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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to current O.E.C.D. Testing Guideline under the GLP regulations and verification of test substance concentration and stability.

Data source

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

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
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
As per Vinyl Neodeconoate IUCLID4 Data Set 2007

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Laboratory rats were acquired from Harlan Sprague Dawley, Indianapolis, In. Weitg range at study start was 262-310 gm males and 179-237 for the females. Animals were maintained insuspended wire bottom stainless steel cages. Pregnant females were housed in plastic shoebox-type cages. Enviroemental conditions were: Temperature 19-25 C; Humidity Range of 30-70%; 12-hour light/dark cycle and 10-12 air changes per hour. Rodent feed was Formulab No. 5008 from PMI Feeds, Inc ad libitum. Drinking water was municipal water available ad libitum.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Animal groups (ten males and ten females per group) were dosed daily with vinyl neodecanoate at 1000, 250, and 100 mg/kg, respectively. A syringe with stainless steel ball-tipped needle of appropriate size was used for dosing the animal by oral gavage. A concurrent vehicle control group was dosed with corn oil by the same way. All animals were dosed with a constant volume of 5 mL/kg. The daily dose was adjusted weekly based on the latest body weight. Males and females were dosed for 14 days prior to mating. While males were dosed for additional 14 days during mating for a total o 28, females were dosed daily until one day before termination (lactation day 4 for those that delivered and post-mating Day 23 or post-cohabitation Day 23 for those that did not deliver).
Details on mating procedure:
After fourteen days of treatment, each female was cohabited with one male from the same treatment groug for a period of two weeks or untilsigns of pregnancy were observed. Pregnancy was determined during the morning when each female was examined for the presence of sperm or vaginal plug. Day 0 of pregnancy was the day the vaginal plug or sperm was found. A maximum of fourteen days was allowed for mating. After confirmation of mating, the male rats were returned to their home cages, and the females were placed in plastic shoebox cages with nesting material.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Test substance dosing mixtures were checked for homogeneity on the first week of dosing in order to assure mixing procedure. One sample was taken from the top, middle and bottom of mixing container and was analyzed for Vinyl Neodeconoate content. The homogeneity was found to be constant for all samples and thus no further evolution was conducted during the study. Only one sample was taken from the middle of weekly prepared dosing formulation during the in-life phase of the study for dose concentration and stabiliy verification. The analytical procedure was a company proprietary methodology.
Duration of treatment / exposure:
Males and females rats were dosed for 14 days prior to mating. While males were dosed for additional 14 days during mating for a total of 28, females were dosed daily until one day before termination (lactation day 4 for those that delivered and post-mating Day 23 or post-cohabitation Day 23 for those that did not deliver).
Frequency of treatment:
Daily
Details on study schedule:
Male animals were treated normally in the morning for 28 days. Female rats were dosed for fourteen days before mating and then up to one day before termination. Body weights of males were recorded on Days 7, 14, 21 and 28 and for females on Days 7, 14, 21 and 28, and/or gestation Days 0, 4, 7, 11, 14, 17 and 20, and on lactation Days 1 and 4. Body weights for pups were recorded on lactation Day 1 and 4. Food consumption was recorded weekly until the termination of the study with the exception of the cohabitation period.
Doses / concentrations
Remarks:
Doses / Concentrations:
1000, 250 and 100 mg/kg body weight
Basis:
nominal conc.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
A range-finding study was conducted with four groups of rat with five males and five females per group were dosed five days/week for two weeks with vinyl neodecanoate at doses of (0, 2000, 1000, 100 mg/kg body weight). Animals were observed daily for general health and food consumption until the study termination on day 14. Body weights were recorded on day 0, 7 and 14. The dose levels for the definitive study were selected from results of the range finder study. The highest dose level was selected based on induction of toxicity without causing death in animals and was determined to be 1000 mg/kg/day. Pretest the Animal body weights were recorded on Day -7 and Day -1 and food consumption was recorded on Day -7 and Day -1. Animals were observed once before exposure for general clinical signs and only naïve health animals were selected and used in the study. On Day-1, by using a weight-stratified randomization procedure, four groups with ten males and ten females per group were identified for placement on-study. Fertility was assessed following confirmation of mating by observing the number of pregnancies.
Positive control:
No

