Pentaerythritol tetrastearate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No data on reproductive toxicity / effects on fertility for the target substance are needed because reliable information on pre-natal developmental toxicity studies for adequate source substances are available. Moreover, based on the results of available sub-acute repeated dose toxicity studies investigating parameters of reproductive toxicity for adequate source substances and on toxicokinetic considerations, no adverse effects on reproductive organs and tissues are expected for the target substance.

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No data on reproductive toxicity / effects on fertility for the target substance are needed because reliable information on pre-natal developmental toxicity studies for adequate source substances are available. Moreover, data taken from repeated dose toxicity studies are available including a sub-chronic study with Pentanoic acid, mixed esters with PE, isopentanoic acid and isononanoic acid (CAS 146289-36-3) and subacute studies for the analogue substances Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7), and Fatty acids, C8-10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8).

In a 90-day oral repeated dose toxicity study with Pentanoic acid, mixed esters with PE, isopentanoic acid and isononanoic acid (CAS 146289-36-3) up to a dose of 1000 mg/kg bw/day no abnormalities were reported for histopathological examination of the reproductive organs including epididymides, ovaries, prostate, seminal vesicle, mammary glands, testes, and uterus, and no effects on organ weights of epididymides, testes, ovaries, and testes were seen.

In a 28-day oral repeated dose toxicity study with Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7) up to a dose of 1450 (males) and 1613 (females) mg/kg bw/day examination of gross pathology and histopathology revealed no adverse effects on reproductive organs (cervix, epididymis, mammary gland, ovaries, prostate gland, seminal vesicles, testes, and uterus).

In a 28-day oral repeated dose toxicity study with Fatty acids, C8 -10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200 -42 -8) up to a dose of 1000 mg/kg

no treatment-related adverse effects on testes and ovaries were observed.

Conclusion on reproductive toxicity / effects on fertility

Based on the results of available oral repeated dose toxicity studies investigating parameters of reproductive toxicity for adequate source substances and on toxicokinetic considerations, no adverse effects on reproductive organs and tissues are expected for the target substance pentaerythritol tetrastearate (CAS 115-83-3).

Effects on developmental toxicity

Description of key information

Oral: OECD 414, GLP, rat, NOAEL developmental ≥ 1000 mg/kg bw/day

Link to relevant study records

Reference

Endpoint:

developmental toxicity

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:

systemic

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: NOAEL is corresponding to the highest dose tested

Remarks on result:

other: Source: CAS 189200-42-8

Key result

Abnormalities:

no effects observed

Key result

Dose descriptor:

NOAEL

Remarks:

developmental

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: NOAEL is corresponding to the highest dose tested

Remarks on result:

other: Source: CAS 189200-42-8, Exxon, 1995h

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Data from 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.

Data from the source substances Fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2) was used as supportive data. In a developmental toxicity study Fatty acids, C5 -9 tetraesters with pentaerythritol (CAS 67762 -53 -2) was administered daily during gestation days 0 -19 via the dermal route of administration at 0, 800, and 2000 mg/kg bw/day. Soft tissue examination in the study revealed an increased number of foetuses with levocardia, but the internal anatomy of the heart was normal and no accompanying heart or other malformations in the thoracic cavity were detected. It is important to note that the term levocardia as used in the study report describes the placement of the heart in the extreme left hemithorax without any reversal of organs or any other malformations. It is therefore concluded that the effect observed has no toxicological relevance for humans. The NOAEL for embryo- / fetotoxicity and teratogenicity in rats was however found to be < 800 mg/kg bw/day and the LOAEL = 800 mg/kg bw/day.

Conclusions:

The read-across approach is justified in the analogue justification. The target and source substances are considered unlikely to differ in their developmental toxicity potential. In a developmental toxicity study with the source substance Fatty acids, C8-10 mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8) administered via oral gavage the NOAEL for maternal toxicity, embryo- / fetotoxicity and teratogenicity were found to be ≥1000 mg/kg bw/day. No hazard for developmental toxicity is expected for the target substance Pentaerythritol tetrastearate (CAS 115-83-3).

