Methyl methanesulphonate

Carcinogenicity

Description of key information

Carcinogenic LOAEC was considered to be 50 mg/L (50000 mg/m3) when Sprague-Dawleymalerat were exposed toMethylmethane sulfonate (MMS) by whole-body inhalation for 30 days.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: inhalation

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:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Principles of method if other than guideline:

Subacute repeated dose inhalation toxicity study of Methylmethane sulfonate in rat

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): Methyl methanesulfonate
- Molecular formula: C2H6O3S
- Molecular weight: 110.1324 g/mole
- Smiles notation: COS(=O)(=O)C
- InChl: 1S/C2H6O3S/c1-5-6(2,3)4/h1-2H3
- Substance type:Organic
- Physical state: Liquid

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

- Source: Charles River Breeding Laboratories, Wilmington, MA
- Age at study initiation: 11 to 12-week-old
- Weight at study initiation: 325 ± 16.8 g,
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): Purina Lab Chow, ad libitum, except during exposure periods.
- Water (e.g. ad libitum): Water, ad libitum, except during exposure periods.
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To: No data available

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Test atmospheres of the chemicals were generated by passing an airstream over the liquids in a generating flask and then feeding the effluent vapor into the chamber air supply.

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available


VEHICLE
- Justification for use and choice of vehicle (if other than water): Air, as it is a inhalation study.
- Concentration in vehicle: 0 and 50 ppm (5 mg/kg)
- 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 analytical verification of doses or concentrations:

No data available

Duration of treatment / exposure:

30 days

Frequency of treatment:

6 hr/day X 5 days/wk

Post exposure period:

No data available

Dose / conc.:

50 mg/L air

No. of animals per sex per dose:

Total : 178
0 mg/L: 98
50 mg/L: 80

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: 50 ppm dose was used for MMS because of the cost of compound.
- Rationale for animal assignment (if not random): Animal was assigned to test group randomly.

Positive control:

No data available

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked in table [No.?] were included: Mortality

DETAILED CLINICAL OBSERVATIONS: No data available
- Time schedule: No data available

DERMAL IRRITATION (if dermal study): No data available
- Time schedule for examinations: No data available

BODY WEIGHT: Yes
- Time schedule for examinations: Monthly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data available
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data available
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data available

FOOD EFFICIENCY: No data available
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available
- Time schedule for examinations: No data available

OPHTHALMOSCOPIC EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available

HAEMATOLOGY: No data available
- Time schedule for collection of blood: No data available
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available

CLINICAL CHEMISTRY: No data available
- Time schedule for collection of blood: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available

URINALYSIS: No data available
- Time schedule for collection of urine: No data available
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined. No data available

NEUROBEHAVIOURAL EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data available

OTHER: No data available

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

Organs examined :
Trachea, larynx, liver, kidneys, testes, and any other organs.

HISTOPATHOLOGY: Yes
A complete necropsy was performed on each animal. The nasal passages were flushed with 10% neutral buffered Formalin; then the entire head and other organs were fixed in the same fixative. The head was then decalcified; and stepwise cross-sections were taken in the dorsoventral plane perpendicular to the long axis of the skull, beginning just posterior to the nostrils and extending caudal as far as the orbit. Histologic sections were taken from each lobe of the lung and from the trachea, larynx, liver, kidneys, testes, and any other organs exhibiting gross pathology. Paraffin sections, 4-5 /µm thick, were prepared in the usual fashion and stained with hematoxylin-eosin and with special stains, if necessary.

Organs examined :
Nasal passages, entire head, lung, Trachea, larynx, liver, kidneys, testes, and any other organs were examined.

Other examinations:

No data available

Statistics:

No data available

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

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

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

effects observed, treatment-related

Other effects:

not specified

Details on results:

Mortality: Cumulative mortality was observed in treated rat as compare to control.

Gross Pathology: Metastatic lesions in the lungs, Rhinitis, Squamous metaplasia, Polyp or papillomas lesions were observed in treated rat as compare to control.

Histopathology: neoplastic: Nasal epithelium, Squamous cell, Adeno- carcinoma. Mixed carcinoma, Osteo- genic sarcoma and tumors in larynx, trachea, adrenal, skin, thyroid, pancreas, mammary gland, salivary gland and parathyroid were observed in treated rat as compare to control.

Dose descriptor:

LOAEL

Effect level:

50 mg/L air

Based on:

test mat.

