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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 28-MAY-2004 to 03-JAN-2005
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was performed according to OECD testing guideline and GLP

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
Dimethyl sulphide
EC Number:
EC Name:
Dimethyl sulphide
Cas Number:
Molecular formula:
Details on test material:
- Name of test material (as cited in study report): dimethyl sulfide
- Substance type: pure active substance
- Physical state: clear, colorless liquid
- Stability under test conditions: Dimethyl sulfide homogeneity and stability in corn oil formulations were evaluated and found to be acceptable for 11 days refrigerated storage at batch sizes of 69 and 138 mL and at concentrations of 6.25, 62.5 (69 mL only) and 250 mg/mL
- Storage condition of test material: the test article was stored refrigerated, and was considered stable under this condition

Test animals

other: Crl:CD®(SD)IGS BR
Details on test animals or test system and environmental conditions:
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina
- Age at study initiation: the animals were approximately 70 days old upon receipt
- Weight at study initiation: Body weight values ranged from 224 g to 281 g on gestation day 0
- Fasting period before study: data not available
- Housing: upon arrival and until pairing, all rats were housed individually in clean, stainless steel, wire-mesh cages suspended above cage-board. The rats were paired for mating in the home cage of the male. Following positive evidence of mating, the females were returned to individual suspended wire-mesh cages.
- Diet: basal diet, PMI Nutrition International, LLC, Certified Rodent LabDiet® 5002, ad libitum
- Water: filtered tap water, ad libitum
- Acclimation period: 14 days

- Temperature: actual mean daily temperature ranged from 68.1°F to 73.0°F (20.1°C to 22.8°C)
- Humidity: mean daily relative humidity ranged from 34.5% to 70.0% during the study
- Air changes: at least 50 air changes per hour, the room air was charcoal-filtered
- Photoperiod: 12-hour light (6 a.m. to 6 p.m.)/12-hour dark photoperiod

IN-LIFE DATES: From 18-MAY-2004 (animal receipt) To 20-AUG-2004 (last fetal skeletal examination)

Administration / exposure

Route of administration:
oral: gavage
corn oil
Details on exposure:
The test article formulations were volume/volume (test article/vehicle) mixtures based on the specific gravity of dimethyl sulfide (0.867 g/mL) at 4°C. For the test article-treated groups, the appropriate amount of vehicle for each group was dispensed into a clear, glass septum vial at least 1 day prior to adding the test article. The vial was stored refrigerated overnight and maintained on crushed ice until the appropriate amount of test article was
added directly to the vehicle using a clean, glass, chilled pipette, taking care to minimize the change in surface tension of the formulation. The vials were immediately capped and sealed, and then the formulations were inverted several times to ensure mixing.

- Justification for use and choice of vehicle (if other than water): data not available
- Concentration in vehicle: 0, 25, 125, 250 mg/mL
- Amount of vehicle: Total Dosage Volume was 4 mL/kg
- Lot/batch no.: data not available
- Purity: 100% pure Mazola® corn oil (expiration dates April 27 and July 14, 2005)
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Analyses to demonstrate the stability (11 days, refrigerated storage) and homogeneity of the test article formulations were conducted in a previous study (WIL-495001, 2004).
These analyses were conducted at similar batch size volumes and concentrations bracketing the range of concentrations used in this study. Triplicate samples (0.1 to 1 mL) for concentration analysis were collected once from each dosing formulation (including the control group) on June 4, 11 and 18, 2004. For the same respective dates, mean concentrations were determined to be between 96.4% and 108%, 99.6% and 106% and 101% and 105% of target concentrations for the dose formulation prepared at 25, 125 and 250 mg/mL.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1
- Length of cohabitation: data not available
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: Positive evidence of mating was confirmed by the presence of an intravaginal copulatory plug or the presence of sperm following vaginal lavage
- Any other deviations from standard protocol: no
Duration of treatment / exposure:
Dose administration was conducted once daily during gestation days 6 through 19
Frequency of treatment:
All animals were dosed once daily at approximately the same time each day.
Duration of test:
Pregnant females were sacrificed on day 20 of gestation
No. of animals per sex per dose:
25 mated females/group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were selected based on the results of a previous study (WIL-495001, 2004) and consultation with the sponsor. The previous study indicated no toxicity in pregnant rats at dose levels of 333, 666 and 1000 mg/kg/day based on evaluations of clinical signs,
body weight gains, food consumption and necropsy findings. No prenatal developmental toxicity was observed at these dose levels based on evaluation of post-implantation loss, live litter size and fetal sex ratios. Because of the small sample size and the lack of any dose-related trends, no test article-related findings were noted.
- Rationale for animal assignment: The bred females were assigned to groups using a WIL Toxicology Data Management System (WTDMS™) computer program which randomized the animals based on stratification of the gestation day 0 body weights in a block design.


