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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

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.

Thus, comparing this effect with the criteria of CLP regulation, Methyl methanesulphonate can be classified as “Category 2” by oral route.

Link to relevant study records
Reference
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
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
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 %
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

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
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
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
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: 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.
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
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
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: 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.
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
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
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
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
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
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
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
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
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
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
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
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.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
20 mg/kg bw/day
Species:
rat
Quality of whole database:
Data is Klimiach 2 and from peer- reviewed journal
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity: Oral

In different studies, Methyl methanesulphonate has been investigated for Reproductive toxicity by oral route to a greater or lesser extent. Often are the studies based on in vivo experiments in rodents, i.e. most commonly in rats for Methyl methanesulphonate are summarized below

In a experimental study conducted by Kuriyamaet al(The journal of toxicology sciences, vol 30, no.2, 91-102, 2005), 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.

In another experimental study conducted by Ozawaet al(Journal of Toxicological Sciences, Vol. 25, special issue, 155 – 162, 2000), Sprague – Dawley male rat treated with Methyl Methansulfonate (MMS) in the concentration of 0, 20 and 40 mg/kg body weight/day orally by gavage. No effects were observed on survival, clinical sign, body weight and food consumption of 20 mg/kg body weight/day treated rat as compared to control. Significant decrease in body weight, food consumption and absolute testes and epididymides weight was observed in 40 mg/kg body weight/day treated rat as compared to control. Similarly, Slight atrophy of testes and seminiferous tubules, decrease and exfoliation of germ cells, vacuolar degeneration of sertoli cells of testes and moderate cell debris in caput, slight caudal epididymal ducts, decrease of permatids (elongated) and spermatic grnuloma of epididymis were observed in 40 mg/kg body weight/day treated rat. In addition, Significant decreased in spermatogoni was observed in stage XII seminiferous tubules of 40 mg/kg body weight/day dose group of F0 generation. Therefore, NOAEL was considered to be 20 mg/kg body weight /day for F0 generation when Sprague – Dawley male rat were treated with Methyl Methansulfonate (MMS) orally by gavage for 2 weeks.

Also it is further supported byexperimental study conducted byKuriyamaet al(Journal of Reproduction and Development, Vol. 51, No. 5, 2005),testicular toxicity and sperm morphology were evaluated in Crj: CD (SD), SPF male rat treated with Methyl Methanesulphonate (MMS) in the concentration of 0 and 40 mg/kg body weight/day orally. Slight but statistically significant decreased in body weight were observed on day 1 in treated rat as compared to control. Similarly, statistically significant morphologically abnormal sperm in cauda epididymis increased between week 3 and week 5 of recovery, increased frequencies of tailless sperm and no hook head sperm during recovery and High frequencies of retention of step 19 spermatids at stage IX were observed from day 1 through week 3 in treated male rats. Necrosis of gram cells in week 1 and Vacuolar degeneration of Sertoli cells, atrophy of somniferous tubules and spermatic grenuloma in epididymis were observed at very low frequency. In addition, significantly decreased number of round spermatids in stage V, spermatogones in stage X, zyotene spermatocytes in stage XII and pachytene spermatocytes in stage XII, Substantially lowered numbers of round spermatids were observed in stage II-II on day 1 and Significantly increased frequency of TUNEL positive seminiferous tubules was observed in stage XIV-1 in week 1 of recovery in 40 mg/kg body weight/day for P treated rat as compared to control. Therefore, LOAEL was considered to be 40 mg/kg body weight/day for P generation when Crj: CD (SD), SPF male rat was treated with Methyl Methanesulphonate (MMS) orally for 5 days.   

Further supported byexperimental study conducted by Yokoiet al(The Journal of Toxicologcal Sciences, Vol 32, No.5 495-503, 2007),femaleCrj:CD (SD)IGS (SD)rat were treated with Methyl Methansulfonate in the concentration of 0 and 200 mg/kg/bw/day. Results show that Methyl Methansulfonate was toxic. Toxic effect was observed as reduction inNumber of live fetuses, placental weight and increased preimplantation loss and postimplantation loss in treated rat as compared to control. In addition gross pathological changes such as malformation of litters and fetus, external malformations in live fetuses and ossified sacral/caudal vertebrae were observed. Therefore,lowest-observed-adverse-effect level (LOAEL) for P and F1 generation was considered to be 200 mg/kg/bw/day when Crj:CD (SD)IGS (SD) female rat were treated with Methyl Methansulfonate orally by gavage for 7 days.

 It is further supported byexperimental study conducted byYokoiet al(The journal of Toxicology Scinces (J. Toxicol. Sci.), Vol33, No.5, 585-598, 2008), the effects ofMethyl Methansulfonate wereevaluated in femaleCrj:CD (SD) IGSrat. Methyl Methansulfonate was administered in a concentration of 200 mg/kg/bw/day. Results show that Methyl Methansulfonate was toxic. Toxic effect was observed as decreased body weight,several newly dead embryos, significant reduction in number of live embryos and development of the embryo and placenta. In addition, histopathological changes such as hypoplasis of placenta and manifasted altered development of live fetuses, change in thickness of LZ and JZ cells of plasenta and smaller size of glycogen trophoblast cell in JZ. Presence of GLUT1 –positive cells in the JZ was also observed in treated rat. Embryonic mortality, reduction in embryos-fetal and placental weight and retarded development of live fetuses were observed. Therefore, LOAEL was considered to be 200 mg/kg/bw/day in female (P) and male and female (F1) rat when exposed toMethyl Methansulfonate by orally route.

