Sodium methanethiolate

Toxicity to reproduction

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Qualifier:

according to guideline

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

Test material information

Constituent 1

Reference substance name:

Sodium methanethiolate

EC Number:

225-969-9

EC Name:

Sodium methanethiolate

Cas Number:

5188-07-8

Molecular formula:

CH4S.Na

IUPAC Name:

sodium methylsulfanide

Details on test material:

Test substance: SODIUM METHYLMERCAPTIDE
Batch number : SMM33 0050-7

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals:
- Breeder: Charles River Laboratories France, L'Arbresle, France.
- Age/Weight: at the beginning of the treatment period, the males were 6 weeks old (body weight range: 183 g to 221 g), the females were 8 weeks old (body weight range: 183 g to 232 g).
- Acclimation: 7 days before the beginning of the treatment period.

Environmental conditions:
- temperature : 22 ± 2°C
- relative humidity : 50 ± 20%
- light/dark cycle : 12h/12h (7:00 - 19:00)
- ventilation : approximately 12 cycles/hour of filtered, non-recycled air.

Housing: Individually in suspended wire-mesh cages. Prior to delivery and during lactation, the animals were housed individually in polycarbonate cages.

Food and water:
- food: A04 C pelleted maintenance diet (SAFE, Villemoisson, Epinay-sur-Orge, France), ad libitum
- water: tap water (filtered with a 0.22 µm filter) ad libitum

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

- Volume administered: 5 ml/kg

Details on mating procedure:

Mating:
Females were paired with males from the same dose-level group. The day of confirmed mating was designated day 0 post-coitum (p.c.).
The pre-coital time was calculated for each pair.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

- Stability: Satisfactory stability over a 9-day period at +4°C.
- Concentration: satisfactory agreement between the nominal and actual concentrations on weeks 1, 4 and 8

Duration of treatment / exposure:

- males:
. 28 days before mating, during the mating and post-mating periods until sacrifice (approximately 8 weeks in total),
- females:
. 28 days before mating,
. during the mating period,
. during pregnancy and lactation, until day 4 post-partum inclusive (between 8 to 9 weeks in total).

Frequency of treatment:

once a day, 7 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
5, 15, 45 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

Rationale for dose-level selection:
The dose-levels were selected on the results of two prior 14-day range-finding toxicity studies (CIT/Study No. 26619 and 27421 TSR).

Examinations

Parental animals: Observations and examinations:

- morbidity and mortality checked twice daily during treatment period and once daily on other days; morbid rats sacrificed (necropsy)
- general clinical observations at least once daily
- body weight recorded on day1 of treatment period and then once weekly
- food consumption determined once weekly (not in males during mating period

Oestrous cyclicity (parental animals):

not done

Sperm parameters (parental animals):

not done

Litter observations:

Observations of the progeny of the f0 females during the lactation period:
- Total litter size and numbers of pups of each sex: as soon as possible after birth.
The litters were observed daily in order to note the numberof live, dead and cannibalized pups.
Any gross malformation in pups was noted.
- Body weight: on days 1 and 4 post-partum.
- Clinical signs: daily

Postmortem examinations (parental animals):

- Sacrifice: The males were killed after the end of the mating period (total treatment period was approximately 8 weeks). The females and their pups were killed on day 5 post-partum (total treatment period was between 8 to 9 weeks).
- Macroscopic post-mortem examination: at termination (or moribund rats during treatment period). In the parent females, the corpora lutea and implantation sites were recorded.
- Organ weights: Testes and epididymides of all males were weighed separately.
- Microscopic examination:
. as tabulated in OECD guideline 422 for five males and five females of the control and high-dose groups killed at the end of the treatment period (including but not limited to epididymides, testes, seminal vesicles, prostate, ovaries, uterus (horns and cervix)).

Postmortem examinations (offspring):

Dead pups and pups killed on day 5 post-partum were carefully examined externally for gross abnormalities and discarded without further investigations.

