Dipentaerythritol hexaesters of 3,5,5-trimethylhexanoic, n-decanoic, n-heptanoic, and n-octanoic acids

Endpoint summary

Description of key information

Oral NOAEL (rat, male): 500 mg/kg bw/day (OECD 422, GLP, substance-specific data)
Oral LOAEL (rat, male): 1000 mg/kg bw/day (OECD 422, GLP, substance-specific data); reduced body weight and body weight gain
Oral NOAEL (rat, female): 1000 mg/kg bw/day (OECD 422, GLP, substance specific data)
Oral NOAEL (rat, m/f): 1000 mg/kg bw/day (OECD 408, GLP analogue approach)

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the polyol esters family will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises adequate, reliable (RL 2 due to read across) studies from reference substances with similar structure and intrinsic properties, as well as substance-specific data (RL1). Read-across is justified based on common origin, common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to endpoint discussion for further details). The selected studies are 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 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

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the polyol esters family will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

 

Justification for grouping of substances and read-across 

Apart from one combined 28-day repeated dose toxicity study with the reproduction/developmental screening test (study no: 21411), there are no data available for the repeated dose toxicity of Dipentaerythritol hexaesters of 3,5,5-trimethylhexanoic, n-decanoic, n-heptanoic, and n-octanoic acids (EC 453-490-7). In order to fulfil the standard information requirements set out in Annex IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted.

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 grouping of substances and 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 regular pattern as a result of structural similarity.

 Overview for repeated dose toxicity, oral

CAS/EC	Oral NOAEL (rat) mg/kg bw/day
EC: 453-490-7 (a) Target substance	500 (m) or 1000 (f)   in addition: RA: CAS 68424-31-7 RA: CAS 146289-36-3 RA: CAS 131459-39-7
CAS 68424-31-7 (b)	1450 (m) 1613 (f)
CAS 146289-36-3	1000 (m,f)
CAS 131459-39-7	1000 (m,f)

(a) Substances subject to the REACh  Phase-in registration deadline of 31 May 2013 are indicated in bold font. Only for this substance a full set of experimental results and/or read-across is given.

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font.

 

The above mentioned substances are considered to be similar on the basis of the structural and similar properties and/or activities. The available endpoint information is used to predict the same endpoints for Dipentaerythritol hexaesters of 3,5,5-trimethylhexanoic, n-decanoic, n-heptanoic, and n-octanoic acids (EC 453-490-7).

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

EC 453-490-7 (former CAS 70983-72-1)

One recent study is available for EC 453-490-7, which was a combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening study in the rat (Nyco, 2022). The study was conducted under GLP conditions and according to OECD 422. The study is considered reliable and valid. This study was designed to investigate the potential adverse effects of the test substance upon repeated, subacute exposure period in Wistar rats, including potential adverse effects on reproductive/developmental endpoints. Females were dosed (50 to 60 days) throughout the study. This included two weeks prior to mating, the variable time to conception, the duration of pregnancy and thirteen days after delivery, up to and including the day before scheduled sacrifice. Males were dosed from the premating period throughout mating and until after mating until a total dosing period of 28 days was reached. Parental animals received the test substance in corn oil orally via gavage once daily at doses of 250, 500 and 1000 mg/kg bw/day. A similarly constituted control group received the vehicle (corn oil) only. Mortality, clinical signs, body weight changes and food consumption were recorded at frequent intervals throughout the study period. Functional tests, including sensory reactivity, grip strength assessment and motor activity were conducted. Thyroid hormones were measured in pups and parents. Laboratory investigations included haematological and clinical biochemistry parameters. All animals sacrificed terminally (males on day 29 and females at lactation day 14) were subjected to a detailed necropsy with special emphasis on the reproductive organs. Additionally, weights of selected organs were recorded, including the thyroid glands. The results of the study suggest that there were no test-item induced effects on any of the parameters investigated, apart from body weight and body weight gain in males, only, where a slight decrease in body weight and body weight gain in parental males during the pre-mating and mating periods was observed. There were no other signs of intoxication. No target organs were identified. Hence, the systemic toxicity NOAEL for males was set at 500 mg/kg bw/day, while the corresponding systemic toxicity NOAEL for females was established at 1000 mg/kg bw/day. For the respective results on reproduction and development, please refer to the EPS under Chapter 7.8.

 

As additional information, in accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5 a read-across from the structurally related analogue substances Fatty acids, C5-10, esters with pentaerythritol (CAS# 68424-31-7), pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3) and 3,5,5-trimethylhexanoic acid mixed tetraesters with PE and valeric acid (CAS# 131459-39-7) was conducted.

 

CAS 68424-31-7

A 28 day study was conducted according to OECD Guideline 407 with Fatty acids, C5-10, esters with pentaerythritol (CAS# 68424-31-7) (Croda, 1993). The test substance was administered in concentrations of 1000 ppm, 5000 ppm, 12500 ppm resembling 112, 562 and 1450 mg/kg bw/day for male and 119, 586 and 1613 mg/kg bw/day for female rats, respectively to 5 animals per sex and dose for 28 consecutive days.

