Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report Date:
2018

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Version / remarks:
2008
Deviations:
no
Remarks:
No deviations occurred that impacted the results of the study.
GLP compliance:
yes
Test type:
up-and-down procedure
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: Liquid
Details on test material:
Name of test material (as cited in study report: MTDID 20422
- Substance type: Pure active substance
- Physical state: Liquid
- Analytical purity: 99.99%
- Purity test date: 02/16/2011
- Expiration date of the lot/batch: 02/16/2013
- Storage condition of test material: At room temperature in the dark.
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 3M Company, Lot 1
- Expiration date of the lot/batch: 05 June, 2019
- Purity test date: 05 June, 2017

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature.
- Stability under test conditions: Stable

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: None, dosed neat.

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 11-12 weeks old.
- Weight at study initiation: 186-215 grams
- Fasting period before study: Yes, maximum 20 hours
- Housing: On arrival and following assignment to the study, animals were group housed (up to 5 animals of the same sex and same dosing group together) in polycarbonate cages (Makrolon MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15,
JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) equipped with water bottles. These housing conditions were maintained unless deemed inappropriate by the Study Director and/or Clinical Veterinarian. The room(s) in which the animals were kept were documented in the study records. Animals were separated during designated procedures/activities. Each cage was clearly labeled.
- Diet (e.g. ad libitum): Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) was provided ad libitum throughout the study, except during designated procedures. The feed was analyzed by the supplier for nutritional components and environmentalcontaminants.
- Water (e.g. ad libitum): Municipal tap-water was freely available to each animal via water bottles. Periodic analysis of the water was performed, and results of these analyses are on file at the Test Facility.
- Acclimation period: At least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24 C
- Humidity (%): 40-70
- Air changes (per hr): At least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 10 October, 2017 To: 31 October, 2017

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
VEHICLE: None, dosed neat.

MAXIMUM DOSE VOLUME APPLIED: No data
Doses:
2,000 mg/kg
No. of animals per sex per dose:
5 female
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Postdose observations were performed at periodic intervals on the day of dosing (at least three times) and once daily thereafter. The observation period was 14 days. All the animals were examined for reaction to dosing. The onset, intensity and duration of these signs was recorded (if appropriate). Signs were graded for severity and the maximum grade was predefined at 3 or 4. Grades were coded as slight (grade 1), moderate (grade 2), severe (grade 3) and very severe (grade 4). For certain signs, only its presence (grade 1) or absence (grade 0) was scored. Animals were weighed individually on Day 1 (predose), 8 and 15. A fasted weight was recorded on the day of dosing. Terminal body weights were collected from animals found dead or euthanized moribund after Day 1.
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, body weights, macroscopic examination upon necropsy

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
One animal was found dead on Day 2, no further mortality occurred.
Clinical signs:
Hunched posture, uncoordinated movements and/or piloerection were noted on Day 1 for the animals. In addition, lethargy was noted for the animal that was found dead.
Body weight:
The incidence of reduced body weight gain or slight body weight loss between Days 8 and 15 in several animals were considered not indicative of toxicity, based on the absence of any corroborative findings in these animals.
Gross pathology:
No test item-related abnormalities were found at macroscopic post mortem examination of the animals. In the animal found dead, cannibalism of the abdominal region was noted at macroscopic post mortem examination. In one surviving animal ectopic splenic tissue was noted at macroscopic post mortem examination. This finding is occasionally seen in rats of this age and strain and was therefore considered not toxicologically significant.

Applicant's summary and conclusion

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
Based on the results of the study, the acute oral LD50 value of the test article is greater than 2,000 mg/kg.
Executive summary:

The acute oral lethality potential of the test article was evaluated in female Wistar rats. The study was conducted according to OECD 425 (2008) and was performed in compliance with OECD GLP regulations. The test article was administered neat via oral gavage to a single rat at 2,000 mg/kg body weight for the pilot test. Subsequently, four additional female rats were dosed at 2,000 mg/kg body weight. Postdose observations were performed at periodic intervals on the day of dosing (at least three times) and once daily thereafter. The observation period was 14 days. All the animals were examined for reaction to dosing. The onset, intensity and duration of these signs was recorded (if appropriate). Signs were graded for severity and the maximum grade was predefined at 3 or 4. Grades were coded as slight (grade 1), moderate (grade 2), severe (grade 3) and very severe (grade 4). For certain signs, only its presence (grade 1) or absence (grade 0) was scored.  Animals were weighed individually on Day 1 (predose), 8 and 15. A fasted weight was recorded on the day of dosing. Terminal body weights were collected from animals found dead or euthanized moribund after Day 1. One animal was found dead on Day 2, no further mortality occurred. Hunched posture, uncoordinated movements and/or piloerection were noted on Day 1 for the animals. In addition, lethargy was noted for the animal that was found dead. No test item-related macroscopic abnormalities were noted in the gross necropsy post mortem examination of the animals. Based on the results of the study, the acute oral LD50 value of the test article is greater than 2,000 mg/kg.