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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

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

Effects on developmental toxicity

Description of key information

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

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

Read-across from structural analogue source substance fatty acids, C8-10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8, key)

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:

refer to analogue justification provided in IUCLID 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: No adverse effects observed up to and including the highest tested dose level.

Remarks on result:

other: Source: CAS 189200-42-8, 1995, RL1

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.

Basis for effect level:

other: No adverse effects observed in the offspring up to and including the highest tested dose level

Remarks on result:

other: Source: CAS 189200-42-8, 1995, RL1

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 results of the key study performed with the source substance fatty acids, C8-10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8) and using the oral route of exposure indicate that the test substance was not a selective developmental toxicant and was not embryotoxic or teratogenic. The maternal and developmental oral NOAELs were established at 1000 mg/kg bw/day, corresponding to the highest dose tested.
No hazard for developmental toxicity is expected for the target substance fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol.

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 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, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 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 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, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Additional information

Justification for read-across

There are no data available regarding the reproduction toxicity or developmental toxicity of the target substance fatty acids C18-C22 (even numbered), tetraesters with pentaerythritol. The assessment was therefore based on studies conducted with analogue source 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 grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 13).

CAS 189200-42-8

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 414 (prenatal developmental toxicity study) and under GLP conditions (ExxonMobil, 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.

CAS 67762-53-2

In another developmental toxicity study fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) was investigated comparable to OECD 414 (prenatal developmental toxicity study) (Exxon, 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. In this study only mild dermal irritation including erythema and flaking of the skin occurred but no adverse systemic effects were found 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 NOAEL 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 and the LOAEL = 800 mg/kg bw/day.

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.

Based on read-across approach, the available data on developmental toxicity as available from analogue substances do not meet the classification criteria according to Regulation (EC) 1272/2008. However, as no reproduction toxicity study is available, the conclusion for classification is ‘data lacking’.