Thus, based on the above studies on Methyl methanesulphonate, it can be concluded that Methyl methanesulphonate is toxic to reproduction above 20 mg/kg bw. Thus, comparing this effect with the criteria of CLP regulation, Methyl methanesulphonate can be classified as “Category 2” by oral route.

Effects on developmental toxicity

Description of key information

LOAEL was considered to be 200 mg/kg/bw/day in female (P) and male and female (F1) generation when exposed toMethyl Methansulfonate by orally. 

Thus, comparing this effect with the criteria of CLP regulation, Methyl methanesulphonate can be classified as “Category 2” by oral route.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
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
Qualifier:
according to guideline
Guideline:
other: as below
Principles of method if other than guideline:
Embryonic and placental development toxicityy study of Methyl Methansulfonate (MMS) in rat
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Methyl Methansulfonate (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 %
Species:
rat
Strain:
other: Crj:CD (SD)IGS (SD)
Details on test animals or test system and environmental conditions:
- Source: Charles River Japan (Shiga, Japan)
- Age at study initiation: No data available
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: Animals were housed individually in a stainless steel mesh cages (260by 230 by 180 mm) with barrier facility
- Diet (e.g. ad libitum): Pellet diet, ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: Yes, period not mention.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2˚C
- Humidity (%): 55 ± 15 %
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): 12 hr light / 12 hr dark cycle (light from 0800 to 2000 hr)

IN-LIFE DATES: From: To: No data available
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
water
Remarks:
distilled
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Methyl Methansulfonate (MMS) was dissolved in distilled water and prepared freshly daily.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Distilled water
- Concentration in vehicle:0 and 200 mg/kg/bw/day
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available
Analytical verification of doses or concentrations:
not specified
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 Presence of a vaginal plug or of sperm in the vaginal smear on the morning after mating is referred as 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)] No data available
- After successful mating each pregnant female was caged (how): No data available
- Any other deviations from standard protocol: No data available
Duration of treatment / exposure:
7 days
Frequency of treatment:
Daily
Duration of test:
20 days
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
200 mg/kg bw/day
No. of animals per sex per dose:
Total: 68
0 mg/kg body weight /day: 8 female
200 mg/kg body weight /day: GD0 :9 female
200 mg/kg body weight /day: GD1 :8 female
200 mg/kg body weight /day: GD2 :9 female
200 mg/kg body weight /day: GD3 :8 female
200 mg/kg body weight /day: GD4 :8 female
200 mg/kg body weight /day: GD5 :9 female
200 mg/kg body weight /day: GD6 :9 female
Control animals:
yes, concurrent vehicle
Details on study design:
not specified
Maternal examinations:
Erythrocyte parameters, Number of pregnant female, Pre-implantation and post implantation loss, Intrathoracic and intraperitoneal organs and Gross abnormalities were examined.
Ovaries and uterine content:
Number of live fetuses, Number of implantation sites and number of corpora lutea was examined.
Fetal examinations:
Number of live and deid fetuses, fetal body weigth, placental weight, External malformation in live fetuses, frequency of visceral malformations and variations in live feuses, frequency of skeletal malormation and progress of ossification in live fetuses were examined.
Statistics:
Statisical analysis were done by using Mann-Whitney rank sum test with the Yates corection for ties to compare the number of corpora lutea, the number of implatations, the number of live fetuses, fetal weight, placental weight, hematologic parameters, indices of postimplantation or variations. The chi-square test was useed to analyze the pregnancy rate. Data are presented as mean ± S.D. unless indicated otherwise. A p value of < 0.05 was considered statistically significant.
Indices:
Fertility index, gestation index, implantation index, Pre and post embryonic viability indices were observed.
Historical control data:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
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:
no effects observed
Description (incidence and severity):
Erythrocyte parameters:
No significant change were observed in treated rat as compared to control.
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):
In GD6, significant decrease in placental weight was observed.
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
not specified
Pre- and post-implantation loss:
effects observed, treatment-related
Description (incidence and severity):
In GD0, significant increase in preimplantation loss were observed.
In GD0, GD3, GD4 and GD6, significant increase in postimplantation loss were observed as compared to control.
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
effects observed, treatment-related
Description (incidence and severity):
Significant difference were observed in fetal mortality data for GD3 to GD6 as compare to control.
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Other effects:
not specified
Dose descriptor:
LOAEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
dead fetuses
early or late resorptions
organ weights and organ / body weight ratios
pre and post implantation loss
Remarks on result:
other: Effect on reproductive performance
Abnormalities:
not specified
Localisation:
not specified
Description (incidence and severity):
not specified
Fetal body weight changes:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Significant decreased in fetal weight were observed for male and female in GD5 and GD6
Reduction in number of live offspring:
not specified
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
effects observed, treatment-related
Description (incidence and severity):
In GD6, malformation in litters and fetus were observed as compared to control.
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
In GD1 and GD2, fetus with misshapen thoracic centrum and fused ribs were observed.
In GD5, ossified sacral/caudal vertebrae were observed as compare to control.
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
In GD5 and GD6, variations consisted of thymic remnant in the neck, persistent left unbilival artery, variation of lobation of lung; dilated ureter and dislated renal pelvis were observed as compared to control.
Other effects:
not specified
Dose descriptor:
LOAEL
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
external malformations
skeletal malformations
visceral malformations
Remarks on result:
other: Effect observed
Abnormalities:
not specified
Localisation:
other: not specified
Description (incidence and severity):
not specified
Developmental effects observed:
not specified
Treatment related:
not specified
Relation to maternal toxicity:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
Lowest-observed-adverse-effect level (LOAEL) for P and F1 generation was considered to be 200 mg/kg/bw/day when Crj:CD (SD)IGS (SD) female rat were treated with Methyl Methansulfonate by orally by gavage for 7 days.
Executive summary:

