000). The study of long term inhalation in rats (Shell, 1982; Clark et al., 1989), with a quoted NOAEC of 165 ppm (825 mg/m3) was considered to be the best available basis for proposing an 8-hour TWA. Since SEG considered that irritation was only observed at much higher doses than systemic effects, no STEL or "skin" notation was considered necessary.

Although new hazard data (addressing repeat dose and developmental effects) has been published since the date of the SEG evaluation, this information is not considered to materially alter the understanding of the hazards of this substance and therefore REACh Appendix R. 8-13 is considered to apply, allowing use of the IOELV to derive 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). 1,3,5-trimethyl-benzene does not present an acute hazard following ingestion or skin contact hence a DNEL will be considered for the inhalation route only (Classified Xn, R20; Acute Tox 4, H332).

The lowest acute LC50 for lethality of 1,3,5-trimethylbenzene in the rat (4 hr exposure) is 18,000 mg/m3 with an RD50 of 2,884 mg/m3 in mice (6 minutes) (Korsak et al 1997). Human data is limited, but Jarnberg et al (1996) reported no irritation or central nervous system effects in 10 volunteers exposed to 2 ppm (11 mg/m3) and 25 ppm (120 mg/m3) for 2 hours in an exposure chamber at a constant work load of 50 W on an ergometer bicycle.

These results do not conflict with the conclusion reached by SEG that, since irritation effects were observed only at much higher concentrations than the systemic effects, no STEL needed to be proposed (also no "skin" notation was considered to be necessary). Consequently the DNELl-t values are considered to be protective of acute effects and no specific DNELacute values (local or systemic) are proposed.

Past decisions from the C&L work group and Classification under DSD and CLP indicate that 1,3,5-trimethylbenzene is irritating to skin, eyes and the respiratory tract (Xi: R36/R37/R38; Skin Irrit 2 (H315), Eye Irrit 2 (H319), STOT Single Exp 3 (H335)) hence appropriate RMM and OCs should 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 toxicity and reproductive (fertility, developmental) testing.

For 1,3,5-trimethylbenzene, the following NOAECs are presented in the IUCLID dossier:

* sub-chronic effects (90-d), inhalation: rat NOAEC = 1230 mg/m3 (no significant systemic effects at this top dose) (Korsak et al, 2000)

* chronic effects (12-m), inhalation: rat NOAEC = 1800 mg/m3 (no significant systemic effects at this top dose) (Clark et al, 1989)

* reproductive effects: rat NOAEC = 2500 mg/m3 (severe systemic toxicity at 7500 mg/mg3) (McKee et al, 1990)

* developmental toxicity: rat NOAEC = 1470 mg/m3 (significant decrease body weight gain and food consumption at 2950 mg/m³) (Saillenfait et al, 2005)

Although additional data has become available since the SEG consideration of an IOELV for TMBs, this does not affect the overall conclusion of the SEG that results from a long term inhalation in rats (Clark et al., 1989), showing a NOAEC of 165 ppm (825 mg/m3), was the best available basis for proposing an 8-hour TWA (IOELV 20 ppm, 100 mg/m3).

Oral

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

Dermal

Dose descriptor

In accordance with REACH guidance (Appendix R.8-13) and since no new scientific information has been obtained under REACH which contradicts use of the IOELV for this purpose, the established IOELV of 20 ppm (100 mg/m3) – 8 hr TWA will be used as the starting point for calculating the chronic dermal DNEL for workers.

Modification of dose descriptor

Correct the IOELV to a dermal NOAEL (mg/kg/day) assuming that uptake of 1,3,5-trimethylbenzene after inhalation is approximately 64% (Jarnberg et al, 1996) while dermal absorption is only 0.057% (Korinth et al, 2003).

Dermal NOAEL = IOELV x wRV8-hour x [64/0.057]

Comment: 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)

Dermal NOAEL = 100 x 0.144 x 1123 = 16171 mg/kg bw

Assessment factors

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

DNELl-t dermal = 16171 mg/kg bw/d

Inhalation

In accordance with REACH guidance (Appendix R.8-13) and since no new scientific information has been obtained under REACH which contradicts use of the IOELV for this purpose, the established IOELV of 20 ppm (100 mg/m3) – 8 hr TWA will be used as the starting point for calculating the chronic dermal DNEL for workers.

