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Administrative data

Description of key information

Oral rat (standard acute method):      LD50 > 5385 mg/kg bw  (no mortality at 5385 mg/kg bw, dose extrapolated to neat WS400123)
Acute dermal rat: Waiving, as this study was considered to be scientifically unjustified.
Acute inhalation rat: Exposure based waiving: Exposure of humans to WS400123 by the inhalation route is unlikely,
because of its very low vapour pressure, its decomposition at high temperature before boiling
and because it is a highly viscous liquid.
Conclusion: No requirement of classification for acute oral, dermal or inhalation toxicity [DIRECTIVE 67/548/EEC & 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 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:
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:
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 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): Males: 210 to 221 g; Females: 200 to 208 g
- Housing: Group housing with 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 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 shortly after dosing (Day 0) and at 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 on Day 14 (end of observation period).
- Necropsy: All animals were necropsied at termination of the study.
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.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 385 mg/kg bw
Based on:
act. ingr.
Remarks:
WS400123
Remarks on result:
other: No deaths at 2692 or 5385 mg/kg bw
Mortality:
There were no deaths during the 14-day observation period post dosing:
Dose of Test Material: Equivalent Dose of WS400123: Mortality
5.0 mL/kg bw 2692 mg/kg bw 0/5 (m); 0/5 (f)
10.0 mL/kg bw 5385 mg/kg bw 0/5 (m); 0/5 (f)

m = male, f = female
Clinical signs:
Group 1
Shortly after dosing and 7 and 14 days afterwards remarkable clinical signs or any findings attributable to the treatment with the test material were not evident.
Group 2
Reflexes slightly decreased; shortly after dosing, increased frequency of respiration (due to dose volume). Differences in appearance and behaviour from "normal" were no longer evident at 7 and 14 days post dosing.
Body weight:
There were no adverse effects on body weight.
Gross pathology:
Necropsy of each animal at the end of the 14-day post treatment observation period did not reveal any macroscopic pathology findings.
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 > 10.0 mL/kg bodyweight corresponding to an LD50 > 5385 mg/kg bw for neat WS400123, 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
5 385 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 WS400123 is considerably 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 WS400123 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 WS400123 is not warranted, as the inhalation exposure of humans to WS400123 is unlikely because of its very low vapour pressure, its decomposition at high temperature before boiling and because it is a higly viscous liquid.

Justification for classification or non-classification

In the acute oral toxicity study, all animals survived a single dose of WS400123 formulation up to 10.0 mL/kg bw equivalent to neat WS400123 up to 5385 mg/kg. Therefore, classification of WS400123 for acute oral toxicity is not required [DIRECTIVE 67/548/EEC and REGULATION (EC) 1272/2008].

 

Non-classification of WS400123 by the dermal route was reasonable, because of the absence of effects indicative of relevant local irritation or systemic toxicity (apart from the sensitization response) in the available in vitro skin and in vivo skin and eye irritation studies and local lymph node assay with topical administration of neat WS400123 or WS400123 formulation, and because for WS400123 the systemic exposure is likely to be higher by the oral than by the dermal administration route.

 

Non-classification of WS400123 by the inhalation route was justified, because WS400123 has a very low vapour pressure, decomposes before boiling and is a highly viscous liquid, making the inhalation exposure of humans to vapour or droplet aerosol unlikely.