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Administrative data

Description of key information

Oral rat (standard acute method):   LD50 > 2515 mg/kg bw  (no mortality at 2515 mg/kg bw, dose extrapolated to neat WS400517)
Dermal and inhalation rat studies were waived, as these studies were considered to be scientifically unjustified.
Conclusion: No requirement of classification for acute oral, dermal or inhalation toxicity [Reg. (EC) 1272/2008].

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 and in compliance with GLP in a contract research organization. The study is scientifically valid and the report is fully adequate for assessment, despite some minor restrictions (e.g. due to limited reporting).
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
of 1987
Deviations:
no
Qualifier:
according to
Guideline:
other: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, Division of Pharmacology, FDA, 1959
Deviations:
not specified
GLP compliance:
yes (incl. certificate)
Remarks:
Certified by BAM according to DIN EN 45001.
Test type:
standard acute method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Wistar rats, strain: Winkelmann, Paderborn (SPF-Quality) with appropriate range of bodyweight at study start.
- Bodyweight at study start (day of dosing): Males: minimum 214 g, maximum 231 g,
Females: minimum 194 g, maximum 210 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 Maintenance" from Altromin, Lage, Germany
- Water was provided ad libitum

ENVIRONMENTAL CONDITIONS

The animal room was maintained at:
- Temperature (°C): 22.5 ± 2.5°C
- Relative Humidity (%): 40 to 60%
- Photoperiod (artificial lighting): 12 h/day
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
- Dose formulation: 20% and 50% of the test material emulsified in the vehicle by warming it to 50°C and using an ultraturrax.
Administration of the dose formulation to the animals at body temperature.
- Dose volume: 1 mL / 100 g bw at each dose.
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:
yes
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 shortly after dosing and over 8 hours after dosing (Day 0), and at 7 and 14 days post dosing.
Mortality: At least at 24 hours and 14 days post dosing.
Weighing of each animal: All animals on Day 0 for calculation of individual dose volume, and on Days 7 and 14 (end of observation period).
- Necropsy: All animals were necropsied at termination of the study.
- Control animals were untreated. As animals from a stock culture served as controls, apparently these were not necropsied concurrent with dosed animals.
Statistics:
LD50 was estimated for 24 hours and 14 days post dosing. Determination of a slope function was inappropriate as there were no deaths in both dose groups.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 515 mg/kg bw
Based on:
test mat.
Remarks:
WS400517
Remarks on result:
other: No deaths at 1006 or 2515 mg/kg.
Mortality:
There were no deaths during the 14-day observation period post dosing:
Single Dose of WS400517 at: Mortality
1006 mg/kg bw 0/5 (m); 0/5 (f)
2515 mg/kg bw 0/5 (m); 0/5 (f)
Clinical signs:
Shortly after dosing and 7 and 14 days afterwards clinical signs attributable to the treatment with the test material were not evident. Apathic behaviour, minimal in degree, was seen in the high dose group within 8 hours post dosing. This was not considered to represent a clear indication of toxicity of the test material.
Body weight:
There were no adverse effects on body weight gain.
Gross pathology:
Macroscopic pathology findings attributable to the treatment with the test material were not evident.
Interpretation of results:
GHS criteria not met
Conclusions:
In view of the attained oral LD50 > 5000 mg/kg bodyweight for the test material equivalent to > 2515 mg/kg bodyweight for WS400517, the outcome of the present study does not necessitate any classification and labelling regarding acute oral toxicity according to EU regulations [DIRECTIVE 67/548/EEC and REGULATION (EC) 1272/2008]. In addition, 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
2 515 mg/kg bw
Quality of whole database:
The study is scientifically valid and the report is fully adequate for assessment.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Waiving the conduct of an acute inhalation toxicity study with the registered substance is adequate and scientifically justified.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Waiving the conduct of an acute dermal toxicity study with the registered substance is adequate and scientifically justified.

Additional information

The acute oral toxicity study demonstrated that the LD50 of WS400517 is considerably higher than the limit dose of 2000 mg/kg b.w. As detailed in the respective justifications for data waiving, the conduct of acute dermal or inhalation toxicity studies would not have added relevant toxicological hazard information.

Justification for classification or non-classification

In the acute oral toxicity study, all animals survived a single dose of WS400517 formulation up to 5000 mg/kg equivalent to neat WS400517 up to 2515 mg/kg. Therefore, classification of WS400517 for acute oral toxicity is not required [REGULATION (EC) 1272/2008].

 

Non-classification of WS400517 by the dermal route was reasonable, because of the absence of effects indicative of relevant systemic toxicity and/or local irritation and the absence of any relevant adverse effects in all available in toxicity studies with WS400517 and the systemic exposure probably being higher by the oral than by the dermal administration route.

 

Non-classification of WS400517 by the inhalation route was justified by its low vapour pressure making the inhalation exposure of humans to any vapour phase unlikely. In addition non-classification regarding any inhalation hazard was reasonable, because the dose achievable in a traditional acute limit test with 4 hours inhalation exposure at 5 mg/L air (OECD 403) is considerably lower than the high dose of WS400517 tested in the acute oral toxicity study and it is considerably lower than the NOEL attained in the Combined Repeated Dose Toxicity Study with Reproduction / Developmental Toxicity Screening Test (OECD 422) in rats treated with WS400517 for five weeks.