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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:
Start January 10, 1983
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was performed according to internationally accepted guidelines and in compliance with GLP.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1983
Report Date:
1983

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
Guideline:
other: FDA (1966) Guidelines for reproduction studies for safety evaluation of drugs for human use
Qualifier:
according to
Guideline:
other: CSM (june 1974) Guidelines on reproduction studies for guidance of applicants for product licences and clinical trial certificates.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 2-ethyl-p-methoxy cinnamate
- Stability : Pure about 1 year
- Isomers composition: trans-isomer

Test animals

Species:
rat
Strain:
other: Fullinsdorf albino
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Institute of Biological and Medical Research, Fullinsdorf
- Age at study initiation: no data
- Weight at study initiation: ca 200 grams (day 1 of gestation)
- Housing: Wire mesh cages during acclimatization and premating period macrolon cages with dust free wood shavings during gestation and lactation.
- Diet (e.g. ad libitum): NAFAG 850 cubes ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period:3 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): ca 22 degrees Celsius
- Humidity (%): ca 50%
- Air changes (per hr): fully airconditioned
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
other: Not relevant
Vehicle:
other: Standard Solvent Vehicle (SSV)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

Frequency: Freshly each week
Storage: Stored in a refrigerator
High sphere mixing during preparation

VEHICLE
- Justification for use and choice of vehicle (if other than water): SSV (standard solvent vehicle )
- Amount of vehicle (if gavage): 10 ml/kg
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Not relevant
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight
- The mating procedure was repeated until enough mated females were available.
- Proof of pregnancy: vaginal plug referred to as day 1 of pregnancy
Duration of treatment / exposure:
From day 7 through day 16 of gestation
Frequency of treatment:
Once daily
Duration of test:
Day 1 of gestation - Day 23 of lactation
Doses / concentrations
Remarks:
Doses / Concentrations:
250 mg/kg; 500 mg/kg; 1000 mg/kg
Basis:
nominal conc.
No. of animals per sex per dose:
36 mated females females per dose group (test # 4R83)
20 mated females (test # 33R83)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: preliminary study with a dose of 1000 mg/kg did not produce any maternal effects or embryotoxic or teratological effects.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
All changes in behaviour and general condition, signs of pharmacological effects etc. Animals which died during the experiment were necropsied.

BODY WEIGHT: Yes
- Time schedule for examinations:On days of gestation 1, 7, 17 and 21 for all females and on parturition (within 24 hours after beginning of parturition) and on days of lactation 4, 12 and 23 for the females of the rearing group.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21 (Subgroup 1)
- Sacrifice after lactation day # 23 (Subgroup 2)
- Organs examined: uteri

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
-Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter (15 litters per dose group)
- Skeletal examinations: Yes: half per litter (15 litters per dose group)
Statistics:
- Descriptive statistics:
In the tables for each group, median and interquartile-range are indicated.
Significance test:
For the statistical examination of each quantity, the following test
algorythm is applied:
a) Trend test.
b) Simultaneous test without ordered alternative.
C) Two sample tests for each dosage group against control.
Experimental unit:
The dam is considered the independent experimental unit within all significant tests.
Indices:
- Relative numbers:
The numbers of resorptions and all numbers of pups reported are transformed for the test calculations. For each dam the relative number = absolute number/number of implantations is determined. Therefore, significant test results refer to the relative number, which can be interpreted as a rate,
the number of implantations being 100 %.
Historical control data:
Yes, control data on used strain available at test facility.

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 drug-related maternal mortality and no signs of maternal toxicity were observed in this study . In the highest dose group the weight development over the whole gestation period was slightly reduced.

Effect levels (maternal animals)

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

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
In the highest dose group the incidence of skeletal variations known at the test facility with this strain of rats was slightly increased but no
malformations were observed indicating that the test substance was not teratogenic.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
It may be concluded that under the conditions of this study the test substance was not embryotoxic and not teratogenic up to the dose of 1000 mg/kg bw/day (NOAEL). Therefore, ethylhexyl methoxycinnamate does not need to be classified as reprotoxic according to the criteria outlined in Annex I of 1272/2008/EC and Annex VI of 67/548/EEC.
Executive summary:

2-ethylhxyl 4 -methoxycinnamate was tested for embryotoxic and teratogenic action in rats in accordance with the guidelines of the American FDA and the English CSM. Doses of 0, 250, 500 and 1000 mg/kg were administered orally in SSV from day 7 through day 16 of gestation. No drug-related maternal death and no signs of maternal toxicity were noted in all dose groups. There was no indication of any embryotoxic or teratogenic action of 2-ethyl-p-methoxy cinnamatein all 3 dose groups tested. The rearing experiment showed

no indication of any functional abnormalities in all dose groups.

It may be concluded that under the conditions of this study the test substance was not embryotoxic and not teratogenic up to the dose of 1000 mg/kg bw/day (NOAEL). Therefore, ethylhexyl methoxycinnamate does not need to be classified as reprotoxic according to the criteria outlined in Annex I of 1272/2008/EC and Annex VI of 67/548/EEC.