Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2008-03-17 to 2008-04-29
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD Guideline study
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report Date:
2009

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Principles of method if other than guideline:
not applicable
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): Vinyl laurate
- Substance type: monomer
- Physical state: liquid
- Stability under test conditions: stable
- Storage condition of test material: At room temperature (20 ± 5 °C)

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories Ltd.; Füllinsdorf / Switzerland
- Age at study initiation: 11 weeks
- Weight at study initiation: 187 to 221 g
- Housing: Standard laboratory conditions.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70%
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12-hour fluorescent light / 12-hour dark cycle with music during the light period.


IN-LIFE DATES: From: 2008-03-17 To: 2008-04-18

Administration / exposure

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

DIET PREPARATION
- Rate of preparation of diet (frequency):once
- Mixing appropriate amounts with (Type of food): Pelleted standard Kliba Nafag 3433 rat/mouse maintenance diet (Provimi Kliba SA, Kaiseraugst / Switzerland)


VEHICLE
- Justification for use and choice of vehicle (if other than water): TS is soluble in corn oil which is non-hazardous
- Concentration in vehicle: depending on dose levels
- Amount of vehicle (if gavage): 5 mL/kg body weight
- Lot/batch no. (if required): 12786337
- Dose formulations were stored at room temperature (20 ± 5 °C) in glass beakers.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
On the first treatment day samples from the control group as well as three samples (top, middle and bottom) of about 2 g of each concentration were taken prior to dosing for analysis of concentration and homogeneity. Samples of about 2 g of each concentration were taken from the
middle only to confirm stability (7 days). During the last week of the treatment, samples were taken from the middle to confirm concentration. The samples were analyzed by GC coupled to an FI detector following an analytical procedure provided by the Sponsor and adapted at Harlan Laboratories. The test item was used as the analytical standard. Analyzed samples were not discarded without written consent from the study director.
Details on mating procedure:
- Impregnation procedure: [cohoused]
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: special automatic mating cages i.e. with synchronized timing to initiate the nightly mating period, until evidence of copulation was observed.
- Further matings after two unsuccessful attempts: [no ]
- Verification of same strain and source of both sexes: [yes ]
- Proof of pregnancy: [vaginal plug or sperm in vaginal smear] referred to as [day 1] of pregnancy
- Any other deviations from standard protocol: no
Duration of treatment / exposure:
Day 6 - 20 post coitum
Frequency of treatment:
once per day
Duration of test:
30 days
Doses / concentrations
Remarks:
Doses / Concentrations:
50, 250 and 1000 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
22 mated females per group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were selected based on a previous non-GLP dose range-finding toxicity study in Han
Wistar rats, Harlan Study Number B78592.
- Rationale for animal assignment (if not random): random

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:once daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily cage-side clinical observations (once daily, during acclimatization and up to day of necropsy)

BODY WEIGHT: Yes
- Time schedule for examinations: Recorded daily from day 0 until day 21 post coitum.

