Toluene

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

192 mg/m³

Most sensitive endpoint:

neurotoxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Modified dose descriptor starting point:

other: SCOEL/SUM/18, March 2001; Dir 2006/15/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:

384 mg/m³

Most sensitive endpoint:

neurotoxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Modified dose descriptor starting point:

other: SCOEL/SUM/18, March 2001; Dir 2006/15/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:

192 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Dose descriptor:

other: SCOEL/SUM/18, March 2001; Dir 2006/15/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:

384 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Dose descriptor starting point:

other: SCOEL/SUM/18, March 2001; Dir 2006/15/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:

384 mg/kg bw/day

Most sensitive endpoint:

neurotoxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Modified dose descriptor starting point:

other: SCOEL/SUM/18, March 2001; Dir 2006/15/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:

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:

no hazard identified

Additional information - workers

LOA is currently reviewing the human and animal data supporting Human Health for Toluene. It is expected to be completed by Q4 2020.

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). Oral and dermal: Toluene does not present an acute hazard following ingestion or skin contact, hence no oral or dermal DNEL will be proposed. Inhalation: Acute inhalation exposures are associated with signs of drowsiness and dizziness at concentrations lower than those which cause lethality, hence a DNEL will be proposed for the inhalation route. The acute LC50 for toluene in the rat (4 hour exposure) is > 20000 mg/m³. The NOAEC for acute CNS effects is 1131 mg/m³ in the rat (from repeat dose study) and 192 mg/m³ in humans (4.5 hour exposure). The current Indicative Occupational Exposure Limit Value (IOELV) and Short Term Exposure Limit (STEL) (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) 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 Muttray et al, 2005 indicate that 50 ppm (192 mg/m³) is a NOAEC for acute subjective effects (i.e. effects on how the person feels) supporting the current IOELV. Consequently, in accordance with REACH guidance (Appendix R.8-13), the established short term IOELV of 100 ppm (384 mg/m³) 15-min STEL. This reflects toxicokinetic information indicating that the steady-state level of toluene in blood is reached after around 25 min of exposure, together with human data suggesting that 80 ppm was a no-effect level for neurobehavioural effects. Taken together, SCOEL concluded that a 15 min exposure to 100 ppm (384 mg/m³) toluene would not lead to adverse health effects. DNELacute inhalation = IOELV- STEL = 384 mg/m³ (Note: mg/m³ values quoted in this document are as reported in the publication or calculated using a conversion at 25°C as used by ACGIH (http://www.cdc.gov/niosh/docs/2004-101/calc.htm). It is recognized that SCOEL used a different calculation.) Irritation Skin: No dose/response information can be derived from data available for liquid toluene and DNELs cannot therefore be determined. However, toluene is irritating to the skin, hence appropriate RMM and OCs should be employed. Eye: Liquid toluene is not irritating to the eye although toluene vapours in ambient air are reported to cause subjective sensations of eye irritation in humans. A NOAEC of 50 ppm (192 mg/m³) was established by Muttray et al, 2005. These data support the current IOELV. Consequently, in accordance with REACH guidance (Appendix R.8-13), the established short term IOELV will be used for eye irritation DNEL for workers. DNELacute eye irritation = IOELV- STEL = 384 mg/m³ Respiratory tract: Toluene can cause respiratory irritation in animals but this has only been observed at very high concentrations. Respiratory irritation potential of toluene in humans is also considered to be a high concentration phenomenon but subjective sensations of “irritation to the throat” have been recorded in a human volunteer study with a LOAEC of 192 mg/m³ (Muttray et al, 2005). However these effects were subjective with no residual effects following completion of exposure and similar effects were not recorded in the chronic occupational exposure studies of Schaper et al, 2003, 2004 or Seeber et al, 2004. Therefore it is considered that current short term IOELV is sufficiently protective for local respiratory effects. DNELacute respiratory irritation = IOELV- STEL = 384 mg/m³ Sensitization:No hazard with respect to skin or respiratory sensitization has been identified in animal studies or in humans and, consequently, no DNEL can or will be proposed. Long-term systemic effects: The potential of a substance to cause long-term systemic effects can be judged based on the results of repeated dose (neuro) toxicity and reproductive (fertility, developmental) testing. For toluene, the following NOAECs are presented in the IUCLID dossier: sub-chronic effects: rat NOAEL = 625 mg/kg/day chronic effects: rat NOAEC = 1131 mg/m³ chronic effects: human NOAEC = 98 mg/m3 reproductive effects: rats NOAEC = 2261 mg/m³ developmental toxicity: rat NOAEC = 2261 mg/m³ However, the values presented above are for information only as the DNEL for long-term systemic effects (all routes) will be based on the IOELV, as permitted in REACH guidance, Appendix R.8-13. Documentation supporting the IOELV states that in standard animal studies, no significant evidence of systemic toxicity was observed upon repeated, prolonged exposure to concentrations up to at least 300 ppm (1149 mg/m³) toluene vapour, with ototoxicity apparent in rats exposed repeatedly to 1000 ppm (3840 mg/m³) and above. The SCOEL recommendation was therefore based on human data indicating possible changes in neurobehavior with a LOAEL of about 75 ppm (237 mg/m³), while data on the subjective effects suggested