2,2-dimethylpropane-1,3-diyl cyclohex-4-ene-1,2-dicarboxylate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.25 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

40

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

50 mg/m³

Explanation for the modification of the dose descriptor starting point:

The No Observed Adverse Effect Level (NOAEL) for 2,2-dimethylpropane-1,3-dicylcyclohex-4-ene-1,2-dicarboxylate over a ninety-day treatment period (OECD 408, Envigo Study Number: YQ17MN) was considered to be 100 mg/kg bw/day, due to adverse histopathological kidney changes for both sexes at the high dosage of 750 mg/kg bw/day.

The boiling point (270 °C), operating temperature (<40°C), low vapour pressure (4.5 x 10-5 Pa at 25 °C) and exposure scenario prescribed personal protective equipment and mechanical risk management measures mitigate any opportunity for exposure to any hazardous properties a conservative approach to risk characterisation has been followed. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation.

Assessment factors:

Interspecies AF of 4

Allometric

scaling default AF (4) to allow for differences in metabolic rate.

Species specific information is available therefore a further AF for

remaining differences is not relevant as according to Section R.8.4.3.3

of the REACH guidance on information requirements and chemical safety

assessment

Intraspecies

AF of 5

Default

assessment factor workers for threshold effects based on the fact that

this sub-population does not include the very young, very old or very ill

Exposure

duration AF of 2

 Extrapolation to chronic exposure based on a sub-chronic 90 d toxicity study

AF for dose response relationship:

2

Justification:

In the absence of route-specific information on the starting route, a default factor of 2 (i.e. the absorbtion percentage is half that of the end route) has been included according to Chapter R.8. of the ECHA guidance on information requirements and chemical safety assessment.

AF for differences in duration of exposure:

2

Justification:

Extrapolation to chronic exposure based on a sub-chronic toxicity study (90-day) extrapolation from sub-chronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling default AF (4) to allow for differences in metabolic rate. Species specific information is available therefore a further AF for remaining differences is not relevant as according to Section R.8.4.3.3 of the REACH guidance on information requirements and chemical safety assessment

AF for intraspecies differences:

5

Justification:

Default assessment factor workers for threshold effects based on the fact that this sub-population does not include the very young, very old or very ill.

AF for the quality of the whole database:

1

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Explanation for the modification of the dose descriptor starting point:

The substance is not classified for acute oral toxicity, and the DNELs derived for long term exposure are considered to be sufficient for protection of the workers, therefore no short-term DNELs are derived for these routes of exposure.

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

40

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The test substance, 1,2,3,6 -Tetrahydrophthalic anhydride, oligomeric reaction products with 2,2 -dimethylpropane-1,3 -diol, was evaluated in an OECD 402 rat acute dermal toxicity study. The acute dermal LD50 was > 2000 mg/kg of body weight. Furthermore, the test substance was not irritating to the skin under the conditions of the study with a 24 hr exposure period. It can therefore be concluded that there is minimal risk associated with dermal exposure. However, a conservative approach for derivation of a dose descriptor starting point is proposed below.

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor is introduced for the oral to dermal extrapolation. The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 1 in case of oral to dermal extrapolation. However, based on the log Kow of 1.14 and molecular weight of the substance (407.44), the skin permeability according to Fitzpatrick et al (2004) of the substance is considered to be marginally permeable to the skin based on a calculated Log skin permeation coefficient of -5.84. Therefore, a ratio of 0.5 for oral to dermal absorption is provisionally suggested for DNEL derivation.

Modified dose descriptor (dermal) = 100/0.5 (skin absorption rate for slightly permeable substance) = 200 mg/kg bw

AF for differences in duration of exposure:

2

Justification:

Extrapolation to chronic exposure based on a sub-chronic 90 d toxicity study

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling default AF (4) to allow for differences in metabolic rate, assuming a rat body weight of 0.250 kg and a human weight of 70kg) as stated in Table R. 8.3 of the REACH guidance on information requirements and chemical safety assessment.

AF for intraspecies differences:

5

Justification:

Default assessment factor workers for threshold effects based on the fact that this sub-population does not include the very young, very old or very ill.

AF for the quality of the whole database:

1

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

According to REACH guidance on information and requirements and chemical safety assessment , a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

 

Short-term toxicity

According to the REACH guideline (R8, Appendix R 8-8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. The substance is not classified for acute oral toxicity, and the DNELs derived for long term exposure are considered to be sufficient for protection of the workers, therefore no short-term DNELs are derived for these routes of exposure. The substance is also classified as irritating to the eye (Cat. 2A) as well as skin sensitizing (Cat .1) but no DNELs could be derived due to the absence of a threshold for effects, as a consequence mitigation for skin sensitization will be via qualitative means as stated in Table E 3-1 of ECHA Part E Risk Characterization guidance. No data is available whether the test substance could cause irritation to the respiratory track and therefore no DNEL could be derived.

Long-term toxicity

Data is available from a repeated dose toxicity study carried out using rats to OECD guideline 408. The No Observed Adverse Effect Level (NOAEL) for 2,2-dimethylpropane-1,3-diyl cyclohex-4-ene-1,2-dicarboxylate over a ninety-day treatment period was considered to be 100 mg/kg bw/day, due to adverse histopathological kidney changes for both sexes at the high dosage of 750 mg/kg bw/day. A route-to-route extrapolation is needed to derive the DNELs for the dermal and inhalation route.

According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach will be taken forward to DNEL derivation. In the absence of route-specific information a ratio of 1 for oral to dermal absorption, considered as worst case scenario, is suggested for the risk assessment of the substance.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified