Bis(1-methylheptyl) adipate

Endpoint summary

Description of key information

NOAEL (oral, 28 days, male/female rat) = 200 mg/kg bw/day (read-across from CAS 103-23-1)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises adequate and reliable (Klimisch score 2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to the endpoint discussion for further details). The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Justification for read-across

There are no data on the repeated dose toxicity of bis(1-methylheptyl) adipate (CAS 108-63-4). The assessment was therefore based on studies conducted with analogue substances as part of a read across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

CAS 103-23-1

In a study according to OECD 407, bis(2-ethylhexyl) adipate (CAS 103-23-1) in corn oil was administered daily via oral gavage to 10 Crj: CD(SD) rats per sex and group at dose levels of 40, 200 and 1000 mg/kg bw/day (Miyata et al., 2006). After 28-day treatment with the test substance, no treatment-related mortalities were observed in the animals. The relative organ weight of kidney was significantly increased in males and females at 1000 mg/kg bw/day. At the same dose level, increased relative adrenal weights in females and increased relative liver weights in both sexes were observed. The changes in kidney weights at 1000 mg/kg bw/day were accompanied by clear spotty pattern in kidney of 2 male rats as well as increased eosinophilic bodies (7/10 males) and hyaline droplets (8/10 males) at microscopic examination. These kidney effects are specific to male rats (alpha-2 micro globulin nephropathy syndrome) and of no concern to man. Further findings at histopathology involved increased ovarian follicle atresia in 4/10 females at 1000 mg/kg bw/day. Examination of vaginal smears revealed prolongation of the estrous stage in 2/10 females of the 1000 mg/kg bw/day dose group. No substance-related effects were observed on sperm parameters and histopathology of reproductive organs in males. Based on the results of this study, the NOAEL for male and female Crj:CD(SD) rats was established at 200 mg/kg bw/day.

CAS 105-99-7

The subacute oral toxicity of dibutyl adipate (CAS 105-99-7) was investigated in a study similar to OECD guideline 407 and in conformity with GLP (MHLW, 1996). Dilutions of the test substance in olive oil were administered once daily via oral gavage to groups of 6 Crj: CD(SD) rats per sex at doses of 20, 140 and 1000 mg/kg bw for a period of 28 days. A similar constituted group received the vehicle and acted as a control. In addition, satellite groups of 6 animals per sex, each for the control and high dose group, were used to investigate the reversibility of effects during a 14-day post-exposure recovery period. No substance-related mortalities occurred during the whole study period. Clinical signs involved slight salivation in males and females at 1000 mg/kg bw/day during treatment. However, this effect disappeared during the 14-day recovery period. Food consumption was similar between treated and control animals and no changes in body and organ weights were noted during the study. No treatment-related alterations in parameters of haematology, clinical chemistry and urinalysis were observed. At gross and histopathological examination, no abnormal findings were reported in treated animals of the whole study. Based on the results of this subacute toxicity study, the NOAEL of dibutyl adipate was considered to be ≥ 1000 mg/kg bw/day.

Overall conclusion

The data for the read-across analogue substances showed that no effects, relevant for humans, were observed up to and including the recommended limit values. Therefore, as the available data did not identify any hazard for humans after a repeated dose administration, the target substance bis(1-methylheptyl) adipate (CAS 108-63-4) is not expected to be hazardous following repeated exposure.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to bis(1-methylheptyl) adipate (CAS 108-63-4), data will be generated from data for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

Therefore, based on the analogue read-across approach, the available data on repeated dose toxicity do not meet the classification criteria according to Regulation (EC) No. 1272/2008 and are therefore conclusive but not sufficient for classification.