a LOAEL of about 60 ppm (230 mg/m³). In contrast, studies describing effects at lower exposures were considered less reliable due to issues with exposure characterisation. Overall, SCOEL concluded that a great deal of human data was available, which produce no reliable evidence of effects at or below toluene concentrations of 50 ppm (192 mg/m3). Therefore the IOELV was set at 50 ppm (192 mg/m³) for the 8 hour TWA. A STEL (15 min) of 100 ppm (384 mg/m³; based on toxicokinetic considerations and human experimental data) was proposed to limit peaks of exposure which might lead to short-term neurobehavioural effects. New studies not referenced in the SCOEL evaluation but summarised in the IUCLID dataset for toluene are those of Seeber et al (2004) and Schaper et al (2003; 2004; 2008). There was no evidence from these more recent reports that long-term exposure to toluene at 26 ppm (98 mg/m³) for 21 years had any effects on cognitive function (Seeber et al, 2004), ototoxicity (Schaper et al (2003; 2008) or colour vision (Schaper et al 2004). These studies demonstrate that adverse changes do not occur when exposures are maintained below the current occupational exposure limit of 50 ppm (192 mg/m³). Oral: The oral route is considered not relevant to workers and a DNEL will not be proposed. Dermal: Dose descriptor Documentation supporting the IOELV concluded that an exposure limit of 50 ppm (192 mg/m³) would protect against chronic effects although it was noted that “absorption of liquid toluene could contribute substantially to the total body burden”. 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 50 ppm (192 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) by converting the dose absorbed after inhalation into a systemic dose, assuming 50% uptake by the lung and 3.6% uptake by skin (ten Berge, 2009): Dermal NOAEL = IOELV x wRV8-hour x [50/3.6] Dermal NOAEL = [192 x 0.144 x 13.89] = 384 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 As the IOELV is based on worker life-time exposure no assessment factor is needed. DNELl-t dermal = 384 mg/kg bw/d Inhalation: The IOELV was determined on the basis of “a great deal of human data is available, which produce no reliable evidence of effects at or below toluene concentrations of 50 ppm (192 mg/m³).” In accordance with REACH guidance (Appendix R.8-13) and since no new scientific information has been obtained under REACH which does not support the use of the IOELV for this purpose, the established IOELV of 50 ppm (192 mg/m³) – 8 hr TWA will be used for the chronic inhalation DNEL for workers. DNELl-t inhalation = IOELV = 192 mg/m³ Reproductive effects Documentation supporting the IOELV concluded that animal data produce no evidence that toluene expresses effects on the gonads or fertility. In accordance with REACH guidance (Appendix R.8-13) and since no new scientific information has been obtained under REACH which does not support the use of the IOELV for this purpose, the established IOELV of 50 ppm (192 mg/m³) – 8 hr TWA will be used for the reproduction DNEL for workers. DNELreproduction = IOELV = 192 mg/m³ Developmental effects In relation to developmental toxicity, documentation supporting the IOELV notes that animal developmental studies show some evidence of a weak effect in rats (but not mice or rabbits) at near-maternally toxic exposures above 400 ppm (1532 mg/m³), while information suggesting a higher abortion rate in pregnant women exposed to an average of 88 ppm (337 mg/m³) toluene vapour was balanced by normal birth outcomes for women deliberately or accidentally exposed to high levels of toluene during pregnancy. Documentation supporting the IOELV indicates that SCOEL has access to the draft risk assessment report for toluene, and was therefore aware of the background information contained therein. New information from Saillenfait et al. (2007), who reported a NOAEC of 500 ppm (1880 mg/m³) does not materially alter this position i.e. the NOAEC is consistent with that of Thiel and Chahoud (1997) which was considered a key animal study in the risk assessment report. Human data considered by the EU RAR to suggest “an increased risk of late spontaneous abortions associated with exposure to toluene at levels around 88 ppm (range 50-150 ppm)” (i.e. Ng et al., 1992) were also known to SCOEL and are discussed in the IOELV support document, however the Committee observed that abortions have not been reported upon accidental high exposure or toluene abuse by pregnant women and that an exposure limit of 50 ppm (192 mg/m³) would be protective. Overall, the IOELV support document concluded that an exposure limit of 50 ppm (192 mg/m³) would protect against potential foetotoxicity as well as chronic systemic effects. In accordance with REACH guidance (Appendix R.8-13) and since no new scientific information has been obtained under REACH which does not support the use of the IOELV for this purpose, the established IOELV of 50 ppm (192 mg/m³) will be used for the developmental DNEL for workers. DNELdevelopmental = IOELV = 192 mg/m³ Long-term local effects Inhalation: Toluene can cause respiratory irritation in animals but this has only been observed at very high exposure concentrations. Respiratory irritation potential of toluene in humans is also considered to be a high concentration phenomenon, although subjective sensations of “irritation to the throat” have been recorded in a human volunteer study with a LOAEC of 192 mg/m³ (Muttray et al, 2005). However these effects were subjective with no residual effects following completion of exposure and similar effects were not recorded in the chronic occupational exposure studies of Schaper et al, 2003, 2004 or Seeber et al, 2004. Therefore it is considered that current IOELV and STEL are sufficiently protective for local respiratory effects. The IOELV of 50 ppm (192 mg/m³) will be used. DNELl-t respiratory irritation = IOELV = 192 mg/m³ Dermal:No information is available to characterise the repeated local effects of toluene 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:

