Fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol

Endpoint summary

Description of key information

Oral: NOAEL (male/female, rat, 90 d) ≥ 1000 mg/kg bw/day

Read-across from structural analogue source substance pentanoic acid, mixed esters with PE, isopentanoic acid and isononanoic acid (CAS 146289-36-3, key)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse and treatment-related effects were observed up to and including the highest tested dose level

Remarks on result:

other: Source: CAS 146289-36-3, 1998, RL1

Critical effects observed:

no

Conclusions:

A subchronic oral repeated dose toxicity study with the source substance CAS 146289-36-3 is available, which resulted in a NOAEL value ≥ 1000 mg/kg bw/day. Applying the read-across approach, the same result is expected for the target substance fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available information comprises adequate and reliable (Klimisch score 1 and 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. 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

Read-across justification

There are no data on the repeated dose toxicity of fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol. 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).

Subacute

CAS 68424-31-7

A 28 day study with fatty acids, C5-10, esters with pentraerythritol (CAS 68424-31-7) was conducted similar to OECD 407 and under GLP conditions (Zeneca, 1993). The test substance was administered in concentrations of 1000 ppm, 5000 ppm and 12500 ppm (corresponding to 112, 562 and 1450 mg/kg bw/day for male and 119, 586 and 1613 mg/kg bw/day for female rats) to 5 Alpk:APfSD rats per sex and dose for 28 consecutive days. Control animals (5 per sex and dose) received the plain diet. There were no toxicologically significant effects on body weight, food consumption and clinical condition and mortality up to and including the highest dose level. Changes in 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. A minimal hepatocyte hypertrophy present in males of the 12500 ppm group was observed and 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/d could be identified for male and female rats, respectively.

CAS 189200-42-8

A 28 day study with fatty acids, C8-10 mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8) was conducted similar to OECD 407 and under GLP conditions (ExxonMobil, 1995). The test substance was administered by gavage in concentrations of 100, 500 and 1000 mg/kg bw/day to 5 Crl:CD BR rats per sex and dose for 28 consecutive days. Control animals (5 per sex and dose) received the concurrent vehicle polyethylene glycol (PEG 400). There were no toxicologically significant effects on body weight, food consumption and clinical condition and mortality up to and including the highest dose level. One male animal of the 500 mg/kg bw group died after the first application due to a gavage error. This animal was replaced on Day 1 with another animal that received one less dose than the other animals. All animals survived the study period to the scheduled termination. The neurobehavioural observations made on Day 8 and Day 27 were unremarkable for the animals treated with the test substance. Due to the absence of a dose-response pattern, these effects were judged to be incidental and not related to treatment. Changes in clinical chemistry and haematology were not considered to be clinically significant due to the absence of a clear dose-response pattern. In the mid dose group, there was a statistically significant increase in the mean relative testes weight. Due to the absence of a dose-response pattern, this effect was judged to be incidental. The necropsy revealed no treatment-related findings. Moreover, no treatment-related histopathologic changes were observed in any of the organs or tissues examined. Since no adverse and treatment-related effects were observed up to and including the highest tested dose level were observed, the NOAEL was found to be ≥ 1000 mg/kg bw/day.

Subchronic

CAS 146289-36-3

A 90-day oral feeding toxicity study with pentaerythritol ester of pentanoic acids and isononanoic acid (CAS 146289-36-3) was performed according to OECD 408 and under GLP conditions (ToxLabs, 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.g. clinical 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.

Overall conclusion for repeated dose toxicity

The data for the analogue source substances considered for read-across showed that no effects were observed up to and including the recommended limit values. Therefore and based on read-across, as the available data from analogue substances did not identify any hazard for repeated dose toxicity, the target substance fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol 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 fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol, 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.