Fatty acids, C14-18 and C16-18-unsatd., 2-phenoxyethyl esters, maleated

Endpoint summary

Description of key information

Oral rat (standard acute method): LD50 > 8295 mg/kg bw  (0% male and 20% female mortality at 8295 mg/kg bw, no death at 6615 mg/kg bw)
Acute dermal and inhalation toxicity testing:  waiving of testing

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:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study was conducted according to internationally accepted technical guidelines in a contract research organization. The study is scientifically valid and adequate for assessment with acceptable restrictions (e.g. due to limited reporting). Purity and stability of the test material were not reported for the batch of test material used.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

of 1981

Deviations:

yes

Remarks:

Doses of test material were quite high. Therefore, this was dosed undiluted and dose volumes could not be kept constant but increased with increasing dose.

Qualifier:

according to guideline

Guideline:

other: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, Division of Pharmacology, FDA, 1959

Deviations:

not specified

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Wistar rats, strain: Winkelmann, Paderborn (SPF-Quality) with appropriate range of bodyweight at study start.
- Weight at study initiation (day of dosing): 200 to 218 g
- Housing: Group housing with up to 5 animals by sex in cages.
- Fasting period: From 16 hours before test start.
- Diet (except for fasting period): Commercially available standard laboratory animal diet:
"Rat/Mouse Mainenance" from Altromin, Lage, Germany
- Water was provided ad libitum

ENVIRONMENTAL CONDITIONS

The animal room was maintained at:
- Temperature (°C): 22 ± 1°C
- Relative Humidity (%): 45 to 55%
- Photoperiod (artificial lighting): 12 h/day

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

- Dose volume: The administered volume of test material, increased with increasing dose thus achieving quite high target doses.
Individual dose volume was calculated based on individual bodyweight
- For different doses and dose volumes, see Table 1 in "Any other information on materials and methods incl. tables"
- Rationale for doses selected: Based on a pre-test, which was not detailed in the study report.

Doses:

see Table 1 in "Any other information on materials and methods incl. tables"

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations:
It has not been clearly specified in the report at what time points clinical signs and mortality were recorded, but the following records have been
reported:
Clinidal signs: At least at 2, 4 (Day 0), 24 and 48 hours post dosing, 3, 5, 7 and 14 days post dosing.
Mortality: At least at 24 hours, 48 hours, 7 days and 14 days post dosing.
Weighing of each animal: All animals on Day 0 for calculation of individual dose volume, and survivors on Day 14 (end of observation period).
- Necropsy performed: Yes, all animals of Groups 1, 2 and 4 and the 9 animals of Group 3 which survived until observation Day 14 were necropsied.
The report does not clearly state whether or not the one premature death of Group 3 was also necropsied.

Statistics:

LD50 was estimated for 24 hours and 14 days post dosing according to Litchfield and Wilcoxon in connection with the Integral of Gauss.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 8 295 mg/kg bw

Based on:

test mat.

Remarks:

unchanged, no vehicle

Remarks on result:

other: At 8295 mg/kg bw , 0% male and 20% female mortality. The one death over the 14 day post dosing observation period happened within 24 h post dosing.

Mortality:

Mortality during the 14-day observation period post dosing:
Dose of Test Material: Equivalent Dose of WS400109: Mortality
5.0 mL/kg bw 5250 mg/kg bw 0/5 (m); 0/5 (f)
6.3 mL/kg bw 6615 mg/kg bw 0/5 (m); 0/5 (f)
7.9 mL/kg bw 8295 mg/kg bw 0/5 (m); 1/5 (f)*
10.0 mL/kg bw 10500 mg/kg bw 5/5 (m); 5/5 (f)*

m = male, f = female

* All premature death happened within 24 h post dosing.

Clinical signs:

Group 1
Shortly after dosing, diminished reflexes, decreased respiration.
Group 2
Haircoat bristle, reflexes slightly decreased; shortly after dosing, apathy, pinched eyes, decreased reflexes, stomach-ache, increased frequency of respiration.
Group 3
Haircoat bristle and untidy, reflexes slightly decreased; at the beginning of the observation period, faeces wet; shortly after dosing, heavy apathy, pinched eye, severely diminished reflexes, stomach-ache, severely decreased frequency of respiration.
Group 4
Shortly after dosing, heavy apathy, pinched eyes, severely diminished reflexes, stomach-ache, severely increased frequency of respiration.

In Groups 1, 2 and 3 differences in appearance and behaviour from "normal" were no longer evident in the survivors at 7 and 14 days post dosing.

Body weight:

There was a dose-related decline in overall group mean body weight gain over the 14 day observation period in the surviving animals of Groups 1, 2 and 3, whereby the bodyweight gain in Group 1 was considered to be normal.

Gross pathology:

In the survivors of Groups 1, 2 and 3 slight haemorrhagia was recorded in the small and large intestine. In the premature deaths in Groups 3 and 4 hyperaemia was noted in gastro-intestinal organs.

Other findings:

For Groups 1, 2 and 3 normal or physiological food consumption was mentioned.

LD50 oral of test material according to Litchfield and Wilcoxon in connection with the Integral of Gauss:

24 h LD50 = 8.3 (7.4 – 9.3) mL/kg bw, Slope function = 1.28 (1.17 - 1.39)

24 h LD50 = 8.3 (7.4 – 9.3) mL/kg bw, Slope function = 1.28 (1.17 - 1.39)

Equivalent LD50 oral for neat WS400109:

24 h LD50 = 8715 (7770 - 9765) mg/kg bw,

14 d LD50 = 8715 (7770 - 9765) mg/kg bw

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

In view of the attained oral LD50 of test material > 7.9 mL/kg bodyweight corresponding to an LD50 > 8295 mg/kg bw for neat WS400109, the outcome of the present study does not necessitate any labelling regarding acute oral toxicity according to EU regulations (DIRECTIVE 67/548/EEC and REGULATION (EC) 1272/2008). In addition, relevant sex-related differences in toxicity of the test material after single oral administration were not evident.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

8 295 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The acute oral toxicity study demonstrated that the LD50 of WS400109 is higher than the limit dose of 2000 mg/kg b.w.

As detailed in the justification for data waiving, the conduct of an acute dermal toxicity study would not have added relevant toxicological hazard information and adequate protection of human health will be granted anyway, as WS400109 has been classified as a skin sensitizer necessitating whole body protective precautions during its handling and use.

The conduct of an acute inhalation toxicity study with WS400109 is not warranted, as the inhalation exposure of humans to WS400109 vapour or aerosol is unlikely, because of its very low vapour pressure, its decomposition at high temperature without boiling, its viscosity (medium in degree) and/or the above whole body protective precautions during its handling and use.

Justification for classification or non-classification

In the acute oral toxicity study, all animals survived the dose of 6615 mg/kg bw and the LD50 was > 8295 mg/kg bw. Therefore, classification of WS400109 for acute oral toxicity is not required [DIRECTIVE 67/548/EEC and REGULATION (EC) 1272/2008].

 

Non-classification of WS400109 by the dermal route was reasonable, because of the absence of adverse effects indicative of relevant systemic toxicity (apart from the sensitization response) in the available skin irritation study, local lymph node assay and repeat dose oral toxicity studies with WS400109 and the systemic exposure probably being higher by the oral than by the dermal administration route.

 

Non-classification of WS400109 by the inhalation route was justified, because WS400109 has a very low vapour pressure, decomposes before boiling, is a viscous liquid (medium in degree) and its sensitizing potential necessitates whole body protective precautions, making the inhalation exposure of humans to vapour or a droplet aerosol unlikely.