56.5 mg/m³

Most sensitive endpoint:

neurotoxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

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

Overall assessment factor (AF):

1.7

Modified dose descriptor starting point:

other: SCOEL/SUM/18, March 2001; Dir 2006/15/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 Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The magnitude of the IOELV was further modified to take into account differences in duration of exposure experienced by workers and the general population. The IOELV has therefore been taken as a human 8-hr NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.

AF for the quality of the whole database:

1

Justification:

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

AF for remaining uncertainties:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

226 mg/m³

Most sensitive endpoint:

neurotoxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

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

Overall assessment factor (AF):

1.7

Modified dose descriptor starting point:

other: SCOEL/SUM/18, March 2001; Dir 2006/15/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 Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The 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:

56.5 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

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

Overall assessment factor (AF):

1.7

Dose descriptor:

other: SCOEL/SUM/18, March 2001; Dir 2006/15/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 Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The magnitude of the IOELV was further modified to take into account differences in duration of exposure experienced by workers and the general population. The IOELV has therefore been taken as a human 8-hr NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.

AF for the quality of the whole database:

1

Justification:

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

AF for remaining uncertainties:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

226 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

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

Overall assessment factor (AF):

1.7

Dose descriptor starting point:

other: SCOEL/SUM/18, March 2001; Dir 2006/15/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 Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The 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:

226 mg/kg bw/day

Most sensitive endpoint:

neurotoxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

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

Overall assessment factor (AF):

1.7

Modified dose descriptor starting point:

other: SCOEL/SUM/18, March 2001; Dir 2006/15/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 Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The magnitude of the IOELV was further modified to take into account differences in duration of exposure experienced by workers and the general population. The IOELV has therefore been taken as a human 8-hr NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.