FOOD CONSUMPTION AND COMPOUND INTAKE : Yes

POST-MORTEM EXAMINATIONS: Yes
- Organs examined: gross macroscopic examination of all internal organs with emphasis on the uterus, uterine contents, position of fetuses in the uterus and the number of corpora lutea was performed and the data recorded
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: No data
Fetal examinations:
- External examinations: Yes: [all per litter ]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter ]
- Head examinations: Yes: [ half per litter ]
Statistics:
The following statistical methods were used to analyze food consumption, body weights and
reproduction data:
• Means and standard deviations of various data were calculated.
• The 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.
• The 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 to the macroscopical findings.
Indices:
From the on-line recorded reproduction data, the following parameters were calculated: Pre- and post-implantation losses, embryonic and fetal deaths, live and dead fetuses, abnormal fetuses, fetal sex ratios and fetal body weights.
For reproduction data, group mean values were calculated both on a litter basis and on a percentage per group basis. Mean fetal weights were calculated from the individual weights both on a per group and on a per litter basis.
Historical control data:
HISTORICAL CONTROL DATA OF RATS RAT: WIST Han/Brl (SPF Quality) DATA FROM PRENATAL DEVELOPMENTAL TOXICITY STUDIES PERFORMED DURING 2004 AND 2005 at Harlan Laboratories Ltd.
REPRODUCTION DATA; SPONTANEOUS ABNORMAL FINDINGS (EXTERNAL) ; ABNORMAL FINDINGS FROM VISCERAL EXAMINATION OF FETUSES; ABNORMAL FINDINGS AND VARIATIONS FROM SKELETAL AND CARTILAGE EXAMINATIONS OF FETUSES - SUMMARY.; SKELETAL EXAMINATION OF FETUSES (STAGE OF DEVELOPMENT); on FETUS BASIS and on LITTER BASIS; ARTILAGE EXAMINATIONS OF FETUSES (STAGE OF DEVELOPMENT AND VARIATIONS) on FETUS BASIS..and on LITTER BASIS.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Details on maternal toxic effects:
General Tolerability: All dams survived until the scheduled necropsy. No clinical symptoms related to treatment with the test item were noted during the study.
Food Consumption and Body Weights: Mean food consumption, body weight, body weight gain and corrected body weight gain (corrected for the gravid uterus weight) were not affected by treatment with the test item in any dose group.
Reproduction Data: The relevant reproduction data (post-implantation loss and the mean number of fetuses per dam) were not affected by treatment with the test item. Macroscopical Findings No macroscopical findings were noted during necropsy of the dams in any group.

Effect levels (maternal animals)

Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
External Examination
During the external examination of the fetuses, no abnormal findings were noted in any group.
Sex Ratios
No test item-related effects on fetal sex ratios were noted in any dose group.
Body Weights
Mean fetal body weight did not reveal any test item-related effect.
Visceral Examination
No findings were observed which were considered to be test item-related.
Skeletal and Cartilage Examination
No findings, which were considered to be test item-related, were observed during examination of
fetal skeletons and cartilages.

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: fetotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the results of this study, the NOEL (No Observed Effect Level) for maternal and fetal organisms was considered to be 1000 mg/kg body weight/day. Under the conditions of this study, Vinyl laurate did not reveal any teratogenic potential up to and including 1000 mg/kg body weight/day.
Executive summary:

Vinyl laurate was analyzed for effects on the pregnant rat and development of the embryo and fetus consequent to exposure of the female to the test item from day 6 post coitum (implantation) to day 20 post coitum (the day prior to Caesarean section) according to OECD Guideline 414.

Four groups of females were treated by gavage with Vinyl laurate once daily at dose levels of:

Group 1: 0 mg/kg body weight/day (control group)

Group 2: 50 mg/kg body weight/day

Group 3: 250 mg/kg body weight/day

Group 4: 1000 mg/kg body weight/day

A standard dose volume of 5 mL/kg body weight with a daily adjustment to the actual body weight was used. Control animals were dosed with the vehicle alone (corn oil).

All dams survived until the scheduled necropsy. No clinical symptoms related to treatment with the test item were noted during the study. Mean food consumption, body weight, body weight gain and corrected body weight gain (corrected for the gravid uterus weight) were not affected by treatment with the test item in any dose group.The relevant reproduction data (post-implantation loss and the mean number of fetuses per dam) were not affected by treatment with the test item. No macroscopical findings were noted during necropsy of the dams in any group.

During the external examination of the fetuses, no abnormal findings were noted in any group.No test item-related effects on fetal sex ratios were noted in any dose group. Mean fetal body weight did not reveal any test item-related effect. No findings were observed which were considered to be test item-related. No findings, which were considered to be test item-related, were observed during examination of fetal skeletons and cartilages.

Based on the results of this study, the NOEL (No Observed Effect Level) for maternal and fetal organisms was considered to be 1000 mg/kg body weight/day. Under the conditions of this study, Vinyl laurate did not reveal any teratogenic potential up to and including 1000 mg/kg body weight/day.