Pentaerythritol tetrastearate

Endpoint summary

Description of key information

Oral (Read-across, OECD 407): sub-acute NOAEL rat ≥ 1000 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

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

Remarks:

Summary of available data used for the endpoint assessment of the target substance

Adequacy of study:

key study

Justification for type of information:

Please refer to the Analogue Approach Justification provided in Section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

28 day, rat

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 effects, NOAEL corresponding to the highest dose tested

Remarks on result:

other: Source: CAS 189200-42-8

Key result

Critical effects observed:

no

The 28 day repeated oral dose toxicity study with the source substance Fatty acids, C8 -10 mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8) was selected as key result for reasons of structural similarity and data reliability. Additionally in vivo data from the source substance Fatty acids, C5 -10, esters with pentaerythritol (CAS 68424 -31 -7, similar to OECD guideline 407) is given. In both studies the NOAEL for systemic toxicity in male and female rats was found to be ≥1000 mg/kg bw/day.

Executive summary:

The read-across approach is justified in the analogue justification. The target and source substance are considered unlikely to differ in their repeated dose toxicity potential. The oral repeated dose toxicity of the target substance is estimated based on adequate and reliable short-term (28 day) toxicity studies with source substances conducted in rats. The NOAEL for systemic toxicity was found to be 1000 mg/kg bw/day. Therefore, a NOAEL for repeated dose toxicity after oral exposure of 1000 mg/kg bw/day is considered for the target substance Pentaerythritol tetrastearate (CAS115-83-3).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

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 (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-X, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) 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

Mode of Action Analysis / Human Relevance Framework

Not applicable.

Additional information

There are no data on the repeated dose toxicity of the target substance pentaerythritol tetrastearate (CAS 115-83-3). 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 source substances 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 is the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

Repeated dose toxicity, oral

CAS 189200-42-8

In another 28-day subacute repeated dose toxicity study performed with Fatty acids, C8-10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8) equivalent or similar to OECD guideline 407 under GLP conditions, male and female Crl:CD BR rats were dosed with 100, 500 and 1000 mg/kg bw/day by oral gavage once daily, 7 day/week for a total of 28 days (key study, 1995). 5 animals per dose and sex were used. A control group receiving the vehicle polyethylene glycol (PEG 400) only was also included in the study design. 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 dose less than the other animals. All animals survived the study period until scheduled termination. No clinical signs occurred that were judged to be treatment-related, no effects on body weights and on food consumption of the treated animals were observed. Moreover, there were no significant differences in the haematology parameters between the negative control and the animals treated. There were also no significant differences in the clinical chemistry parameters which were judged to be test substance related. Neurobehavioural observations made on day 8 and day 27 were unremarkable. The necropsy revealed no treatment-related findings. Single effects were observed but were considered to be incidental and not treatment-related. No significant differences in mean absolute organ weight and no histopathologic changes were observed in any of the organs or tissues examined between the test substance treated and negative control animals. 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 oral NOAEL was therefore determined to be ≥ 1000 mg/kg bw/day.

 

CAS 68424-31-7

In a short-term (28 day) repeated dose toxicity study Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7) was investigated according to OECD guideline 407 and under GLP conditions (supporting study, 1993). The test substance was administered in the diet 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 bw/day could be identified for male and female rats, respectively.

CAS 146289-36-3

In addition to the short-term repeated dose studies referred to above, a sub-chronic (90-day) oral toxicity study with Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS 146289-36-3) was performed according to OECD guideline 408 and under GLP conditions (supporting study, 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. Therefore, a 90-day oral NOAEL of ≥ 1000 mg/kg bw/day was found for the test substance in male and female rats.

 

Overall conclusion for repeated oral dose toxicity

Since no toxicologically relevant findings were detected in any of the studies and hence all NOAELs determined correspond to the highest doses tested, a NOAEL of ≥ 1000 mg/kg bw/day is expected to be applicable for the target substance.

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 pentaerythritol tetrastearate (CAS 115-83-3), 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.