AF for the quality of the whole database:

1

Justification:

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

AF for remaining uncertainties:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

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:

8.13 mg/kg bw/day

Most sensitive endpoint:

neurotoxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

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

Overall assessment factor (AF):

1.7

Modified dose descriptor starting point:

other: SCOEL/SUM/18, March 2001; Dir 2006/15/EC

Explanation for the modification of the dose descriptor starting point:

The IOELV (mg/m3) was converted into a human oral 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 Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The magnitude of the IOELV was further modified to take into account differences in duration of exposure experienced by workers and the general population. The IOELV has therefore been taken as a human 8-hr NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.

AF for the quality of the whole database:

1

Justification:

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

AF for remaining uncertainties:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

LOA is currently reviewing the human and animal data supporting Human Health for Toluene. It is expected to be completed by Q4 2020.

General population DNELs for toluene have used the worker IOELV as their starting point. This is considered scientifically justifiable since information supporting the IOELV has been examined for consistency and biological plausibility by SCOEL, with only robust data used in the limit setting process. Importantly, results from human investigations played a key part in this process. It was also considered that the use of a common starting point (the IOELV) for both population groups would result in greater consistency in hazard (dose-response) identification than would be the case if different methods of assessment had been used for workers and the general population. The IOELV has therefore been taken as a human 8-hour no adverse effect level (NAEL) which, after modification (though use of an assessment factor), would be more broadly applicable to the general population. Similar considerations apply to the IOELV-STEL, which has been taken as a surrogate human 15-minute NAEL.

The IOELV was modified to take into account differences in duration of exposure experienced by workers (8-hours) versus the chronic exposure experienced by the general population (24-hours).

An assessment factor (AF) was used to adapt the IOELV for use with the general population. As the IOELV relied heavily on human data, only a factor to account for human intra-species variation was considered necessary. In addition, since no particularly susceptible human sub-populations (including groups exhibiting polymorphisms or other predisposing factors) had been identified in the human literature for toluene, a factor reflecting the general relationship between the intra-species AF for workers and that for the general population was considered applicable.

An AFgeneral population = 1.7, reflecting the ratio between an intra-species AF = 5 for the general population and an intra-species AF = 3 for workers, was therefore applied to the IOELV to give a general population DNEL. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which indicated that the distribution of variability in toxicokinetic and toxicodynamic parameters for human populations of different ages, genders and disease states supports use of these AFs.

It is noted that a slightly larger AFgeneral population (AF = 2) would have resulted if intra-species defaults from REACH guidance had been used, however this would have had only a small effect on the magnitude of the DNEL.

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).

Oral and dermal:

Toluene does not present an acute hazard following ingestion or skin contact hence a DNEL will not be derived.

Inhalation:

Acute inhalation exposures are associated with signs of drowsiness and dizziness at concentrations lower than those which cause lethality, hence a DNEL will be proposed for the inhalation route. The acute LC50 for toluene in the rat (4 hour exposure) is > 20000 mg/m³. The NOAEC for acute CNS effects is 1131 mg/m³ in the rat (from repeat dose study) and 192 mg/m³ in humans (4.5 hour exposure). The current IOELV and 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 Muttray et al, 2005 indicate that 50 ppm (192 mg/m³) is a NOAEC for acute subjective effects supporting the current IOELV. Consequently, the established 15-min STEL of 100 ppm (384 mg/m³) will be used to determine the short-term acute inhalation DNEL for the general population.

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

IOELV-STEL = 384 mg/m³

Modification of dose descriptor

None required (human inhalation exposure).

NOAELacute 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.

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 Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The 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.

