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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Data is from peer-reviewed journal

Data source

Reference
Reference Type:
publication
Title:
A time-course characterizaton of male rerpocuctive toxicity in rats treated with Methyl methanesulphonate (MMS)
Author:
Kazuya Kuriyama, Ryohei Yodoi, Kazuya Kobayashi, satoshi Suda, Morimichi Hayashi, Shigenari ozawa, Junji kuroda and Hirotada Tsulii
Year:
2005
Bibliographic source:
The journal of toxicology sciences, vol 30, no.2, 91-102, 2005

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: as below
Principles of method if other than guideline:
Reproductive toxicity study of Methyl methanesulphonate (MMS) in rat
GLP compliance:
not specified
Limit test:
no
Justification for study design:
Not spcified

Test material

Constituent 1
Chemical structure
Reference substance name:
Methyl methanesulphonate
EC Number:
200-625-0
EC Name:
Methyl methanesulphonate
Cas Number:
66-27-3
Molecular formula:
C2H6O3S
IUPAC Name:
methyl methanesulfonate
Test material form:
other: Solid
Details on test material:
- Name of test material (as cited in study report): Methyl methanesulphonate (MMS)
- Molecular formula (if other than submission substance): C2H6O3S
- Molecular weight (if other than submission substance): 110.1324 g/mole
- Substance type: Organic
- Physical state: Solid
- Impurities (identity and concentrations): 00.1 %
Specific details on test material used for the study:
- Name of test material (as cited in study report): Methyl methanesulphonate (MMS)
- Molecular formula (if other than submission substance): C2H6O3S
- Molecular weight (if other than submission substance): 110.1324 g/mole
- Substance type: Organic
- Physical state: Solid
- Impurities (identity and concentrations): 00.1 %

Test animals

Species:
rat
Strain:
other: Crj:CD (SD), SPF
Details on species / strain selection:
Not spcified
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Source: Charles river Japan, Inc (kanagawa, Japan)
- Age at study initiation: (P) x wks; (F1) x wks: P: 10 weeks
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g: No data available
- Fasting period before study: No data available
- Housing: Animals were housed in a stainless mesh individual cage (sized 260 X 230 X 180 mm
- Diet (e.g. ad libitum): Pellet diet, ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: 17 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.8 to 24.6˚C
- Humidity (%):40.9 to 57.0 %
- Air changes (per hr): 11.13 times/hr ventilation
- Photoperiod (hrs dark / hrs light): 12 hr light/12hr dark

Administration / exposure

Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
water
Remarks:
Distilled
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: MMS were administrated in water

VEHICLE
- Justification for use and choice of vehicle (if other than water): Water
- Concentration in vehicle: 0, 20, 30 and 40 mg/kg bw
- Amount of vehicle (if gavage): 5 ml / kg bw
- Lot/batch no. (if required): No data available
- Purity: No data available
Details on mating procedure:
- M/F ratio per cage: 1:1 ratio
- Length of cohabitation: Overnight
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy Plug observed in the following morning were considered to be Day 0 of gestation.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. No data available
- Further matings after two unsuccessful attempts: [no / yes (explain)] Yes, male that fail to copulate were allowed to pair up to 3 consecutive night for overnight in 1:1 ratio
- After successful mating each pregnant female was caged (how): No data available
- Any other deviations from standard protocol: No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
5 days
Frequency of treatment:
Daily
Details on study schedule:
not specified
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
20 mg/kg bw/day
Dose / conc.:
30 mg/kg bw/day
Dose / conc.:
40 mg/kg bw/day
No. of animals per sex per dose:
Total : 220
0 mg/kg body weight/day: 55 male
20 mg/kg body weight/day: 55 male
30 mg/kg body weight/day: 55 male
40 mg/kg body weight/day: 55 male

Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose and route od administration was selsected based on previous study. in which testicular toxicity was observed after 2 to 4 weeks treatment
Positive control:
not specified

Examinations

Parental animals: Observations and examinations:
Mortality , clinical sign and body weight were observed
Oestrous cyclicity (parental animals):
Any irregularities in the estrous cycle were investigated.
Sperm parameters (parental animals):
Sperm mortality, sperm morphological and caudal epodidymal sperm count were examined
Litter observations:
Number of live embreyos and Number of dead embreyos were observed
Postmortem examinations (parental animals):
Gross abnormalities were examined.

