Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers

Endpoint summary

Description of key information

Oral: OECD 408, rat, NOAEL ≥ 1000 mg/kg bw/day
 Inhalation: OECD 411, rat, NOAEC≥ 0.56 mg/L (nominal concentration)
 Dermal: OECD 413, rat, NOAEL ≥ 2000 mg/kg bw/day 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2 due to read-across) and consistent 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 study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 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 adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2) from a reference substance 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 study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2) from a reference substance 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 study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2) from a reference substance 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 study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2) from a reference substance 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 study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Additional information

Justification for read-across

There are no data available for the repeated dose toxicity of Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers. In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for the read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a comparable pattern as a result of structural similarity, the substances Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) and Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) are selected as source substances.

Repeated dose toxicity: oral, subchronic

CAS 403507-18-6

A subchronic 90-day oral toxicity study with Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) was performed following a protocol comparable to OECD guideline 408 and under GLP conditions (McRae, 2004). Groups of 10 Sprague-Dawley rats/sex were exposed to the substance at 5, 50 and 1000 mg/kg bw/day by gavage, 7 days/week for 90 days. Control animals (10/sex/dose) received the vehicle arachis oil. Observations and examinations of the animals included mortality, clinical signs, body weight, food consumption, opthalmoscopic examination, haematology, clinical chemistry, organ weights, neurobehaviour, gross necropsy and histopathology. One male treated with 5 mg/kg bw/day was found dead on Day 36 and one male treated with 50 mg/kg bw/day was terminated on Day 53. There was no evidence to indicate these deaths were attributable to test material toxicity; the most likely cause of death was gavage mis-administration. Neither death was considered to be toxicologically relevant. Increased salivation was detected immediately after dosing for 1000 mg/kg bw/day females from Day 17 and for 1000 mg/kg bw/day males from Day 18 onwards. Hunched posture was observed for individual 1000 mg/kg bw/day females from Day 37 with isolated incidents of tiptoe gait also observed on Days 37 and 38 and exophthalmia present in two females from Day 75 and 76 onwards. Exophthalmia was also evident in two 50 mg/kg bw/day females from Day 81 and hunched posture was observed in a different 50 mg/kg bw/day female from Day 81 onwards. There were no toxicologically significant effects on body weight, food consumption and clinical condition up to and including the highest dose level. The females in all the treatment groups showed significant reductions in leucocyte count, specifically in the lymphocyte fraction, but these were attributed to higher than expected control values and not a consequence of treatment. Furthermore, mid-dose males showed a reduction in haemoglobin concentration, however, in the absence of a convincing dose response, this value was considered to be an incidental. The reduction in erythrocyte count detected for 1000 mg/kg bw/day males achieved a statistical significance of p<0.01, however, it was considered not to be toxicologically relevant as no effect was noted in females. The relative liver weight was increased (13%) for animals in the high-dose groups. The toxicological significance of this finding is unclear due to the absence of correlating biochemical or histopathological changes, suggesting that the organ weight increase is not a direct consequence of treatment. Therefore, a 90-day oral NOAEL ≥ 1000 mg/kg bw/day was determined for Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane in male and female rats.

Repeated dose toxicity, inhalation, subchronic

CAS 67762-53-2

A 90-day subchronic inhalation toxicity study was performed with Fatty acids, C5-9, tetraesters with pentaerythritol, following a protocol similar to OECD guideline 413 (Dulbey, 1992). 15 rats/sex/dose were exposed whole-body to the test substance aerosol for 6 hours/day, 5 days/week at concentrations of 0.05, 0.15 and 0.5 mg/L (0.05, 0.16 and 0.56 mg/L nominal concentration). The sham-control group (15 animals/sex) was treated with clean air under the same conditions, while a second control group remained untreated. 10 additional male animals were included in every group for pulmonary function tests (deflation quasistatic pressure-volume cureved, functional residual capactiy, and maximal forced exhalation manoeuvre) and histopathological examination (analysis of hydroxyproline content and analysis of test material remaining in the lung).

