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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:
key study
Study period:
02.12.2003 to 27.05.2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to the appropriate OECD test guideline, and in compliance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report Date:
2005

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD guideline 422
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- Age at study initiation: 9 weeks minimum
- Weight at study initiation: Males: 289.6 to 339.7 g; females: 183.3 to 244.1 g.
- Fasting period before study: No
- Housing: Individually in suspended wire-mesh cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Six days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 64-79
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 19.04.2004 To: 09.08.2004

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 2000 l stainless steel and glass Rochester-style inhalation chambers.
- Method of holding animals in test chamber: stainless steel exposure caging (four layers of 20 animal compartments).
- Source and rate of air: Room air
- Method of conditioning air: Air passed through HEPA and activated charcoal filters before delivery to the chamber. Moisture was added to maintain relative humidity.
- System of generating particulates/aerosols: Not applicable
- Temperature, humidity, pressure in air chamber: 22±3oC, 50±20%,
- Air flow rate: No data
- Air change rate: 10-15 air changes/hour
- Method of particle size determination: Not applicable.
- Treatment of exhaust air: No data


TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatograph with flame ionisation detection
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test atmosphere from each chamber was sampled by an automated sampling system. The test atmosphere was continuously pulled from the chamber and delivered to the analyser. Analysis was by gas chromatograph with flame ionisation detection (GC/FID) and each chamber was evaluated at least once per hour during the exposure period.
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: Continuous until proof of mating.
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy.
- Further matings after two unsuccessful attempts: No
- After successful mating each pregnant female was caged (how): Individually in home cage.
Duration of treatment / exposure:
6 hours/day
Males: 29 days (including 14 days premating).
Females: 14 days premating, through mating, gestation and up to day for postpartum.
Females, toxicity group: 28 days
Frequency of treatment:
Daily
Duration of test:
approximately 46 days
Doses / concentrations
Remarks:
Doses / Concentrations:
200, 1000, 5000 ppm
Basis:
other: target concentrations
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
- Dose selection rationale: Based on the results of a range-finding study.
- Rationale for animal assignment (if not random): Random

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mortality, morbidity and moribundity noted at least twice daily (all animals). Clinical observations made once per day (all animals).


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the first exposure, and weekly thereafter (all animals).


BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were determined before the first exposure and at least weekly thereafter, and the day of necropsy. Pregnant females were weighed on gestation days 0, 7, 14 and 20, within 24 hours after parturition, and on day 4 postpartum.


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No


WATER CONSUMPTION: No
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
Fetal examinations:
- External examinations: Yes, all per litter
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No
Statistics:
All data analysis was conducted using SAS version 8.2. Statistically significant probabilities were reported for p-values of <0.05, 0.02 and 0.01.
Indices:
Mean gestation length, mean number of implantation sites, mean number of corpora lutea, mean mating and fertility indices. Mean litter size, mean live litter size, mean litter weight, mean ratio live births/litter size.
Historical control data:
No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
There was no significant toxicity in dams.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
>= 5 000 ppm
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
>= 5 000 ppm
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no adverse effects on the offspring.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 5 000 ppm
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In an inhalation OECD 422 study conducted to GLP (reliability score 1) the NOAELs for general systemic toxicity of the dams and developmental toxicity were both at least 5000 ppm (the highest concentration tested) in rats.
Executive summary:

In an inhalation OECD 422 study conducted to GLP (reliability score 1) the NOAELs for general systemic toxicity of the dams and developmental toxicity were both at least 5000 ppm (the highest concentration tested) in rats.