2-Butenedioic acid (E)-, di-C12-18-alkyl esters

Endpoint summary

Description of key information

The available acute oral toxicity study within this category (according to OECD TG 423) resulted in an acute oral LD50 value > 5000 mg/kg bw. 
The available acute dermal toxicity study within the category (according to OECD TG 402) resulted in an acute dermal LD50 value > 5000 mg/kg bw. 

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Justification for grouping of substances and read-across

The PFAE fumarates (Polyfunctional Aliphatic Ester) category consists of six members, which are either well-defined mono-constituent substances or related UVCB substances, with varying fatty alcohol chain lengths. The distinguishing feature of this category of chemicals is that its members are diester derivatives of fumaric acid (CAS 110-17-8). The alcohol moiety of the dicarboxylic esters generally falls in the C8-C22 carbon number range, including linear, even numbered alcohols. 

In order to avoid the need to test every substance for every endpoint, the category concept is applied for the assessment of environmental fate, environmental toxicity and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by inter- or extrapolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. Structural similarities and similarities in properties and/or activities of the source and target substances in the category are the basis of read-across.

The available studies providing information on the human health hazard assessment within the PFAE fumarates category were conducted with the category member Didodecyl fumarate (CAS 2402-58-6). This substance was selected for testing, because it represents the category member with the shortest fatty alcohol side chain, and consequently with the lowest molecular weight, which is regarded as worst-case approach in terms of hazard assessment of the PFAE fumarates for the local as well as for systemic effects.

Furthermore, the category is supported by another polyfunctional aliphatic ester, namely Bis(2-ethylhexyl) adipate (CAS 103-23-1). This supporting chemical is used to cover toxicological endpoints, exclusively. The read across of Bis(2-ethylhexyl) adipate (CAS 103-23-1) to the PFAE fumarate category is justified due to the similar structural and physico-chemical properties, as well as their toxicological, and ecotoxicological profiles.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

Endpoint specific data matrix:

ID #	CAS	Acute toxicity - oral	Acute toxicity - inhalation	Acute toxicity - dermal
1	2402-58-6	Experimental result: LD50 > 2000 mg/kg bw	Waiving statement	Experimental result: LD50 > 5000 mg/kg bw
2	10341-03-4	RA: CAS 2402-58-6	Waiving statement	RA: CAS 2402-58-6
3	68610-90-2	RA: CAS 2402-58-6	Waiving statement	RA: CAS 2402-58-6
4	68921-51-7	RA: CAS 2402-58-6	Waiving statement	RA: CAS 2402-58-6
5	68921-52-8	RA: CAS 2402-58-6	Waiving statement	RA: CAS 2402-58-6
6	68921-53-9	RA: CAS 2402-58-6	Waiving statement	RA: CAS 2402-58-6

Acute toxicity - oral

CAS 2402-58-6

In a GLP-compliant study according OECD guideline 423, the acute oral toxicity of Didodecyl fumarate (CAS 2402-58-6) was studied in female Wistar rats (Höger, 2013). Two groups of three female rats consecutively received the test substance in corn oil at a dose of 2000 mg/kg bw and were observed for a period of 14 days. During the whole study, no mortalities were reported.In all animals of the first 2000 mg/kg bw test group impaired general state and piloerection were observed at hour 1 and persisted in two animals until hour 4 or 5 after administration. Diarrhea was noted in one animal at hour 0 while cowering position was observed in all animals at hour 1.Clinical signs in the second 2000 mg/kg bw test group revealed impaired general state and piloerection and were observed in one animal from hour 0 until hour 2 after administration. In two animals of this test group no clinical signs were observed during clinical examination.The mean body weight of the test groups increased throughout the study period within the normal range.There were no macroscopic pathological findings in any of the animals sacrificed at the end of the observation period.

Under the conditions of this study, the oral LD50 value of Didodecyl fumarate was greater than 2000 mg/kg bw.

Acute toxicity - inhalation

PFAE fumarates are pasty solids with calculated vapour pressures below 0.0001 Pa at 20 °C. Therefore, exposure via the inhalation route can be considered negligible under the identified use conditions.

Acute toxicity – dermal

CAS 2402-58-6

The acute dermal toxicity of Didodecyl fumarate (CAS 2402-58-6) was tested in a GLP-conform study according to OECD guideline 402 (Höger, 2013). The clipped skin of dorsal and dorsolateral parts of 5 Wistar rats per sex was exposed to the test substance in corn oil at a limit dose of 5000 mg/kg bw for 24 h under semiocclusive conditions. After removal of the test substance, animals were observed for a period of 14 days. No mortality and no clinical signs of toxicity were observed up to the end of the observation period. Overall body weight gains were not affected by treatment with the test substance in male and female animals. Necropsy and histopathological examination revealed no substance-related findings. Skin effects at the application site comprised very slight erythema (grade 1) in one out of five male and female animals at day 1. Animals had fully recovered by day 2.

Based on these results, the dermal LD50 value of Didodecyl fumarate was greater than 5000 mg/kg bw.

Conclusion for acute toxicity

One study is available studying the acute oral toxicity of PFAE fumarates category members resulting in oral LD50 values greater than 5000 mg/kg bw. As PFAE fumarates are pasty solids with calculated vapour pressures below 0.0001 Pa at 20 °C exposure via the inhalation route can be considered negligible under the identified use conditions and no further test are necessary. In the available acute dermal toxicity study with the same category member an LD50 value of 5000 mg/kg bw was determined.

Thus, the available data indicate a very low level of acute toxicity for the category members and thus no hazard for acute oral, inhalation and dermal toxicity was identified.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.