Registration Dossier

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2008-06-18 to 2009-04-15
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD Guideline study under GLP

Data source

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

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
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
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories Ltd, Füllinsdorf/Switzerland
- Age at study initiation: (P) 11 wks
- Weight at study initiation: (P) Males: 287 to 329 g; Females: 180 to 215 g
- Fasting period before study: no
- Housing: macrolon type 3 cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12712


IN-LIFE DATES: From: 2008-06-18 To: 2008-08-18

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility of test item
- Concentration in vehicle: depending on concentration used
- Amount of vehicle (if gavage): 5ml/kg bw
- Lot/batch no. (if required): 18787208
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: until signs of copulation was observed
- Proof of pregnancy: vaginal plug 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 (how): alone
- Any other deviations from standard protocol: no
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 aliquots for analysis of dose formulations were frozen (-20 ± 5 °C) and delivered on dry ice to the responsible analyst and stored there at -20 ± 5 °C until analysis.
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.
Duration of treatment / exposure:
Males: Minimum 4 weeks
Females: Approximately 7 weeks
Frequency of treatment:
once daily
Details on study schedule:
not applicable
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 250 and 1000 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
10
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, RCC Study Number B85072, using dose levels of 100, 300, and 1000 mg/kg/day.
- Rationale for animal assignment (if not random): random
Positive control:
not applicable

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked in table were included.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily cage-side clinical observations (once daily, during acclimatization and up to day of necropsy).
Additionally females were observed for signs of difficult or prolonged parturition, and behavioral abnormalities in nesting and nursing.


BODY WEIGHT: Yes
- Time schedule for examinations:Recorded daily from treatment start to day of necropsy.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): not applicable

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): not applicable
Oestrous cyclicity (parental animals):
no abnormalities observed
Sperm parameters (parental animals):
Parameters examined in P male parental generations:
[testis weight, epididymis weight ]
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
[number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies]


GROSS EXAMINATION OF DEAD PUPS:
[ yes, for external and internal abnormalities.]
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals were sacrificed after treatment of at least 28 days, when no longer needed for the assessment of reproductive effects.
- Maternal animals: All surviving animals were sacrificed on day 25 post coitum


GROSS NECROPSY
- All animals sacrificed or found dead were subjected to a detailed macroscopic examination to establish, if possible, the cause of death. Specimens of abnormal tissue were fixed in neutral phosphate buffered 4% formaldehyde solution. All animals were sacrificed by an injection of sodium pentobarbital (Eutha 77 ®). All P generation animals were exsanguinated. Dead pups, except those excessively cannibalized, were examined macroscopically. All parent animals and pups were examined macroscopically for any structural changes, either at the scheduled necropsy or during the study if death occurred. For the parent animals, special attention was directed at the organs of the reproductive system. The number of implantation sites and corpora lutea was recorded for all dams with litters. The uteri of non-pregnant females were placed in a solution of ammonium sulfide to visualize possible hemorrhagic areas of implantation sites


HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated were prepared for microscopic examination and weighed, respectively:
Prostate
Seminal vesicles with coagulating gland
Testes (in Bouin’s fixative)
Epididymides (in Bouin’s fixative)
Ovaries
Brain
Spinal chord
Small and large intestines (incl. Peyer’s patches)
Stomach
Liver
Kidneys
Adrenals
Spleen
Heart
Thymus
Thyroids, and parathyroids if possible
Trachea and lungs (preserved by inlation with fixative and then immersion)
Uterus (with vagina)
Urinary bladder
Lymph nodes (mesenterial, mandibular)
Peripheral nerve (sciatic)
Bone marrow
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring 4 days post partem.
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 not 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 finding
Reproductive indices:
mean precoital time, duration of gestation, corpora lutea per dam, number of implantations and the post-implantation loss, number of living pups, Postnatal Loss Days 0 - 4 Post Partum
Offspring viability indices:
External Examination at First Litter Check and during Lactation, sex ratios, body weight of the pups, Macroscopical Findings

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

no effects

Effect levels (P0)

Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: overall effects

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

no effects

Effect levels (F1)

Dose descriptor:
NOEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: overall effects

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Substance had no effect on the animals under the conditions used.
Executive summary:

The effects of Vinyl laurate on the possible health hazards likely to arise from repeated exposure over a relatively limited period of time were assessed in a OECD 422 study. . In addition this combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in the Han Wistar rat provides information on possible effects on male and female reproductive performance such as gonadal function, mating behavior, conception, development of the conceptus and parturition.

Vinyl laurate 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. The following dose levels were applied:

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 parent animals survived until the scheduled necropsy. No clinical signs or observations were noted for any male or female in any groups during the duration of the study. No test item-related findings were noted in the Functional Observational Battery. Mean food consumption and body weights were note affected by treatment with the test item in the males and females during the study. No test item-related effects were noted from the clinical laboratory investigations. All female mated. No effects were noted in the reproduction and breeding data. No test item-related effects were noted in the organ weights. No test item-related macroscopical or histopathological findings were observed.

No test item-related findings at first litter check and during lactation were noted. Pup weights to day 4 post partumwere unaffected by treatment with the test item. No test item-related macroscopical findings were observed in the pups. .

The general NOEL (No Observed Effect Level) was considered to be 1000 mg/kg body weight/day.

The NOEL (No Observed Effect Level) for reproduction/developmental toxicity was also considered to be1000 mg/kg body weight/day.