Number of implantation sites and number of corpora lutea was examined.
Postmortem examinations (offspring):
not specified
Statistics:
All quantitative data were tested for equal variance. If equal variance was found, one-way analysis of variance was used. If not, the Kruskal-Wallis procedure for nonparametric analysis was used. If not, the Kruskal-Wallis procedure for nonprametric analysis was used. When significant inter-group differences were found, the Dunnett multiple comparison tests or the Dunnett rank test was applied for the analysis of copulation index and fertility index and fertility index, the chi square test was employed. For the analysis of implantation index and post-implantation loss Wilcoxon test was used. Probabilities less than 5% were considered statistically significant.
Reproductive indices:
Fertility index, gestation index and implantation index were examined.
Offspring viability indices:
not specified

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs of toxicity were observed in treated rat as compare to control.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
No mortality were observed in reated rats
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
When treated with 40 mg/kg slight but statistically significant decrease in body weight was observed on 5 day of treatment which is at the end of recovery period almost comparable to control.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, treatment-related
Description (incidence and severity):
When treated with 40 mg/kg/day , significant decreased were observed in number of corpora lutea and number of implants on 1 day of treatment and in 1,2 and 3 week of recovry.
Reproductive function: sperm measures:
effects observed, treatment-related
Description (incidence and severity):
When treated with 40 mg/kg, slightly decreased sperm counts were observed throughout the study period. Chronological change such as tailless sperm followed by no-hook head sperm in caput epididymis was also observed.

During recovery: The frequency of morphologically abnormal sperm in caput epididymis increased in 2 and 3 week which recovered in 4 week
When treated with 30 mg/kg, significantly increased frequencies of morphologically abnormal sperm in cauda epididymis were observed from week 3 to 5.
During recovery
Significantly increased frequencies of tailless sperm in 4 week and no-hook sperm in 4and 5 week were observed as compared to control in recovery.
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
Significant increase in no. of dead embryos, no. of corpora lutea and decreased in no. of live embryos in first week were observed in 40 mg/kg body weight/ day treated rat as compared to control.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
organ weights and organ / body weight ratios
gross pathology
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance
Remarks on result:
other: No effect observed

Target system / organ toxicity (P0)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs of toxicity were observed in treated rat as compare to control.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
No mortality were observed in treated rats
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
When treated with 40 mg/kg slight but statistically significant decrease in body weight was observed on 5 day of treatment which is at the end of recovery period almost comparable to control.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
When treated with 40 mg/kg, significant decreased were observed in absolute epididymis weight in 1 and 5 week of recovery in male as compare to control.
When treated with 30 mg/kg, significant decreased were observed in absolute epididymis weight in 4 week of recovery as compare to control.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
During recovery
Number of cauda epidiymis was significantly decreased in 1 week and significant increase in frequencies of morphologically abnormal sperm in cauda epididymis were observed from week 3 to 5 as compared to control.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
effects observed, treatment-related
Description (incidence and severity):
When treated with 40 mg/kg/day , significant decreased were observed in number of corpora lutea and number of implants on 1 day of treatment and in 1,2 and 3 week of recovery.
Reproductive function: sperm measures:
effects observed, treatment-related
Description (incidence and severity):
When treated with 40 mg/kg, slightly decreased sperm counts were observed throughout the study period. Chronological change such as tailless sperm followed by no-hook head sperm in caput epididymis was also observed.

During recovery: The frequency of morphologically abnormal sperm in caput epididymis increased in 2 and 3 week which recovered in 4 week
When treated with 30 mg/kg, significantly increased frequencies of morphologically abnormal sperm in cauda epididymis were observed from week 3 to 5.

During recovery
Significantly increased frequencies of tailless sperm in 4 week and no-hook sperm in 4and 5 week were observed as compared to control in recovery.
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
Significant increase in no. of dead embryos, no. of corpora lutea and decreased in no. of live embryos in first week were observed in 40 mg/kg body weight/ day treated rat as compared to control.

Effect levels (P1)

Dose descriptor:
NOAEL
Effect level:
20 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
organ weights and organ / body weight ratios
gross pathology
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance
Remarks on result:
other: No effect observed

Target system / organ toxicity (P1)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
other: not specified
Generation:
other: not specified
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: not specified
Remarks on result:
other: not specified

Target system / organ toxicity (F1)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Results: F2 generation

General toxicity (F2)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not specified

Effect levels (F2)

Dose descriptor:
other: not specified
Generation:
other: not specified
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: not specified
Remarks on result:
other: not specified

Target system / organ toxicity (F2)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
The no-observed-adverse-effect-level (NOAEL) was considered to be 20 mg/kg/day for P generation when Crj:CD (SD), SPF male and female rat were exposed to Methyl methanesulphonate (MMS) orally for 5 days.
Executive summary:

In a reproductive toxicity study, male and female Crj:CD (SD), SPF rat were exposed Methyl methanesulphonate (MMS) orally in the concentration 0, 20, 30 and 40 mg/kg/day. In the parental generation, decreased in body weight and absolute epididymis weight were observed in 30 and 40 mg/kg/day treated rat as compare to control. In addition, significant decreased in number of corpora lutea and number of implants, Chronological change such as tailless sperm followed by no-hook head sperm in caput epididymis were observed in male and female rat. Effect on number of cauda epidiymis, significant increased in number of dead embryos, number of corpora lutea and decreased in number of live embryos during recovery was observed when treated with 40 and 30 mg/kg body weight/day. Therefore, the no-observed-adverse-effect-level (NOAEL) is considered to be 20 mg/kg body weight/day for P generation when rats are exposed to Methyl methanesulphonate (MMS) orally for 5 days.