There were no toxicologically significant effects on body weight, food consumption and clinical condition up to and including the highest dose level. Changes in some clinical chemistry and red cell related parameters were observed in male rats at 12500 ppm but these were minor and considered not to be of toxicological significance. There were no clinical sings indicative of neurological changes in the brains of the 12500 ppm group. A minimal hepatocyte hypertrophy, present in males in the 12500 ppm group, is considered to be evidence of an adaptive response. Microscopic examination of the kidneys from male animals from all dose groups revealed an increase in hyaline droplet formation (the main constituent of which is alpha-2µ-globulin) and tubular basophilia; this phenomenon is widely accepted to be specific to the male rat and as such is considered to have no relevance to man. A NOAEL of 1450 and 1613 mg/kg/day could be identified for male and female rats, respectively.

 

CAS 146289-36-3

A 90-day oral feeding toxicity study with the source substance pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3) was performed according to OECD Guideline 408 and under GLP conditions (Emery, 1998). Groups of 10 male and 10 female Wistar rats were exposed to the substance at 100, 300 and 1000 mg/kg bw/day by gavage daily, 7 days/week for 90 days. Satellite control and high dose groups containing 10 male and female animals each were observed for additional 28 days. Control animals (10 per sex and dose) received the concurrent vehicle, distilled water containing 1% Tween 80. Observations and examinations of the animals included clinical signs, body weight, food consumption, haematology, clinical chemistry, organ weights, neurobehaviour, gross necropsy and histopathology. The daily oral administration of the test substance was tolerated without any adverse effects up to 1000 mg/kg bw/day. No mortality was observed except for two animals that died shortly after administration due to incorrect gavage. Absolute and relative kidney weights were increased in all male animals in the high dose group which was still present after the recovery period. However, histopathology revealed no adverse effects in the kidney. Absolute and relative liver weights were increased in both sexes but this was no longer apparent after the recovery period in females. Other significant differences seem to be incidental. The activity of alkaline phosphatase of the serum significantly increased in the high dose group, males and females. This indicates damage to liver cells and/or an increased function rate. This finding was no longer apparent at the end of the treatment-free period. Except for the increased kidney weights and liver weight in the males, all changes ( e.gclinical chemical changes) were no longer apparent at the end of the treatment-free period. The increase in kidney weights in all male animals could be correlated to the formation of hyaline droplets a phenomenon widely accepted to be specific to the male rat and as such considered to have no relevance to man, a 90-day oral NOAEL of 1000 mg/kg bw/day was found for Pentaerythritol ester of pentanoic acids and isononanoic acid in male and female rats.

 

CAS 131459-39-7

A 28 day study was conducted according with a method similar to OECD Guideline 407 with 3,5,5-trimethylhexanoic acid mixed tetraesters with PE and valeric acid, CAS# 131459-39-7 Croda, 1999) and GLP compliant. The test substance was administered in arachis oil by gavage in concentration of 15, 150 and 1000 mg/kg bw/day to 5 animals per sex and dose for 28 consecutive days.

No mortalities were observed. An incidence of increased salivation was detected around the time and up to five hours after dosing in 1000 mg/kg bw/day animals from day 14 onwards. Sporadic incidents of diuresis, red/brown staining of the ano-genital region and wet fur were also detected at this dose level.

No adverse effect on body weight development and dietary intake were detected. However a slight increase in water consumption for animals of either sex treated with 1000 mg/kg bw/day during the final week in the study was detected. With regard to organ weight males treated with 1000 mg/kg bw/day showed a statistically significant increase in kidney weight, relative to terminal body weight, with females from this treatment group showing an increase in relative liver weight when compared with controls. No treatment-related adverse effects were detected among animals of either sex treated with 150 or15 mg/kg bw/day. All males treated with 1000 mg/kg bw/day showed speckled kidneys at terminal kill whilst one female from this treatment group showed pallor of the liver with accentuated lobular pattern. No treatment-related macroscopic abnormalities were observed in the other groups.

The liver changes identified during the study are generally considered to be adaptive in nature whilst the kidney changes are consistent with well documented changes that are peculiar to the male rat in response to treatment with some hydrocarbons. These effects are, therefore, not indicative of a hazard to human health and, for purposes of hazard evaluation, the NOAEL should be regarded as 1000 mg/kg bw/day for both sexes.

 

Conclusion for Repeated Dose Toxicity – Oral

 

The available data from a combined repeated-dose toxicity study with the reproductive/developmental screening test (according to OECD 422) performed in Wistar rats revealed general systemic toxicity at a dose level of 1000 mg/kg bw/day in males, where a decrease in body weight and body weight gain was observed during the mating and pre-mating period. Females were considered unaffected at this dose level. No target organs were identified. Additionally, read-across from structurally related analogue substances was applied in order to fulfill the standard information requirements set out in Annex IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, was conducted. The 28- and 90-day oral toxicity studies with Fatty acids, C5-10, esters with pentaerythritol (CAS# 68424-31-7), 3,5,5-trimethylhexanoic acid mixed tetraesters with pentaerythritol and valeric acid, (CAS# 131459-39-7) and Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3) showed no overt signs of toxicity up to the high dose group of 1000 mg/kg bw. Taking all information together, the NOAEL for repeated oral toxicity was found to be 1000 mg/kg bw/day in females and 500 mg/kg bw/day in males. 

 

There is no data available on the repeated dose toxicity after dermal application and inhalation.

Justification for classification or non-classification

Based on substance-specific data and read-across from structurally similar substances, the available data on repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.