Statistics:

- mean quantitative values compared by one-way analysis of variance and Dunnett test; proportions are compared by the Fisher exact probability test
- organ weight: test for normality of distribution, Bartlett test (homogeneity of variances between groups), Dunn test (not homogeneous) or Dunnett test
- *: p<0.05; **: p<0.01

Reproductive indices:

The following calculations were performed for each group:
- Mating index = Number of mated animals/Number of paired animals x 100
- Fertility index = Number of pregnant female partners/Number of mated pairs x 100
- Gestation index = Number of females with live born pups/Number of pregnant females x 100
- Live birth index = number of live born pups/Number of delivered pups x 100

Offspring viability indices:

- Viability index on day 4 post-partum = Number of surviving pups on day 4 post-partum/Number of live born pups x 100

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Details on results (P0)

CLINICAL EXAMINATION
- Mortality: there were no deaths in any group.
- Clinical signs:
. 45 mg/kg/d: hypotonia was transiently observed in all males and females during the whole dosing period, ataxia was observed at detailed clinical observations in 4 males and in one female during week 5 or 6 of dosing, ptyalism was observed in most males and females a few days after the beginning of the study until the end of dosing.
. 5 and 15 mg/kg/d: no clinical sign was noted.
- Body-weight :
. 45 mg/kg/d: in the males, the group mean body weight gain was statistically significantly lower during the first week of dosing (days 1 to 8: 45 g vs. 55 g, -18%, p<0.01) and remained marginally lower during the dosing period. In the females, the group mean body weight gain was marginally lower during the premating period and significantly lower during the first week of pregnancy (day 0 to 7, 27 g vs. 42 g in controls, -36%, p<0.001).
. 5 and 15 mg/kg/d: no effect was noted.
- Food consumption:
. 45 mg/kg/d: in the males, the food consumption was marginally lower during the whole study.
. 5 and 15 mg/kg/d: no effect was noted.

MATING AND FERTILITY DATA
- Mating index : no treatment-related effects.
- Pre-coital time : no treatment-related effects.
- Fertility index : 100% in all groups.
- Duration of gestation : no treatment-related effects.
- Gestation index (number of female with live
concepti/number of pregnant females) : 100% in all groups.
- Post-natal and neo-natal losses : no treatment-related effects.

PATHOLOGY
- Necropsy: no substance related effect at any dose-levels.
- Organ-weights: no substance related effect on the reproductive organs.
- Microscopic examination: No treatment-related microscopic abnormalities were noted in the testis, prostate, and seminal vesicles, ovary and uterus.

Effect levels (P0)

1

Dose descriptor:

NOAEL

Remarks:

Reproductive performance and developmental toxicity

Effect level:

>= 45 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: No effect on reproductive performance and developmental toxicity

Remarks on result:

other: Generation: P and F1 (migrated information)

2

Dose descriptor:

NOAEL

Remarks:

Systemic toxicity

Effect level:

15 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

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 examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Details on results (F1)

OBSERVATION OF THE PUPS AFTER BIRTH
- Mortality : no treatment-related effects.
- Clinical signs : no treatment-related effects.
- No gross external abnormalities were noted on day 5 post-partum before sacrifice.
- Pup body weight: no treatment-related effects.
- Sex ratio : no treatment-related effects.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The combined repeated dose toxicity and reproductive/developmental toxicity of SODIUM METHYLMERCAPTIDE, was evaluated, in male and female
Sprague-Dawley rats, after oral administration (gavage) of 5, 15 or 45 mg/kg/day, during an 8-week premating and mating periods until sacrifice for the males, or during a 4-week premating period, and through pregnancy and lactation, until day 4 post-partum, for the females.
There were no substance-induced effects on the parental male or female reproductive performance, or on the progeny at any dose-level.
The No Observed Effect Level (NOEL) for reproductive performance and developmental toxicity is established at 45 mg/kg/day.

Executive summary:

In a combined repeated-dose/reproductive/developmental toxicity screening study (OECD TG 422), Sprague-Dawley rats (10/sex/dose) were administered 0, 5, 15 or 45 mg/kg bw/day of sodium methanethiolate in water by gavage daily at a volume of 5 ml/kg during an 8-week premating and mating periods until sacrifice for the males, or during a 4-week premating period, and through pregnancy and lactation, until day 4 post-partum, for the females.Females were paired with males from the same dose-level group until mating occurred or2 weeks had elapsed. Gestation was monitored. Females were allowed to deliver normally and torear their progeny until day 5 post-partum. During the lactation period, the pups were examineddaily for survival and clinical signs and body weights were recorded on days 1 and 4 postpartum. At final sacrifice of the parents, specified organs were weighed and a complete macroscopic post-mortem examination was performed.

No substance-related effects were noted on the male and female reproductive performance and no indication of substance-induced developmental toxicity were observed at any dose levels.

The No Observed Effect Level (NOEL) for reproductive performance and developmental toxicity is established at 45

mg/kg/day.