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Description of key information

There are good quality GLP Guidelines studies for acute toxicity by the oral and dermal routes. The dermal routee being the most likely route of exposure during the manufacture and use of the substance.

Acute oral toxicity, the LD50 in rats is greater than 300mg/kg bodyweight and less than 2000mg/kg bodyweight. This is CLP(GHS) Category 4.

Acute dermal toxicity, the dermal LD50 in rats is greater than 2000mg/kg bodyweight. In the absence of any indication of toxicity this is considered to not meet any CLP or GHS criteria for classification for acute dermal toxicity.

Acute inhalation toxicity, the test substance is manufactured and sold as a solution in 2-ethylhexanol, inhalation exposure is not expected to be a normal route of exposure. Therefore acute inhalation testing has not be performed, the study is waived as not scientifically justified.

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
Study period:
Study started 5th September 2006 - Reported 16th February 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Specific details on test material used for the study:
Identity Witconate P-1460
Description Light brown paste
Batch number 2140-5901
Activity 88.8 %
Stability of test item Stable under storage conditions.
Expiry date 07-APR-2007
Stability of test item dilution Unknown in water; excluded from the statement of
compliance.
Storage conditions At room temperature (range of 20 +/- 5 °C), light protected.
Species:
rat
Strain:
Wistar
Remarks:
HanRCC:WIST (SEF)
Sex:
female
Details on test animals and environmental conditions:
Test system: Rat, Hacc:WlST (SPF)

Rationale Recognized by the international guidelines as a recommended test system.

Source: RCC Ltd, Laboratory Animal Services CH-4414 Füllinsdorf / Switzerland

Number of animals per group 3 females

Total number of animals 12 females

Age when treated 11 weeks

Identification: Unique cage number and corresponding color-coded spots on the tail. The animals were marked at acclimatization start.

Randomization: Selected by hand at time of delivery. No computer generated randomization program.

Acclimatization: Under laboratory conditions, after health examination, Only animals without any visible signs of illness were used for the study.

HUSBANDRY

Conditions: Standard Laboratory Conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with ranges for room temperature 22 +/- 3 °C and for relative humidity between 30-70 % (values above 70 % during cleaning process possible), automatically controlled light cycle of 12 hours light and 12 hours dark, music during the daytime light period.

Accommodation: In groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland).

Diet: Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no, 36/06 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland) ad Iibitum. Results of analyses for contaminants are archived at RCC Ltd.

Water: Community tap water from Füllinsdorf ad Iibitum. Results of ' bacteriological, chemical and contaminant analyses are archived at RCC Ltd.
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
Purified water prepared at RCC Ltd (deionised water which was processed and treated by the PURELAB Option-R unit. This latter links four purification technologies: reverse osmosis, adsorption. ion-exchange and photo oxidation).
Details on oral exposure:
Dose levels are in terms of the test item as supplied by the sponsor.
The dose formulations were made shortly before each dosing occasion using a magnetic stirrer, a spatula and an Ultrasonic bath as homogenizers.
The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight/volume).

Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.

TREATMENT

The animals received a single dose of the test item by oral gavage administration after being fasted for approximately 18 to 19 hours (access to water was permitted). Food was provided again approximately 3 hours after dosing.
The dosing volume was 10 ml/kg body weight.
TREATMENT
The animals received a single dose of the test item by oral gavage administration after being fasted for approximately 18 to 19 hours (access to water was permitted). Food was provided again approximately 3 hours after dosing.

The dosing volume was 10 ml/kg body weight.

Doses:
Two groups of three female rats were treated at the start dose of 2000 mg/kg body weight. Due to spontaneous death of two of the animals of the latter dosing group, the study was extended to a lower dose level as requested by the referred guideline. Thus, two further groups of three animals were treated at the dosage of 300 mg/kg body weight.
No. of animals per sex per dose:
3 females per group
Control animals:
no
Details on study design:
Two groups of three female rats were treated at the start dose of 2000 mg/kg body weight. Due to spontaneous death of two of the animals of the latter dosing group, the study was extended to a lower dose level as requested by the referred guideline. Thus, two further groups of three animals were treated at the dosage of 300 mg/kg body weight.