Effect on developmental toxicity: via oral route

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 an adequate and reliable (Klimisch score 2) study from a source substance with similar structure and intrinsic properties. Read-across is justified based on common precursors and hydrolysis products and consistent trends in environmental fate, ecotoxicological and toxicological profile. The selected study is thus sufficient to fulfil the standard information requirements set out in Annexes VIII - X, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) 1907/2006.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

800 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable (Klimisch score 2) study from a source substance with similar structure and intrinsic properties. Read-across is justified based on common precursors and hydrolysis products and consistent trends in environmental fate, ecotoxicological and toxicological profile. The selected study is thus sufficient to fulfil the standard information requirements set out in Annexes VIII - X, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) 1907/2006.

Additional information

No data on the potential for reproduction toxicity of the target substance pentaerythritol tetrastearate (CAS 115-83-3) are available. 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) 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 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).

Developmental toxicity

Studies from two source substances investigating pre-natal developmental toxicity were available. While administration of the test substance in one study was by oral gavage, the dermal route of exposure was utilised in the second study.

The developmental toxicity of Fatty acids C8-10, mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8) was investigated according to OECD guideline 414 (prenatal developmental toxicity study) and under GLP conditions (key study, 1995). 50 male Sprague-Dawley rats were mated with females to achieve groups of 25 pregnant Sprague-Dawley rats which then received daily oral gavage doses of the test substance at concentrations of 100, 500 and 1000 mg/kg bw/day during gestational days 6 to 15. Control animals received the vehicle polyethylene glycol (PEG 400) only. On day 21 of gestation the animals were euthanized and examined for maternal and fetal parameters. There were no adverse effects found for all parameters examined in maternal animals. Based on the number of implantations, number of total litter losses by resorption, mortality, clinical signs, body weight, gross pathology and organ weights of maternal animals the NOAEL for maternal systemic toxicity was found to be 1000 mg/kg bw/day. Examination of fetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external, head, soft tissue and skeletal abnormalities showed only incidental malformations in two high dose females. The NOAEL for embryo-/fetotoxicity and teratogenicity in rats of the test substance was therefore found to be 1000 mg/kg bw/day.

In another developmental toxicity study Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) was investigated comparable to OECD guideline 414 (prenatal developmental toxicity study) (supporting study, 1988). Groups of 15 presumed pregnant female Sprague-Dawley rats received daily dermal doses of the test substance at concentrations of 800 and 2000 mg/kg bw/day during gestational days 0 to 19. Control animals remained untreated. On day 20 of gestation the animals were euthanized and examined for maternal and fetal parameters. There were no adverse effects found for all parameters examined in maternal animals. Based on the number of implantations, number of total litter losses by resorption, mortality, clinical signs, body weight, gross pathology and organ weights of maternal animals the NOAEL for maternal systemic toxicity was found to be 2000 mg/kg bw/day. Examination of fetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external, head, soft tissue and skeletal abnormalities revealed no differences to controls and thus no indication for teratogenic effects. Soft tissue examination revealed an increased number of fetuses with “levocardia” but the internal anatomy of the heart was normal and no accompanying heart or other malformations in the thoracic cavity were detected. It is important to note that the term levocardia as used in the study report describes the placement of the heart in the extreme left hemithorax without any reversal of organs or any other malformations or adverse effects. It is therefore concluded that the effect observed has no toxicological relevance for humans. However, since levocardia was observed in both treated groups, the LOAEL for embryo- / fetotoxicity and teratogenicity in rats for Fatty acids, C5 -9, tetraesters with pentaerythritol under the experimental conditions of the study was determined to be 800 mg/kg bw/day.

Conclusion on developmental toxicity

Although in one of the studies referred to “levocardia” in rats after dermal exposure was detected, it could be demonstrated that this effect has no toxicological relevance for humans as the effect described the positioning of the heart in the extreme left hemithorax was without any further adverse implications and malformations. Therefore, based on the available data and following the analogue approach, no hazard for developmental toxicity was identified for the target substance Pentaerythritol tetrastearate (CAS 115 -83 -3).

Mode of Action Analysis / Human Relevance Framework

Not applicable.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) 1907/2006 information on intrinsic properties of substances may be generated by means other than tests, e.g. using information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI 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 read-across concept is applied to the target substance pentaerythritol tetrastearate (CAS 115 -83 -3), data gaps can be filled by interpolation from representative structural analogue source substances to avoid unnecessary animal testing.

The read-across concept is also used to derive the classification of the target substance taking the properties of the source substances into account. Based on the read-across concept, all available data on reproductive and developmental toxicity do not indicate a hazard for reproduction toxicity.