DNELacute inhalation = 384 mg/m3 / 1.7 = 226 mg/m3

Irritation

Skin:

No dose/response information can be derived from data available for liquid toluene and DNELs cannot therefore be determined. However, liquid toluene is irritating to the skin hence appropriate RMM and OCs should be employed.

Eye:

Liquid toluene is not irritating to the eye although toluene vapours in ambient air are reported to cause subjective sensations of eye irritation in humans. A NOAEC of 50 ppm (192 mg/m³) was established by Muttray et al, 2005 supporting the current IOELV. Consequently the established 15-min STEL of 100 ppm (384 mg/m³) will be used to determine the eye irritation DNEL for the general population.

Dose descriptor

IOELV-STEL = 384 mg/m³

Modification of dose descriptor

None required (human inhalation exposure).

NOAELeye irritation = 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.

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 Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The 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.

DNELeye irritation = 384 mg/m³ / 1.7 = 226 mg/m³

Respiratory tract:

Toluene can cause respiratory irritation in animals but this has only been observed at very high concentrations. Respiratory irritation potential of toluene in humans is also considered to be a high concentration phenomenon but subjective sensations of “irritation to the throat” have been recorded in human volunteer studies with a LOAEC of 188 mg/m³ (Muttray et al, 2005). However these effects were subjective with no residual effects following completion of exposure and similar effects were not recorded in the chronic occupational exposure studies of Schaper et al, 2003, 2004 or Seeber et al, 2004. The data do not contradict the current IOELV, consequently, the established IOELV-STEL will be used as the basis for determining the acute respiratory irritation DNEL for the general population.

Dose descriptor

The IOELV-STEL of 384 mg/m³ will be used.

Modification of dose descriptor

Not modified

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.

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 Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The 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.

DNELacute respiratory irrit = 384 mg/m³ / 1.7 = 226 mg/m³

Sensitization

No hazard with respect to skin or respiratory sensitization has been identified in animal studies or in humans and, consequently, no DNEL can or will be proposed.

Long-term systemic effects

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

For toluene, the following NOAECs are presented in the IUCLID dossier:

sub-chronic effects: rat NOAEC = 625 mg/kg/day

chronic effects: rat NOAEC = 1131 mg/m³

chronic effects: human NOAEC = 98 mg/m³

reproductive effects: rats NOAEC = 2261 mg/m³

developmental toxicity: rat NOAEC = 2261 mg/m³

However the values presented above are for information only as the DNEL for long-term systemic effects (all routes) will be based on the IOELV, as explained above.

Documentation supporting the IOELV states that in standard animal studies, no significant evidence of systemic toxicity was observed upon repeated, prolonged exposure to concentrations up to at least 300 ppm (1149 mg/m³) toluene vapour, with ototoxicity apparent in rats exposed repeatedly to 1000 ppm (3840 mg/m³) and above. The SCOEL recommendation was therefore based on human data indicating possible changes in neurobehavior with a LOAEL of about 75 ppm (237 mg/m³), while data on the subjective effects suggested a LOAEL of about 60 ppm (230 mg/m³). In contrast, studies describing effects at lower exposures were considered less reliable due to issues with exposure characterisation. Overall, SCOEL concluded that a great deal of human data was available, which produce no reliable evidence of effects at or below toluene concentrations of 50 ppm (192 mg/m³). Therefore the IOELV was set at 50 ppm (192 mg/m³) for the 8 hour TWA.

A STEL (15 min) of 100 ppm (384 mg/m³; based on toxicokinetic considerations and human experimental data) was proposed to limit peaks of exposure which might lead to short-term neurobehavioural effects.

New studies not referenced in the SCOEL evaluation but summarised in the IUCLID dataset for toluene are those of Seeber et al (2004) and Schaper et al (2003; 2004; 2008). There was no evidence from these more recent reports that long-term exposure to toluene at 26 ppm (98 mg/m³) for 21 years had any effects on cognitive function (Seeber et al, 2004), ototoxicity (Schaper et al (2003; 2008) or colour vision (Schaper et al 2004). These studies demonstrate that adverse changes do not occur when exposures are maintained below the current occupational exposure limit of 50 ppm (192 mg/m³).

