Registration Dossier

Administrative data

Endpoint:
toxicity to reproduction: other studies
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
other information
Study period:
First day of treatment: 13 April 2004. Experimental completion date: 16 June 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

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

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Reproduction/developmental toxicity screening test Method:
Deviations:
no
GLP compliance:
yes
Type of method:
in vivo

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Test substance: SODIUM METHYLMERCAPTIDE
Supplier: Arkema SA
Batch number : SMM33 0050-7

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals 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
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- Control of the stability: before the start of treatment
- Control of the 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:

No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
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

Results and discussion

Effect levels

Dose descriptor:
NOAEL
Remarks:
reproductive performance and developmental toxicity
Effect level:
>= 45 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: No effect on reproductive performance and developmental toxicity

Any other information on results incl. tables

CHEMICAL ANALYSIS OF THE DOSAGE FORMS
- Stability: Satisfactory stability over a 9-day period at
+4°C.
- Concentration: satisfactory agreement between the nominal
and actual concentrations 

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.

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.

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.

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 or 2 weeks had elapsed. Gestation was monitored. Females were allowed to deliver normally and to rear their progeny until day 5 post-partum. During the lactation period, the pups were examined daily 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.