OBSERVATIONS

Mortality/Viability: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.

NECROPSY

All animals which died spontaneously during the observation period were necropsied as soon as they were found dead. '

All surviving animals were killed at the end of the observation period by Carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. No organs or tissues were retained.

Body weights: On test days 1 (prior to administration), 8 and 15.

Clinical signs: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. Al abnormalities were recorded.
Statistics:
No statistical analysis was used.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
300 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
The following animals were treated and percentage of mortality was observed:
6 females treated at 2000 mg/kg 33 %
6 females treated at 300 mg/kg 0 %
Two animals treated at 2000 mg/kg Witconate P-1460 were found dead two days after test item administration. Four of the animals treated at 2000 mg/kg and all animals treated at 300 mg/kg survived until the end of the study period.
Clinical signs:
A hunched posture was noted in all animals treated at 2000 mg/kg from the 1-hour reading up to day 2 or 3 with the exception of the 5-hour reading for three out of the 6 animals. In addition, a slightly or moderately ruffled fur was observed in three of these animals from the 3-hour reading up to the spontaneous death on day 3 or day 6 of the study. Soft/watery faeces were also noted for these three animals 3-5 hours after dosing, and, they were found moderately sedated on day 2 of the study. From day 3 or 7 up to the end of the observation period the surviving animals treated at 2000 mg/kg showed no clinical findings.
The animals treated at 300 mg/kg were observed in a hunched posture from the 2-hour reading up to the end of the day of dosing or up to day 2. Thereafter, no clinical signs were noted up to the end of the observation period.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
No macroscopic findings were recorded at necropsy.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The median lethal dose of Witconate P-1460 after single oral administration to female rats, observed over a period of 14 days is:

300 mg/kg body weight < LD50 (female rat) < 2000 mg/kg body weight

The mortalities seen at 2000mg/kg together with the lack of mortalities at 300 mg/kg bodyweight result in an EU CLP/GHS classification of Category 4
Executive summary:

SUMMARY

Four groups, each of three female Hacc:WlST (SPF) rats, were treated with Witconate P-1460 by oral gavage administration at a dosage of 2000 mglkg or 300 mglkg body weight.

The test item was diluted in vehicle (purified water) at a concentration of 0.2 gImL or 0.03 g/mL and administered at a dosing volume of 10 mL/kg.

The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2 -15.

Body weights were recorded on day1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically.

The following animals were treated and percentage of mortality was observed:

6 females treated at 2000 mglkg 33 %

6 females treated at 300 mglkg 0 %

Two animals treated at 2000 mglkg Witconate P-1460 were found dead two days after test I item administration. Four of the animals treated at 2000 mglkg and all animals treated at 300

mg/kg survived until the end of the study period.

A hunched posture was noted in all animals treated at 2000 mglkg from the 1-hour reading up to day 2 or 3 with the exception of the 5-hour reading for three out of the 6 animals. In addition, a slightly or moderately ruffled fur was observed in three of these animals from the 3-hour reading up to the spontaneous death on day 3 or day 6 of the study. Soft/watery feces were also noted for these three animals 3—5 hours after dosing, and, they were found moderately sedated on day 2 of the study. From day 3 or 7 up to the end of the observation period the surviving animals treated at 2000 mglkg showed no clinical findings.

The animals treated at 300 mglkg were observed in a hunched posture from the 2-hour reading up to the end of the day of dosing or up to day 2. Thereafter, no clinical signs were noted up to the end of the observation period.

The body weight of the animals was within the range commonly recorded for this strain and age.

No macroscopic findings were recorded at necropsy.

CONCLUSION

The median lethal dose of Witconate P-1460 after single oral administration to female rats, observed over a period of 14 days is:

300 mglkg body weight < LD50 (female rat) < 2000 mglkg body weight

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
300 mg/kg bw
Quality of whole database:
Th

Additional information

Justification for classification or non-classification