Examinations

Parental animals: Observations and examinations:
Aduly animals were observed twice daily for classical signs of morbidity and mortality and once daily for signs of pharmacologic and/or toxicologic effects. General clinical observations were also made to skin, fur, eye and mucous membranes, respiratory and circulatory effects, salivation, lacrimation, excessive urination, tremors, convulsions, activity level, gait, posture, reactivity to handling, unusual behavior. The severity and duration of any of the above signs were recorded. More detailed clinical observations were conducted on a weekly basis in a way similar to that of pretest.
Estrous cyclicity (parental animals):
Not conducted
Sperm parameters (parental animals):
Not conducted
Litter observations:
Following birth body weights for the pups were recorded on lactation Day 1 and 4. The litters were sexed, examined for gross malformations and the number of stillbirths and live pups was recorded. Any changes or abnormalities in nesting or nursing behavior were recorded. Pups were observed daily for general appearance, behavior and survival.
Postmortem examinations (parental animals):
Necropsy examination was conducted on all animals used in the study including male, female rats and their pups at the time of discovery of death or at the time of sacrifice. Necropsy was conducted on external surfaces and internal cavities and their viscera with special emphasis on the reproductive organs of both male and females. In female rats, number of corpora lutea was recorded and ovaries with oviducts were carefully removed, trimmed and weighed. The testes and epididymides of all males were also collected, trimmed and weighed. Organs from reproductive systems of both male and female along with organs that showed macroscopic pathologic lesions were collected and preserved in 10% neutral buffered formalin. Organs such as liver, kidneys, thymus, spleen, brain, and heart from five animals from each treatment group were removed, trimmed and weighed and then preserved in 10% neutral buffered formalin for further evaluation. Histopathologic examination was conducted on all organs collected from five males and all females from control and high dose groups. Special emphasis was put on the stages spermatogenesis of the male gonads and interstitial testicular cell structure. All organs and tissues were embedded in paraffin, sectioned and stained hematoxylin and eosin for microscopic examination.
Postmortem examinations (offspring):
Necropsy examination was conducted on all rat pups at the time of discovery of death or at the time of sacrifice.
Statistics:
One-way analysis of variance (ANOVA) and Dunnett's t-test were used to identify differences from control when identified by ANOVA.
Reproductive indices:
Percent Conception and Fertility Index
Offspring viability indices:
Mean number of pups/litter, Mean live pups per litter, Mean stillborn and Mean pup body weights on lactation days 1 and 4.

Results and discussion

Results: P0 (first parental animals)

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
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: estrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

Details on results (P0)

Animals were observed daily for any clinical abnormalities and behavior. In the control group, one female rat had piloerection and decreased activity on Day 17 and died the next day. Death was confirmed to be due to accidental injury during the dosing procedure. On days 4-8, one female of the high dose group was found with red discharge around muzzle and piloerection with signs of emaciation. One male rat of the same group was sensitiveto touch on Days 20-28 and another male was found with signs of emaciation of Days 27-28. Animals of the 250 mg/kg and 100 mg/kg dose groups did not show abnormalities during the general health observations of the animals throughout the study.

No treatment-related differences were found in group mean body weights through Day 28 for males and females of all groups when compared by analysis of variance. Females of control and treated groups exhibited similar weight profile during the gestation and lactation periods, which suggested that pregnancies of the treated animals progressed similarly to those of controls. No dose-related differences were found in group mean food consumption for males and females during the study period.

There were no test substance related gross pathology or adverse histological findings other than male rat kidney effects at any dose level. The male rat histopathological findings at the high dose of 1000 mg/kg/day were indicative of alpha-2-u-microglobin nephropathy. This type of male rat specific nephropathy is not clinically relevant to human health. Mean liver weights of the males and females were elevated at the high dose. This effect isbelieved to be an adaptive metabolic one and not adverse.

The percent conception rate was nor signficantly different among groups and varied from 70 - 80%. There was no significant differences of the Firtility Index from the test substance treated groups and the vehicle control group. Corpora lutea counts per pregnant dam were not significantly different among the control and treated groups.


Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: see 'Remark'

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:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified

Details on results (F1)

The total pups per dam were not significantly different amongst the control and treatment groups at parturition day 0, with a mean count between 13.4 and 14.1 pups/dam. There was no significant difference or dose related trend in the number of stillborn pups per dam, with the mean number varying between 0.1 and 0.8 per litter. There was no significant difference in mean pup body weights among the control and test substance treated groups on days one and four of lactation. Daily obsrvations of the litters revealed no abnormalities among the live pups.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: No significant adverse effects at the high dose

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
There were no adverse findings for adult rats and pups in this study. Therefore, the NOAEL is 1000 mg/kg/day.
Executive summary:

An O.E.C.D. 422 Testing Guideline study was conducted with Vinyl Neodecanoate in order to access reproductive performance. There were no significant adverse findings for adult rat parameters or reproductive end-points in this oral-gavage repeated-dose reproductive screening study with Vinyl Neodeconoate. The NOAEL for this study was the high dose level of 1000 mg/kg/day.