DNELl-t inhalation = IOELV = 100 mg/m3

Long-term local effects

Past decisions from the C&L work group and Classification under DSD and CLP indicate that 1,3,5-trimethylbenzene is irritating to skin, eyes and the respiratory tract (Xi: R36/R37/R38; Skin Irrit 2 (H315), Eye Irrit 2 (H319), STOT Single Exp 3 (H335)) hence appropriate RMM and OCs should be employed.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

29.4 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

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

Overall assessment factor (AF):

1.7

Modified dose descriptor starting point:

other: SEG/SUM/34, 1999; Dir 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, 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 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 (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:

29.4 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

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

Overall assessment factor (AF):

1.7

Modified dose descriptor starting point:

other: SEG/SUM/34, 1999; Dir 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 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, 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 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 (8-hr) used as starting point (human NAEL)

AF for remaining uncertainties:

1

Justification:

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

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

29.4 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/34, 1999; Dir 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, 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 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 (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:

29.4 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

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

Overall assessment factor (AF):

1.7

Dose descriptor starting point:

other: SEG/SUM/34, 1999; Dir 2000/39/EC

AF for dose response relationship:

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

AF for remaining uncertainties:

1

Justification:

IOELV (8-hr) 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:

9 512 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

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

Overall assessment factor (AF):

1.7

Modified dose descriptor starting point:

other: SEG/SUM/34, 1999; Dir 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, 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 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 (8-hr) used as starting point (human NAEL)

AF for remaining uncertainties:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

15 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):

40

Modified dose descriptor starting point:

NOAEL

Value:

600 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

none applied

AF for dose response relationship:

1

Justification:

default, clear NOAEL

AF for differences in duration of exposure:

2

Justification:

default for sub-chronic to chronic extrapolation

AF for interspecies differences (allometric scaling):

4

Justification:

default for oral route (rat)

AF for other interspecies differences:

1

Justification:

default, none identified

AF for intraspecies differences:

5

Justification:

There are no data to quantify variability in susceptibility to the effects of exposure to trimethylbenzenes 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:

GLP-compliant guideline study

AF for remaining uncertainties:

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 trimethylbenzene, 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.

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

A comparison of toxicological data available for the individual isomers of trimethylbenzene demonstrates that effects reported and the corresponding effect and no effect levels obtained are generally similar. This is consistent with the current EU position on trimethylbenzenes for which SEG established a single IOELV (8 hr TWA) of 20 ppm (100 mg/m3) (SEG, 1994; European Commission, 2000). The study of long term inhalation in rats (Shell, 1982; Clark et al., 1989), with a quoted NOAEC of 165 ppm (825 mg/m3) was considered to be the best available basis for proposing an 8-hour TWA. Since SEG considered that irritation was only observed at much higher doses than systemic effects, no STEL or "skin" notation was considered necessary.

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 has been examined for consistency and biological plausibility by Scientific Expert Group on Occupational Exposure Limits, 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 NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population.

Although new hazard data (addressing repeat dose and developmental effects) has been published since the date of the SEG evaluation, this information is not considered to materially alter the understanding of the hazards of this substance and therefore REACh Appendix R. 8-13 is considered to apply, allowing use of the IOELV to derive 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). 1,3,5-trimethyl-benzene does not present an acute hazard following ingestion or skin contact hence a DNEL will be considered for the inhalation route only (Classified Xn, R20; Acute Tox 4, H332).

The lowest acute LC50 for lethality of 1,3,5-trimethylbenzene in the rat (4 hr exposure) is 18,000 mg/m3 with an RD50 of 2,884 mg/m3 in mice (6 minutes) (Korsak et al 1997). Human data is limited, but Jarnberg et al (1996) reported no irritation or central nervous system effects in 10 volunteers exposed to 2 ppm (11 mg/m3) and 25 ppm (120 mg/m3) for 2 hours in an exposure chamber at a constant work load of 50 W on an ergometer bicycle.

These results do not conflict with the conclusion reached by SEG that, since irritation effects were observed only at much higher concentrations than the systemic effects, no STEL needed to be proposed (also no "skin" notation was considered to be necessary). Consequently the DNELl-t values are considered to be protective of acute effects and no specific DNEL acute values (local or systemic) are proposed.