In a developmental toxicity study, femaleCrj:CD (SD)IGS (SD)rat were treated with Methyl Methansulfonate in the concentration of 0 and 200 mg/kg/bw/day. Results show that Methyl Methansulfonate was toxic. Toxic effect was observed as reduction inNumber of live fetuses, placental weight and increased preimplantation loss and postimplantation loss in treated rat as compared to control. In addition gross pathological changes such as malformation of litters and fetus, external malformations in live fetuses and ossified sacral/caudal vertebrae were observed. Therefore,lowest-observed-adverse-effect level (LOAEL) for P and F1 generation was considered to be 200 mg/kg/bw/day when Crj:CD (SD)IGS (SD) female rat were treated with Methyl Methansulfonate by orally by gavage for 7 days.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
200 mg/kg bw/day
Species:
rat
Quality of whole database:
Data is Klimiach 2 and from peer- reviewed journal
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Developmental toxicity: Oral

In different studies, Methyl methanesulphonate has been investigated for developmental toxicity by oral route to a greater or lesser extent. Often are the studies based on in vivo experiments in rodents, i.e. most commonly in rats for Methyl methanesulphonate are summarized below

In a experimental study conducted byYokoiet al(The journal of Toxicology Scinces (J. Toxicol. Sci.), Vol33, No.5, 585-598, 2008), the effects ofMethyl Methansulfonate wereevaluated in femaleCrj:CD (SD) IGSrat. Methyl Methansulfonate was administered in a concentration of 200 mg/kg/bw/day. Results show that Methyl Methansulfonate was toxic. Toxic effect was observed as decreased body weight,several newly dead embryos, significant reduction in number of live embryos and development of the embryo and placenta. In addition, histopathological changes such as hypoplasis of placenta and manifasted altered development of live fetuses, change in thickness of LZ and JZ cells of plasenta and smaller size of glycogen trophoblast cell in JZ. Presence of GLUT1 –positive cells in the JZ was also observed in treated rat. Embryonic mortality, reduction in embryos-fetal and placental weight and retarded development of live fetuses were observed. Therefore, LOAEL was considered to be 200 mg/kg/bw/day in female rat (P) and male and female rat (F1) generation when exposed toMethyl Methansulfonate by orally. 

It is further supported byexperimental study conducted by Yokoiet al(The Journal of Toxicologcal Sciences, Vol 32, No.5 495-503, 2007),femaleCrj:CD (SD)IGS (SD)rat were treated with Methyl Methansulfonate in the concentration of 0 and 200 mg/kg/bw/day. Results show that Methyl Methansulfonate was toxic. Toxic effect was observed as reduction inNumber of live fetuses, placental weight and increased preimplantation loss and postimplantation loss in treated rat as compared to control. In addition gross pathological changes such as malformation of litters and fetus, external malformations in live fetuses and ossified sacral/caudal vertebrae were observed. Therefore,lowest-observed-adverse-effect level (LOAEL) for P and F1 generation was considered to be 200 mg/kg/bw/day when Crj:CD (SD)IGS (SD) female rat were treated with Methyl Methansulfonate by orally by gavage for 7 days.

Thought, the LOAEL value of 200 mg/kg bw were available for Methyl methanesulphonate, above studies consists of limitations such as single dose (200 mg/kg) and short study duration (7 day and 1 day), which does not provide as detailed information. Thus, the reliability of result is not dependable. 

Thus, based on the above studies on Methyl methanesulphonate, it can be concluded that Methyl methanesulphonate is toxic to development up to 200 mg/kg bw. Thus, comparing this effect with the criteria of CLP regulation, Methyl methanesulphonate can be classified as “Category 2” by oral route.

Justification for classification or non-classification

Based on the above studies on Methyl methanesulphonate, it can be concluded that Methyl methanesulphonate is toxic to reproduction and development. Thus, comparing this effect with the criteria of CLP regulation, Methyl methanesulphonate can be classified as “Category 2” by oral route.

Additional information