Didodecyl fumarate

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

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP - Guideline Study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

(adopted 17 Dec 2001)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

(adopted 30 May 2008)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

adopted Dec 2002

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japan MAFF Testing Guideline of 12 Nosan No. 8147

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Landesanstalt für Umwelt, Messungen und Naturschutz Baden-Württemberg

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: 10 weeks (nulliparous, non-pregnant females)
- Weight at study initiation: 164 - 178 g
- Fasting period before study: Feed was withdrawn from the animals at least 16 hours before administration, but water was available ad libitum.
- Housing: single housing in Makrolon cage, type III
- Diet: VRF1 (P); SDS Special Diets Services, 67122 Altrip, Germany
- Water: tap water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 30 - 70
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: March 04, 2013 To: March 27, 2013

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw


MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Due to the chemical structure of the test substance acute toxicity was not expected. Thus a dose level of 2000 mg/kg bw was selected as starting dose.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

Group 1: 3 females
Group 2: 3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Individual body weights shortly before administration (day 0), weekly thereafter and on the last day of observation. Recording of clinical signs several times on the day of administration, and at least once daily thereafter each workday for the individual animals.
- Necropsy of survivors performed: Necropsy with gross-pathology examination on the last day of the observation period after sacrifice by CO2-inhalation in a chamber with increasing concentrations over time.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred in both 2000 mg/kg bw test groups throughout the study.

Clinical signs:

other: 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 wa

Gross pathology:

There were no macroscopic pathological findings in the animals sacrificed at the end of the observation period.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study the median lethal dose of Didodecyl fumarate after oral administration was found to be greater than 2000 mg/kg bw in female rats.

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

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP - Guideline Study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

(adopted 30 May 2008)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Version / remarks:

(adopted Aug 1998)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: - Japan MAFF Testing Guideline of 12 Nosan No. 8147 402.

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Landesanstalt für Umwelt, Messungen und Naturschutz Baden-Württemberg

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: male animals approx. 8 weeks, female animals approx. 12 weeks (nulliparous and non-pregnant)
- Weight at study initiation: males: 219-241 g, females: 198-218 g
- Fasting period before study: no
- Housing: single housing in Makrolon cage, type III
- Diet: VRF1 (P); SDS Special Diets Services, 67122 Altrip, Germany
- Water: tap water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: 04 to 19 Mar 2013

Type of coverage:

semiocclusive

Vehicle:

corn oil

Details on dermal exposure:

TEST SITE
- Area of exposure: about 40 cm² clipped skin of the dorsal and dorsolateral parts of the trunk
- % coverage: at least 10% of the body surface
- Type of wrap if used: The test item was covered with an air-permeable dressing (4 layers of absorbent gauze and stretch bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with warm water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 12.50 mL/ kg
- Concentration (if solution): 400 mg/mL
- Constant volume or concentration used: yes
- For solids, paste formed: yes, preparation was prepared and applied lukewarm

Duration of exposure:

24 hours

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Individual body weight shortly before administration (day 0), weekly thereafter and on the last day of observation. Recording of clinical signs several times on the day of administration, and at least once daily thereafter each workday for the individual animals.
- Necropsy of survivors performed: yes
- Scoring of skin findings: Individual readings 30 – 60 minutes after removal of the semi-occlusive dressing (day 1), several times and on the last day of observation. Scoring was performed according to Draize.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred within the study period.

Clinical signs:

other: No systemic clinical signs were observed during clinical examination within the study period.

Gross pathology:

No macroscopic pathologic abnormalities were noted in the animals (5 males and 5 females) examined on the last day of observation.

Other findings:

Skin effects at the application site comprised very slight erythema (grade 1) in one out of five male animals and in one out of five female animals and was observed on study day 1.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study the median lethal dose (LD50) of Didodecyl fumarate after dermal application was found to be greater than 5000 mg/kg bw in male and female rats.

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.

Justification for selection of acute toxicity – oral endpoint
GLP study

Justification for selection of acute toxicity – dermal endpoint
GLP Study

Justification for classification or non-classification

The category assessment for acute toxicity states that there is no concern. No acute toxicity classification is deemed necessary