Past decisions from the C&L work group and Classification under DSD and CLP indicate that 1,3,5-trimethylbenzene is irritating to skin, eyes and the respiratory tract (Xi: R36/R37/R38; Skin Irrit 2 (H315), Eye Irrit 2 (H319), STOT Single Exp 3 (H335)) hence appropriate RMM and OCs should 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 toxicity and reproductive (fertility, developmental) testing.

For 1,3,5-trimethylbenzene, the following NOAECs are presented in the IUCLID dossier:

* sub-chronic effects (90-d), inhalation: rat NOAEC = 1230 mg/m3 (no significant systemic effects at this top dose) (Korsak et al, 2000)

* chronic effects (12-m), inhalation: rat NOAEC = 1800 mg/m3 (no significant systemic effects at this top dose) (Clark et al, 1989)

* reproductive effects: rat NOAEC = 2500 mg/m3 (severe systemic toxicity at 7500 mg/mg3) (McKee et al, 1990)

* developmental toxicity: rat NOAEC = 1470 mg/m3 (significant decrease body weight gain and food consumption at 2950 mg/m³) (Saillenfait et al, 2005)

Although additional data has become available since the SEG consideration of an IOELV for TMBs, this does not affect the overall conclusion of the SEG that results from a long term inhalation in rats (Clark et al., 1989), showing a NOAEC of 165 ppm (825 mg/m3), was the best available basis for proposing an 8-hour TWA (IOELV 20 ppm, 100 mg/m3).

Oral

Dose descriptor

A rat oral NOAEC of 600 mg/kg bw/d (rat, 90-d) will be used (IITRI, 1995)

Modification of dose descriptor

No modification required

Assessment factors

 

Uncertainty	AF	Justification
Interspecies differences	4	default for oral route (rat)
Intraspecies differences	5	There are no data to quantify variability in susceptibility to the effects of exposure to trimethylbenzene 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 reviewof 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 95^thpercentile of human toxicokinetic and toxicodynamic variability) to account for intra-species variability present within the general population.
Differences in duration of exposure	2	default for subchronic to chronic
Dose response and endpoint specific/severity issues	1	clear NOAEL – no significant effects at top dose
Quality of database	1	GLP-compliant guideline study
Overall AF	40

 

DNELl-t oral = 600 mg/kg bwt/d / 40 = 15 mg/kg bwt/d

Dermal

Dose descriptor

In accordance with REACH guidance (Appendix R.8-13) and since no new scientific information has been obtained under REACH which contradicts use of the IOELV for this purpose, the established IOELV of 20 ppm (100 mg/m3) – 8 hr TWA will be used as the starting point for calculating the chronic dermal DNEL for workers.

Modification of dose descriptor

Correct the IOELV to a dermal NOAEL (mg/kg/day) assuming that uptake of 1,3,5-trimethylbenzene after inhalation is approximately 64% (Jarnberg et al, 1996) while dermal absorption is only 0.057% (Korinth et al, 2003).

Dermal NOAEL = IOELV x wRV8-hour x [64/0.057]

Comment: 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)

Dermal NOAEL = 100 x 0.144 x 1123 = 16171 mg/kg bw

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.

   

Uncertainty	AF	Justification
Interspecies differences	1	human data
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, 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 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.
Differences in duration of exposure	1	chronic exposure
Dose response and endpoint specific/severity issues	1	default AF
Quality of database	1	Default
Overall AF	1.7

 

DNELl-t dermal = 16171 mg/kg bw/d / 1.7 = 9512 mg/kg bw/d

Inhalation

Dose descriptor

A DNEL based on the IOELV of 100 mg/m3 will be used.

Modification of dose descriptor

Inhalation NOAEL = IOELV x (wRV8-hour / sRV24-hour) = 100 x (0.144 / 0.288) = 50 mg/m3

Comment: 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)

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.

   

Uncertainty	AF	Justification
Interspecies differences	1	human data
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, 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 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.
Differences in duration of exposure	1	chronic exposure
Dose response and endpoint specific/severity issues	1	default AF
Quality of database	1	Default
Overall AF	1.7

 

DNELl-t inhal = 50 / 1.7 = 29.4 mg/m3

Long-term local effects

Past decisions from the C&L work group and Classification under DSD and CLP indicate that 1,3,5-trimethylbenzene is irritating to skin, eyes and the respiratory tract (Xi:R36/R37/R38; Skin Irrit 2 (H315), Eye Irrit 2 (H319), STOT Single Exp 3 (H335)) hence appropriate RMM and OCs should be employed.