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Administrative data

Description of key information

Adequate acute oral gavage studies in rats and mice were identified. An adequate acute dermal toxicity study in rats has been performed.

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:
1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Although conducted prior to current protocol or GLP requirements, the study conformed to recognized protocols current at the time.
Principles of method if other than guideline:
Performed prior to current protocol or GLP requirements but by a method acceptable at the time.
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
not specified
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Male and female rats were given an aqueous solution of the test substance by gavage.
Doses:
3200 mg/kg bwt
No. of animals per sex per dose:
4
Control animals:
not specified
Sex:
male
Dose descriptor:
LD50
Effect level:
> 3 200 mg/kg bw
Sex:
female
Dose descriptor:
LD50
Effect level:
> 3 200 mg/kg bw
Mortality:
One of four male and one of four female rats died.
Clinical signs:
Clinical signs included prostration, diarrhea, rough hair coat, depressed appetite, and slight to moderate weakness post dosing.
Conclusions:
The LD50 value of the test substance in male and female rats was greater than 3200 mg/kg bwt.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 200 mg/kg bw
Quality of whole database:
Reliable studies in rats and mice were identified.

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
Study period:
October 3, 2013 - October 17, 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study has been performed according to OECD and/or EC guidelines and according to GLP principles.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
(1987)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
(2008)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
(1998)
Deviations:
no
Qualifier:
according to
Guideline:
other: Food and Agricultural Materials Inspection Centre (FAMIC), 12 Nohsan, Notification No. 8147, April 2011; including the most recent partial revisions.
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Wistar strain, Crl:WI (Han)
Sex:
male/female
Details on test animals and environmental conditions:
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Young adult animals (approx. 10 weeks old)
- Weight at study initiation: Body weight variation was within +/- 20% of the sex mean (males: 297-342 g; females: 204-233 g)
- Housing: Individually in labeled Macrolon cages
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 – 24
- Humidity (%): 40 - 70
- Air changes (per hr): approx 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: October 3, 2013 - October 17, 2013
Type of coverage:
occlusive
Vehicle:
water
Details on dermal exposure:
- Clipping: One day before exposure (Day -1) an area of approximately 5x7 cm on the back of the animal was clipped
- Application: The formulation was applied in an area of approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females. The formulation was held in contact with the skin with a dressing, consisting of a surgical gauze patch, successively covered with aluminum foil and Coban elastic bandage. A piece of Micropore tape was additionally used for fixation of the bandages in females only.
- Frequency: Single dosage, on Day 1
- Washing: Following application, dressings were removed and the skin cleaned of residual test substance using tap water.
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw

No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
VEHICLE
- Justification for choice of vehicle: The vehicle was selected based on trial formulations performed at WIL Research Europe and on test substance data supplied by the sponsor.

Dose volume: 2000 mg/kg (10 mL/kg) body weight.

DOSAGE PREPARATION: The formulation (w/w) was prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level.

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Twice daily
Body weights: Days 1 (pre-administration), 8 and 15
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15
(only the results of the clinical observation on Day 5 were not recorded, but the study integrity was not affected, since sufficient data was available)
- Necropsy of survivors performed: Yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No mortality occurred
Mortality:
No mortality occurred
Clinical signs:
- Chromodacryorrhoea (snout) was noted in the majority of animals between Days 1 and/or 2 (grade 1)
- Yellow discoloration of the treated skin site was noted in all animals during the observation period
Body weight:
- Incidences of slight body weight loss or reduced body weight gain were seen in females during the first week post treatment. All females regained weight during the second week, except for one female that showed some body weight loss during the second week
- The changes noted in body weight gain in males were within the range expected and were therefore considered not indicative of toxicity
Gross pathology:
Macroscopic examination of the animals did not reveal any abnormalities.
Other findings:
None reported
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In an acute dermal toxicity study with rats, performed according to OECD/EC test guidelines, the LD50 >2000 mg/kg bw was determined for the substance.
Executive summary:

The acute dermal toxicity of the substance was determined in the rat, in accordance with OECD 402 (1987) and according to GLP principles. The substance was administered to five Wistar rats of each sex by a single dermal application of 2000 mg/kg bw for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice. No mortality occurred. Chromodacryorrhoea (snout) was noted in the majority of animals between Days 1 and/or 2 (grade 1), as well as yellow discoloration of the treated skin site in all animals during the observation period. Incidences of slight body weight loss or reduced body weight gain were seen in females during the first week post treatment. Macroscopic examination of the animals did not reveal any abnormalities. The dermal LD50 value of the substance in Wistar rats was established to be >2000 mg/kg bw. Based on the results, the substance does not have to be classified for acute dermal toxicity according to the CLP Regulation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Acute Oral Toxicity

In an acute oral gavage study (water vehicle) in groups of male and female rats (4/sex), a single male and female rat dosed at 3200 mg/kg bw died. Clinical signs included protration, diarrhea, rough hair coat, depressed appetite, and slight to moderate weakness post dosing. The LD50 value in male and female rats was > 3200 mg/kg bw. In another study in rats (10/group), animals dosed by gavage (water vehicle) at dose levels ranging from 200 to 3200 mg/kg bw were not affected. The LD50 for this study was reported as > 3200 mg/kg bw. In another acute oral study in mice (10/group), animals dosed by gavage (water vehicle) at dose levels ranging from 200 to 3200 mg/kg bw were not affected.

Acute Dermal Toxicity

The acute dermal toxicity of the substance was determined in the rat, in accordance with OECD 402 (1987) and according to GLP principles. The substance was administered to five Wistar rats of each sex by a single dermal application of 2000 mg/kg bw for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice. No mortality occurred. Chromodacryorrhoea (snout) was noted in the majority of animals between Days 1 and/or 2 (grade 1), as well as yellow discoloration of the treated skin site in all animals during the observation period.Incidences of slight body weight loss or reduced body weight gain were seen in females during the first week post treatment. Macroscopic examination of the animals did not reveal any abnormalities. The dermal LD50 value of the substance in Wistar rats was established to be >2000 mg/kg bw.

In acute dermal toxicity studies, groups of 3 guinea pigs were exposed to a water solution of the subject material under occlusive wrap for a 24 -h exposure period. Slight skin irritation was noted but no mortality up to the limit dose of 1000 mg/kg bw.

Acute Toxicity: Other Routes

Groups of 10 rats were administered a 10% solution of the subject material in water by intraperitoneal injection at doses ranging from 200 to 3200 mg/kg bw. Mortality occurred from 1 to 7 days following exposure. Clinical signs in affected animals included weakness, prostration, labored respiration, tremors, and rough coats. The LC50 in the study was reported as 800 mg/kg bw. Groups of 10 mice were administered a 10% solution of the subject material in water by intraperitoneal injection at doses ranging from 200 to 3200 mg/kg bw. Mortality occurred from 1.5 h to 3 days following administration. Clinical signs in affected animals included weakness and rough coat. The LC50 reported in this latter study was 400 mg/kg bw.


Justification for selection of acute toxicity – oral endpoint
No adverse effects were noted in acute oral gavage studies in mice and rats.

Justification for selection of acute toxicity – dermal endpoint
An adequate acute dermal toxicity study in rats has been performed.

Justification for classification or non-classification

In a reliable oral acute toxicity study in experimental animals, there was no significant toxicity noted. Thus, no classification for acute toxicity is warranted. Also, no classification for STOT (single) is warranted.

Based on the performed acute dermal toxicity study, the substance does not have to be classified for acute dermal toxicity according to the CLP Regulation.