There was no mortality during the study period. No toxicologically relevant clinical signs were observed. The body weight of treated male animals was increased significantly compared with the control group. As the difference was less than 10% this is considered to be an incidental occurrence. The body weight and body weight gain of females was comparable between the control and treatment groups. No substance-related adverse effects were observed clinical biochemistry and haematological parameters. The lungs of the high-dose animals had a minimal increase in weight which correlated with slightly increased numbers of macrophages in the pulmonary alveoli. Microscopic examination of the lungs of animals in the high-dose group revealed one to two plump macrophages with sparse cytoplasmic vacuoles in less than 1.0% of the alveoli (in controls less than 0.1%). However, as the changes observed in the lungs were minor, they were not considered to be toxicologically relevant. No treatment-related effects were noted in sperm morphology or in sperm and spermatid counts. There were no significant differences between any groups for any of the pulmonary function parameters. The total weight of the five lung lobes of the high-dose group was significantly higher than for the sham-exposed controls and other exposed groups, but not greater than the untreated controls. This effect is not considered to be toxicologically relevant. Therefore, the NOAEC was considered to be ≥ 0.56 mg/L (nominal concentration).

Repeated dose toxicity, dermal, subchronic

CAS 67762-53-2

A 90-day dermal toxicity study with Fatty acids, C5-9, tetraesters with pentaerythritol was performed following a protocol similar to OECD guideline 411 (Cruzan, 1988). 10 Sprague-Dawley rats/sex/dose were exposed to 800 and 2000 mg/kg bw/day of the test substance via open application for 90 days (5 days/week). The application was continuous (24 hours/day), and the application site was washed clean once per week. The animals wore collars to reduce the possibility of ingestion through grooming. 5 additional rats/sex were included in the control and high-dose group to assess the dermal bioavailability of the test substance. The penetration rate was measured as recovery of radioactivity in the urine and faeces as well as the remaining radioactivity in tissue samples. There was no mortality during the study period. No toxicologically relevant clinical signs were observed. The body weight gain was 7% lower in the low-dose group, and 10% lower in the high-dose group, compared with the control males. As the difference was relatively low, the decrease in body weight gain was not considered to be toxicologically relevant. The body weight and body weight gain of females was comparable between the control and treatment groups. The aspartate aminotransferase level in high-dose females was significantly increased. The increased activity of hepatic enzymes indicates an adaptive increase in hepatic metabolism caused by the treatment, but is not considered to be toxicologically relevant as no other effects were noted in the liver. Other changes observed in clinical chemistry parameters in the low-dose group only or in one sex only are considered to be incidental. No toxicologically relevant changes were seen on organ weights. No effects on sperm morphology were observed. Both treated groups showed minimal erythema and flaking of the skin at the application site. Microscopic examination showed very minor epidermal hyperplasia and chronic inflammation of the superficial dermis. The macroscopic inspection at autopsy and subsequent histopathological examination of remaining organs and tissues did not reveal any treatment-related changes.

The results of the in vivo skin penetration study performed as part of the repeated dose toxicity study indicate that the 90-day treatment did not increase the skin penetration of the test substance significantly overall, as only the value for females was statistically different from the penetration in untreated animals. The skin penetration of untreated rats was less than 2% and the mean value for rats treated for 90 days was approximately 6%. As no effects of systemic toxicity were identified up to the highest dose tested, the 90 day dermal NOAEL was found to be ≥ 2000 mg/kg bw/day for rats.

 

Conclusion for repeated dose toxicity

The data for the source substances showed that no effects were observed up to and including the recommended limit values in studies conducted via the oral, inhalation and dermal routes. Therefore, as the available data did not identify any hazard for repeated dose toxicity, Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers is not expected to be hazardous following repeated exposure.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between the source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between the source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between the source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between the source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between the source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

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 Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers, 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) 1272/2008, and are therefore conclusive but not sufficient for classification.