Oral:

Dose descriptor

The IOELV of 192 mg/m³ will be used.

Modification of dose descriptor

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

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.

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

DNELl-t oral = 13.8 mg/kg bw/d / 1.7 = 8.13 mg/kg bw

Dermal:

The IOELV of 192 mg/m³ will be used.

Modification of dose descriptor

Correct the IOELV to an dermal NOAEL (mg/kg/day) by converting the dose absorbed after inhalation into a systemic dose, assuming 50% uptake by the lung and 3.6% uptake by skin (ten Berge, 2009):

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

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.

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

DNELl-t dermal =384 mg/kg bw/d / 1.7 = 226 mg/kg bw, once per week

Inhalation:

The IOELV was determined on the basis of “a great deal of human data is available, which produce no reliable evidence of effects at or below toluene concentrations of 50 ppm (192 mg/m³).” Since no new scientific information has been obtained under REACH which changes this assessment, the established IOELV of 50 ppm (192 mg/m³) – 8 hr TWA will be used as the starting point for developing a chronic inhalation DNEL for the general population.

Dose descriptor

A DNEL based on the IOELV of 192 mg/m³ will be used.

Modification of dose descriptor

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

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

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.

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

DNELl-t inhal = 96 mg/m³ / 1.7 = 56.5 mg/m³

Reproductive and developmental effects

Documentation supporting the IOELV concluded that animal data provide no evidence that toluene expresses effects on the gonads or fertility.

In relation to developmental toxicity, documentation supporting the IOELV notes that animal developmental studies show some evidence of a weak effect in rats (but not mice or rabbits) at near-maternally toxic exposures above 400 ppm (1532 mg/m³), while information suggesting a higher abortion rate in pregnant women exposed to an average of 88 ppm (337 mg m3) toluene vapour was balanced by normal birth outcomes for women deliberately or accidentally exposed to high levels of toluene during pregnancy. Documentation supporting the IOELV indicates that SCOEL has access to the draft risk assessment report for toluene, and was therefore aware of the background information contained therein.

New information from Saillenfait et al. (2007), who reported a NOAEC of 500 ppm (1880 mg/m³) does not materially alter this position i.e. the NOAEC is consistent with that of Thiel and Chahoud (1997) which was considered a key animal study in the risk assessment report.

Human data considered by the EU RAR to suggest “an increased risk of late spontaneous abortions associated with exposure to toluene at levels around 88 ppm (range 50-150 ppm)” (i.e. Ng et al., 1992) were also known to SCOEL and are discussed in the IOELV support document, however the Committee observed that abortions have not been reported upon accidental high exposure or toluene abuse by pregnant women and that an exposure limit of 50 ppm (192 mg/m³) would be protective.

Since no new scientific information has been obtained under REACH which changes this assessment, the established IOELV of 50 ppm (192 mg/m³) – 8 hr TWA will be used as the starting point for developing a DNEL for reproductive and developmental effects for the general population.

The process for DNEL derivation leads to a result that is identical to that for long-term systemic effects after inhalation, therefore a DNEL of 56.5 mg/m³ is proposed.

DNELreproductive/developmental = DNEL l-t inhalation = 56.5 mg/m³

Long-term local effects

Inhalation:

Toluene can cause respiratory irritation in animals but this has only been observed at very high concentrations. Respiratory irritation potential of toluene in humans is also considered to be a high concentration phenomenon but subjective sensations of “irritation to the throat” have been recorded in a human volunteer study with a LOAEC of 188 mg/m³ (Muttray et al, 2005). However these effects were subjective with no residual effects following completion of exposure and similar effects were not recorded in the chronic occupational exposure studies of Schaper et al, 2003, 2004 or Seeber et al, 2004. It is considered that the proposed long-term systemic DNEL for the general population is sufficiently protective for local respiratory effects, therefore a DNEL of 56.5 mg/m³ is proposed.

DNELlt respiratory irrit = DNEL l-t inhalation = 56.5 mg/m³

Dermal:

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