Registration Dossier

Administrative data

Description of key information

The available acute oral toxicity studies within this category  resulted in an acute oral LD50 value > 2000 mg/kg bw. 
The available acute dermal toxicity studies within the category resulted in an acute dermal LD50 value > 2000 mg/kg bw.
Inhalation: no study available

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2 due to read-across) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products and similarities in physicochemical and toxicological properties (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

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
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2 due to read-across) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products and similarities in physicochemical and toxicological properties (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Additional information

Justification for grouping of substances and read-across

The PFAE fumarates (Polyfunctional Aliphatic Ester) category consists of seven 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 C12-C22 carbon number range, including linear, even and odd 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 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. Additionally, experimental data is available from the category member Di-C12-15 Alkyl Fumarate.

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 (no exposure)

Experimental result:

LD50 > 5000 mg/kg bw

2

10341-03-4

RA: CAS2402-58-6

Waiving (no exposure)

RA: CAS2402-58-6

3

no CAS / List No. 938-575-3

RA: CAS2402-58-6

RA: Di-C12-15 Alkyl Fumarate

Waiving (no exposure)

RA: CAS2402-58-6

RA: Di-C12-15 Alkyl Fumarate

4

no CAS / Di-C12-15 Alkyl Fumarate

Experimental result:

LD50 > 2000 mg/kg bw

--

Experimental result:

LD50 > 2000 mg/kg bw

5

no CAS / List No. 938-576-9

RA: CAS2402-58-6

RA: Di-C12-15 Alkyl Fumarate

Waiving (no exposure)

RA: CAS2402-58-6

RA: Di-C12-15 Alkyl Fumarate

6

1187576-41-5

RA: CAS2402-58-6

RA: Di-C12-15 Alkyl Fumarate

Waiving (no exposure)

RA: CAS2402-58-6

RA: Di-C12-15 Alkyl Fumarate

7

68921-53-9

RA: CAS2402-58-6

Waiving (no exposure)

RA: CAS2402-58-6

Discussion: 

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.

Di-C12-15 Alkyl Fumarate

In an acute oral toxicity study in rats, a group of three males and three females were treated by gavage with the test material at 2000 mg/kg bw. The animals were examined for clinical signs and the mortality/viability was recorded during the study period. Body weights were recorded on day 1 prior to administration and on days 8 and 15. All animals were necropsied and examined macroscopically. All animals survived until the end of the study period. No clinical signs were evident during the course of the study. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were observed at necropsy. The LD50 observed over a period of 14 days 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.

Di-C12-15 Alkyl Fumarate

The acute dermal toxicity of Di-C12-15 Alkyl Fumarate was tested in a study according to OECD guideline 402 in a limit test (Leberco-Celsis Testing, 1996). 10/10 animals survived a topical application at a dose of 2000 mg/kg bw of the test material at the 14thday. Few feces and diarrhea were observed in a few animals at different observation time points. Scattered incidences of these findings for short periods of time are common occurrences in rabbits and are thus not considered to be test material related. At gross necropsy, one female had fluid in the cecum, no gross abnormalities observed in any of the other animals. Based on these results, the dermal LD50 value was determined to be greater than 2000 mg/kg bw.

 

Conclusion for acute toxicity

Two studies are available studying the acute oral toxicity of PFAE fumarates category members resulting in oral LD50 values greater than 2000 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 studies with the same category member an LD50 value of >2000 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.

 

 


Justification for selection of acute toxicity – oral endpoint
Hazard assessment is conducted by means of read-across. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties and overall quality assessment (refer to the endpoint discussion for further details).

Justification for selection of acute toxicity – dermal endpoint
Hazard assessment is conducted by means of read-across. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties and overall quality assessment (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on read-across from category members, the available data on the acute oral and dermal toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

There are no data available on acute inhalation toxicity.