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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Justification for type of information:
ADAPTATION ACCORDING TO REACH ANNEX XI, section 1 - see justifications attached to IUCLID section 13.2.
- Justification WoE_RDT_Reprotox_Feb2019
- Justification RA_CAS 122-20-2_Dev.tox.2ndspecies_Nov2018

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report Date:
2016

Materials and methods

Principles of method if other than guideline:
Female onn-pregnant rabbits were administered the test substance orally by gavage for 21 days, after blood sampling all animals will be sacrificed and examined.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH / Charles River Laboratories, France
- Housing: single
- Diet (e.g. ad libitum): Pelleted Kliba maintenance diet rabbit and guinea pig “GLP”, Provimi Kliba SA, Kaiseraugst/Switzerland; ad libitum
- Water (e.g. ad libitum): drinking water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-22
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Dose: 1000 mg/kg bw
Duration of treatment / exposure:
21 days
Frequency of treatment:
daily
No. of animals per sex per dose:
Control group: 3 animals
Test group (1000 mg/kg bw): 5 animals (due to the premature dead of 2 animals (1 found dead and 1 sacrificed after gavage error) from test group 1 (1000 mg/kg bw/d) 2 animals will be added)
Control animals:
yes, concurrent no treatment
Details on study design:
The test substance was administered to the animals orally by gavage for 21 days. For this purpose, disposable syringes (e.g. B. Braun Melsungen AG, Melsungen, Germany) and suitable gavage tubes (e.g. Nelaton soft rubber tubes, Willy Ruesch GmbH, Kernen, Germany) were used. During the study, all animals were observed for any clinically abnormal signs. One day after the last administration blood samples were obtained from all surviving animals from the ear veins. After blood sampling all animals were sacrificed and examined.

Examinations

Maternal examinations:
Mortality: A check for moribund and dead animals was made twice daily from Mondays to Fridays and once daily on Saturdays, Sundays and public holidays.
Clinical signs: A cageside examination was conducted at least once daily for any signs of morbidity, pertinent behavioral changes and/or signs of overt toxicity. During the administration period all animals were checked daily for any abnormal clinically signs before the administration as well as within 5 hours after the administration. Abnormalities and changes were documented for each animal.
Food consumption: Food consumption was recorded daily for days -4 - 0 and 0 - 21.
Body weight: Body weights was recorded on day 0, 2, 4, 6, 9, 11, 14, 16, 20 and 21.
Post-Mortem Examinations:The surviving animals were sacrificed by an intravenous injection of pentobarbital (dose: 2 mL/animal). After exsanguination the animals were necropsied and examined according to 3.12. Animals which died intercurrently or were sacrificed in a moribund state were necropsied in the same way as soon as possible after their death (with the exception of the organ weights).
Clinical Pathology: Blood samples were taken from the ear veins. The following parameters were examined: Hematology: Leukocytes, Erythrocytes, Hemoglobin, Hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelets, differential blood count, reticulocytes. Clinical chemistry: Alanine aminotransferase, Aspartate aminotransferase, Alkaline phosphatase,serum γ-glutamyl transferase, Inorg. phosphate, Calcium, Urea, Creatinine, Glucose, total bilirubin, total protein, Albumin, Globulins, Triglycerides, Cholesterol.
Pathology:
Necropsy: The sacrificed animals were necropsied and assessed by gross pathology. All animals which died intercurrently or were sacrificed in a moribund state were necropsied as soon as possible after their death and assessed by gross pathology.
Organ weights: The following weights were determined in all does sacrificed on schedule: Adrenal glands, kidneys, liver and spleen. The final body weights (ToxLims-System) will be transferred to the ACOPAT-System to calculate the relative organ weights.
Organ / tissue fixation: The following organs or tissues were fixed in 4% buffered formaldehyde solution: All gross lesions, adrenal glands, kidneys, liver and spleen.
Statistics:
Dunnett-test (two-sided)
Kruskal-Wallis and Wilcoxon test

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Details on results:
The test substance was administered dissolved in drinking water for 21 days to groups of 3 – 5 female New Zealand White rabbits, via daily gavage. The dose levels were 0 and 1000 mg/kg body weight/day.
In the dose group (1000 mg/kg bw/d) all 5 females had reduced food consumption and lost body weight throughout the study. These animals also had reduced feces or diarrhea. Two rabbits died on the 3rd and 5th treatment day, respectively. The deceased animals showed no other pre-terminal clinical signs of toxicity, nor were there any specific necropsy findings.

Any other information on results incl. tables

Female non-pregnant rabbits were exposed to the test substance.

Applicant's summary and conclusion