Maternal examinations:

- Time schedule: individual detailed clinical observations were recorded from gestation days 0 through 20 (prior to dose administration during the treatment period)

- Time schedule for examinations: Individual maternal body weights were recorded on gestation days 0 and 6-20 (daily). Group mean body weights were calculated for each of these days. Mean body weight changes were calculated for each corresponding interval and also for gestation days 6-9, 9-12, 12-20, 6-20 and 0-20.

- Sacrifice on gestation day 20
- Organs examined: The thoracic, abdominal and pelvic cavities were opened by a ventral mid-line incision, and the contents were examined. The uterus and ovaries were then exposed and excised. The placentae were also examined.
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:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: Each viable fetus was subjected to a visceral examination using a modification of the Stuckhardt and Poppe fresh dissection technique to include the heart and major blood vessels
- Skeletal examinations: Yes: All carcasses, including the carcasses without heads, were eviscerated, skinned and fixed in 100% ethyl alcohol.
- Head examinations: Yes: The heads were removed from approximately one-half of the fetuses in each litter and placed in Bouin’s solution for subsequent processing and soft-tissue examination using the Wilson sectioning technique (Wilson, 1965). The heads from the remaining fetuses were examined by a mid-coronal slice.
Mean maternal body weights (absolute and net), body weight changes (absolute and net) and food consumption, gravid uterine weights, numbers of corpora lutea, implantation sites and viable fetuses, and fetal body weights (separately by sex and combined) were subjected to a parametric one-way analysis of variance (ANOVA) (Snedecor and Cochran, 1980) to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunnett's test (Dunnett, 1964) was used to compare the test article-treated groups to the control group.
Mean litter proportions (percent per litter) of prenatal data (viable and nonviable fetuses, early and late resorptions, total resorptions, pre- and postimplantation loss, and fetal sex distribution) and total fetal malformations and developmental variations (external, visceral, skeletal and combined)
and of each particular external, visceral and skeletal malformation or variation were subjected to the Kruskal-Wallis nonparametric ANOVA test (Kruskal and Wallis, 1952) to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, the Mann-Whitney U-test (Kruskal and Wallis, 1952) was used to compare the test article-treated groups to the control group.
Historical control data:
data are presented in the report.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Details on maternal toxic effects:
One female in the 1000 mg/kg/day group was found dead on gestation day 8 due to intubation error (esophageal perforation). All other females survived to the scheduled laparohysterectomy on gestation day 20. No significant clinical findings were noted. Maternal body weights, net body weights, gravid uterine weights and food consumption values in the test article-treated groups were unaffected by test article administration.
See also summary tables in the attached document.

Effect levels (maternal animals)

Dose descriptor:
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects

Maternal abnormalities

no effects observed

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
Intrauterine growth and survival were unaffected by test article administration at any dose level. No test article-related fetal external, visceral or skeletal malformations or developmental variations were observed in the test article-treated groups.
See also summary tables in the attached document.

Effect levels (fetuses)

Dose descriptor:
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

no effects observed

Overall developmental toxicity

Developmental effects observed:

Any other information on results incl. tables

See summary tables in the attached document

Applicant's summary and conclusion

Because there was no fetal developmental or maternal toxicity noted in this study, the no-observed-adverse-effect-level (NOAEL) was 1000 mg/kg/day when dimethyl sulfide was administered orally by gavage to pregnant rats.
Executive summary:

In a developmental toxicity study conducted in compliance with OPPTS Guideline 870.3700 and OECD TG 414, pregnant female rats were given dimethyl sulfide at doses of 100, 500, or 1000 mg/kg bw/day by gavage on days 6-19 of gestation.  Dose groups consisted of 25 pregnant rats.  No treatment-related changes in clinical signs, maternal body weight (absolute or corrected for gravid uterine weight), food consumption, intrauterine growth, fetal numbers, fetal weight, sex ratio or fetal survival were observed.  In addition, no fetal external, visceral, or skeletal malformations or developmental variations were observed in any treatment group.  The NOAELs for maternal toxicity, developmental toxicity and teratogenicity were 1000 mg/kg bw/day.