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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011-01-13 to 2011-12-20
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study and GLP conform
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report date:
2012

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories, B.V. Kreuzelweg 53 5961 NM Horst / Netherlands
- Age at study initiation: 11 weeks
- Weight at study initiation: males 309 to 341 g; females 188 to 225 g
- Fasting period before study: no
- Housing: singly in Makrolon type-3 cages with wire mesh tops and standard softwood bedding
- Diet: pelleted standard diet (Kliba Nafag 3433 rodent maintenance diet) ad libitum
- Water: tap water ad libitum
- Acclimation period: minimum 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Humidity: 30-70%
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
peanut oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

- Rate of dose formulation preparation: weekly
- Separate formulations were prepared for each dose level
- Homogeneity was maintained during the daily administration period using a magnetic stirrer
- Storage conditions: at room temperature (20 ± 5 °C) in the dark

VEHICLE
- Justification for use and choice of vehicle (if other than water): low water solubility of the test item
- Concentration in vehicle: up to 25, 75, and 250 g/L
- Amount of vehicle (if gavage): 4 mL/kg
- Lot/batch no. (if required): 280160017
- Provider: Carl Roth, Karlsruhe, Germany
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
GC-FID using calabrication curve; samples were analysed in duplicate. For further details see study report Appendix IV.
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 14 days until evidence of mating was observed
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged singly
Duration of treatment / exposure:
Males: 4 weeks (2 weeks pre-pairing, 2 weeks pairing period)
Females: 7 weeks (2 weeks pre-pairing, 2 weeks pairing period, 3 weeks gestation)
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 300, 1000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
--viability/mortaility: twice daily
--clinical signs: once daily
- Cage side observations checked were included (report p 68/614).

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to the first treatment, weekly thereafter (report p 75/614).

BODY WEIGHT: Yes
- Time schedule for examinations: daily from treatment start to necropsy

FOOD CONSUMPTION:
- Food consumption for each animal determined (not during pairing): 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: Not required

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood:
males: the day before scheduled necropsy
females: day 5 post partum
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: 5 per sex
- Parameters listed in section 3.10.1 were examined. Covers and exceeds parameters listed in OECD TG 422.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
males: the day before scheduled necropsy
females: day 5 post partum
- Animals fasted: Yes
- How many animals: 5 per sex
- Parameters listed in section 3.10.2 were examined. Covers and exceeds parameters listed in OECD TG 422.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: at the end of the treatment period.
-- Males: shortly before scheduled sacrifice
-- Females on day 3 or 4 post partum
- Dose groups that were examined: 5 male and female rats from each dose group
- Battery of functions tested: sensory activity / grip strength / motor activity /
- Test parameters listed in report Appendix V, p 424.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups (p 144)
stillbirths, live births, postnatal mortality (p 144-145)
weight gain (p 166 - 167)
presence of gross anomalies, physical or behavioural abnormalities (p 168)

GROSS EXAMINATION OF DEAD PUPS:
yes
Statistics:
The following methods were used to analyse food consumption, body weights, and reproduction data:
- calculation of means and standard deviations.
- Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
- Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
- Fisher's exact-test was applied if the variables could be dichotomized without loss of information.
Indices:
Birth index (p 145)
Viability index Day 4 (p 145)
Historical control data:
yes

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Details on maternal toxic effects:
No effects at any tested dose

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
No effects at any tested dose

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
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:
Treatment had no effect on development. The NOAEL value for toxicity to reproduction (development) was 1000 mg/kg bw in this screening study.
Executive summary:

n/i-C13 -C15 aldehyde was tested in an OECD TG 422 oral gavage study in rats under GLP conditions. The test item was administered to 10 male and female rats over approximately 28 days suspended in peanut oil as vehicle at dosages of 100, 300, and 1000 mg/kg body weight/day, and controls received the vehicle only. The dose volume was 4 mL/kg bw and day throughout the study. The test substance was administered to male rats for at least 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum.  

All parental animals terminated the study as scheduled without signs of toxicity. The NOAEL for general toxicity was therefore 1000 mg/kg bw and day for male and female rats. Details are reported in section 7.5.1.

 

Regarding developmental toxicity, no effects on implantation rate and post-implantation, viability and weight at birth, sex ratio, and the occurrence of external malformations were noted at any dose level.

Based on the above it is concluded that the NOAEL value for toxicity to reproduction (development) was 1000 mg/kg bw and day in this rat OECD TG 422 screening study. The study is considered to be valid and suitable for assessment.

 

Information on toxicity to fertility is reported in section 7.8.2.