Sex:

male

Basis for effect level:

gross pathology

histopathology: neoplastic

mortality

other: Effect observed

Critical effects observed:

yes

Lowest effective dose / conc.:

50 ppm

System:

other: Not specified

Organ:

adrenal glands

larynx

mammary gland

oral cavity

pancreas

parathyroid gland

salivary glands

skin

thyroid gland

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

Table: Median life-span and time of tumor appearance following exposure to alkylating agents

Treatment	No. of animals	Median life days	Animals with tumors, No (%)	Time of tumor appearance, days
				Median	Range
5 mg/L X 30 exp	80	495	47 (59)	513	256-775

 

Table: Specific types of tumors and other lesions of the nasal mucosa in rats exposed to various alkylating agents

	Treatment	MMS, 5 mg/L X 30 exp
	No. of animals examined	80
No. of tumors and other lesions of nasal mucosa	Tumors bearing animals, No (%)	47 (59)
	Rhinitis	49
	Squamous metaplasia	5
	Polyps or papillomas	11
	Squamous cell carcinoma	33
	Adenocarcinoma	2
	Mixec carcinoma	2
	Osteogenicsarcome	-

Conclusions:

Carcinogenic LOAEC was considered to be 50 mg/L (50000 mg/m3) when Sprague-Dawleymalerat were exposed toMethylmethane sulfonate (MMS) by whole-body inhalation for 30 days.

Executive summary:

In a subacute carcinogenic study, Sprague-Dawleymalerat were exposed toMethylmethane sulfonate (MMS)bywhole-body inhalationin the concentrations of 0 and 50 ppm. The results showed thatMethylmethane sulfonate (MMS) wascarcinogenic. Carcinogenic changes were observed as cumulative mortality as the week of exposure increase and gross pathological changes such asmetastatic lesions in the lungs, Squamous metaplasia, Polyp or papillomas lesions and Adenomatous polyps in larynx and adenomatous polyps in trachea were observed. In addition, carcinogenic effect on the nasal epithelium and Squamous cell Adeno-carcinoma.Mixed carcinoma,Osteo-genic sarcoma and tumors in larynx, trachea, adrenal, skin, thyroid, pancreas, mammary gland, salivary gland and parathyroid were observed in treated rat as compare to control. Therefore, Carcinogenic LOAEC was considered to be 50 mg/L (50000 mg/m³) when Sprague-Dawleymalerat were exposed toMethylmethane sulfonate (MMS) by whole-body inhalation for 30 days.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LOAEC

50 000 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimisch 2 and from peer-reviewed journal

System:

respiratory system: upper respiratory tract

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the above studies on Methyl methanesulphonate, it can be concluded that Methyl methanesulphonate is carcinogenic by inhalation. Thus, comparing this effect with the criteria of CLP regulation, Methyl methanesulphonate can be classified as “Category 2 carcinogen” by inhalation.

Additional information

Carcinogenicity: Inhalation

In different studies, Methyl methanesulphonate has been investigated for Carcinogenicity by inhalation 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.

In a study conducted by Sellakumaret al(J. Natl Cancer Inst, VOL. 79, NO.2, August 1987, page no. 285-289),Sprague-Dawleymalerat were exposed toMethylmethane sulfonate (MMS)bywhole-body inhalationin the concentrations of 0 and 50 ppm. The results showed thatMethylmethane sulfonate (MMS) wascarcinogenic. Carcinogenic changes were observed as cumulative mortality as the week of exposure increase and gross pathological changes such asmetastatic lesions in the lungs, Squamous metaplasia, Polyp or papillomas lesions and Adenomatous polyps in larynx and adenomatous polyps in trachea were observed. In addition, carcinogenic effect on the nasal epithelium, Squamous cell, Adeno-carcinoma.Mixed carcinoma,Osteo-genic sarcoma and tumors in larynx, trachea, adrenal, skin, thyroid, pancreas, mammary gland, salivary gland and parathyroid were observed in treated rat as compare to control. Therefore, Carcinogenic LOAEC was considered to be 50 mg/L (50000 mg/m³) when Sprague-Dawleymalerat were exposed toMethylmethane sulfonate (MMS)bywhole-body inhalation for 30 days.

In another study conducted by Carrollet al(Cancer Letter Vol. 33, pp 175-181, 1986), Sprague-Dawley male rat were exposed to Methylmethane sulfonate (MMS)bywhole-body inhalationin the concentrations of 0 and 50 ppm. The results showed that Methylmethane sulfonate (MMS) was carcinogenic. Carcinogenic changes were observed as cumulative mortality as the week after fist exposure increase. In addition, carcinogenic effect on the nasal mucosal macromolecules and abilities to bind to nasal mucosal DNA was also observed in treated rat as compare to control. Therefore, Carcinogenic lowest-observed-adverse-effect level (LOAEL) was considered to be50 mg/L (50000 mg/m³)when Sprague-Dawley male rat were exposed to Methylmethane sulfonate (MMS) by whole-body inhalation for 6 weeks.

Thus, based on the above studies on Methyl methanesulphonate, it can be concluded that Methyl methanesulphonate is carcinogenic by inhalation. Thus, comparing this effect with the criteria of CLP regulation, Methyl methanesulphonate can be classified as “Category 2 carcinogen” by inhalation.