Registration Dossier

Acute oral toxicity:

Acute oral toxicity dose (LD50) was considered based on different studies conducted on rats for the given test chemical. The studies concluded that the LD50 value is >2000 mg/kg bw, for acute oral toxicity. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute oral toxicity.

Acute Inhalation toxicity:

Acute Inhalation toxicity dose (LC50) was considered based on study conducted on rats. The LC50 value was considered to be >600 mg/L (600000 mg/m3). The study concluded that the LC50 value is >5 mg/L air. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute Inhalation toxicity.

Acute Dermal toxicity:

The acute dermal toxicity dose (LD50) was considered based on study conducted on rabbits for the test chemical. The LD50 value was considered to be >5000 mg/kg bw. The study concluded that the LD50 value is >2000 mg/kg bw, for acute dermal toxicity. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute dermal toxicity.

Reference

Endpoint:

acute toxicity: oral

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 mentioned below

Principles of method if other than guideline:

Acute oral toxicity of the substance was assessed in Sprague-dawley rats.

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories (Raleigh, NC, USA).
- Age at study initiation: 6 weeks old
- Weight at study initiation: 206–220 g (males), 146–165 g (females)
- Housing: housed individually in solid-bottomed polycarbonate cages lined with heat-treated hardwood chip bedding
- Diet (e.g. ad libitum): Certified Rodent Diet #5002
- Water (e.g. ad libitum): tap water public
water supply
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): between 69 and 750 °F
- Humidity (%): between 37 and 60%.
- Photoperiod (hrs dark / hrs light): 12-h light/dark cycle.

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

sterile water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 2g/kg
MAXIMUM DOSE VOLUME APPLIED: 10ml/kg

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

10 male and 10 female rats

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were checked for clinical signs and mortality twice a day. Each rat was weighed on days 1, 5, 8, 12 and 15.
- Necropsy of survivors performed: yes, rats were sacrificed on day 15 by CO2 asphyxiation.
Necropsy examinations included a thorough inspection of all external surfaces, organs and orifices. The following organs and tissues were examined: adrenals, aorta, brain, cecum, colon, duodenum, epididymides, esophagus, eyes, heart, ileum, jejunum, kidneys, larynx, liver, lungs, lymph nodes (mesenteric, mandibular), mammary glands, ovaries, pancreas, parathyroid, prostate, rectum, salivary glands, skeletal muscle, skin, spleen, stomach (fundic area), testes, thyroid, tongue, trachea, urinary bladder, uterus and vagina.

Statistics:

not specified

Preliminary study:

not specified

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No mortality observed

Mortality:

No mortality was observed at the dose concentration of 2000 mg/kg bw.

Clinical signs:

other: No adverse effects or clinical signs of toxicity were observed for any animals dosed during the study.

Gross pathology:

No gross lesions were noted in any rats on necropsy.

Other findings:

not specified

Interpretation of results:

other: Not classified

Conclusions:

The acute oral LD50 value was considered to be >2000 mg/kg bw, when 10 male and 10 female Sprague-dawley rats were treated with the given test chemical via oral gavage route.

Executive summary:

The acute oral toxicity study was conducted by using the given test chemical in when 10 male and 10 female Sprague-dawley rats at the dose concentration of 0 and 2000 mg/kg bw.

The given test chemical was dissolved in sterile water and administered as 10 ml/kg via oral gavage route. The control animals received sterile water only.

Animals were checked for clinical signs and mortality twice a day. Each rat was weighed on days 1, 5, 8, 12 and 15. Necropsy of survivors performed. Rats were sacrificed on day 15 by CO2 asphyxiation. Necropsy examinations included a thorough inspection of all external surfaces, organs and orifices. The following organs and tissues were examined: adrenals, aorta, brain, cecum, colon, duodenum, epididymides, esophagus, eyes, heart, ileum, jejunum, kidneys, larynx, liver, lungs, lymph nodes (mesenteric, mandibular), mammary glands, ovaries, pancreas, parathyroid, prostate, rectum, salivary glands, skeletal muscle, skin, spleen, stomach (fundic area), testes, thyroid, tongue, trachea, urinary bladder, uterus and vagina.

No mortality was observed at the dose concentration of 2000 mg/kg bw. No adverse effects or clinical signs of toxicity were observed for any animals dosed during the study. No discernible differences in weight gain were noted between treatment groups. No gross lesions were noted in any rats on necropsy.

Under the condition of the study, the LD50 value was considered to be >2000 mg/kg bw, when 10 male and 10 female Sprague-dawley rats were treated with the given test chemical via oral gavage route.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from peer-reviewed journal.

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Justification for type of information:

Data is from secondary database

Qualifier:

according to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

The toxicity study was conducted to evaluate the acute toxic effects of administration of the given test chemical in rat by the inhalation route.

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Species:

rat

Strain:

other: Crl:CD(SD)BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

inhalation

Type of inhalation exposure:

nose only

Vehicle:

other: water

Remark on MMAD/GSD:

not specified

Details on inhalation exposure:

VEHICLE
- Concentration of test material in vehicle (if applicable): MSM was administered as a 16% solution in water by the intranasal route at a dose of 0.6 ml/kg.

Analytical verification of test atmosphere concentrations:

not specified

Remarks on duration:

Acute study but duration is not reported.

Concentrations:

0.6 ml/kg (600 mg/kg)

No. of animals per sex per dose:

5 per sex

Control animals:

not specified

Details on study design:

- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology.

Statistics:

not specified

Preliminary study:

not specified

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 600 mg/L air

Based on:

test mat.

Remarks on result:

other: Intranasal administration of MSM did not induce mortality, signs of toxicity or local irritation reactions.

Mortality:

No deaths were noted.

Clinical signs:

other: No general/local clinical changes were noted.

Body weight:

No body weight growth abnormalities were noted.

Gross pathology:

No treatment-related changes were noted.

Other findings:

not specified

Interpretation of results:

other: Not classified

Conclusions:

The acute lethal concentration (LC50) of the given test chemical in rat was considered to be >600 mg/L.

Executive summary:

The toxicity study was conducted to evaluate the acute toxic effects of administration of the given test chemical in Crl:CD(SD)BR rat (n = five per sex) by the inhalation route.

The given test chemical was administered as a 16% solution in water by the intranasal route at a dose of 0.6 ml/kg to six male rats. Clinical observations, body weight determinations and gross pathology examinations were conducted. A detailed post-mortem examination, including gross pathology and histology was performed on nasal turbinate.

No deaths or general/local clinical changes or body weight growth abnormalities were noted. At the post-mortem examinations, no treatment-related changes were noted. It is concluded that intranasal administration of test chemical did not induce mortality, signs of toxicity or local irritation reactions.

Thus, based on the results obtained from present investigation, it can be concluded that test compound is acutely non toxic to rats at the tested concentration of 600 mg/L. The acute lethal concentration (LC50) of test chemical was considered to be >600 mg/L.

Thus, according to CLP criteria for acute toxicity rating for the chemicals, the test compound can be classifying under acutely non toxic compound at the tested dose levels.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

600 000 mg/m³ air

Quality of whole database:

Data is Klimisch 4 and from secondary database.

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from handbook.

Qualifier:

according to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

The toxicity study was examined to evaluate the acute toxic effects of administration of the test chemical in male New Zealand White rabbits by the dermal route.

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Skippack Farms
- Weight at study initiation: mean wt: 2.23

Type of coverage:

occlusive

Vehicle:

physiological saline

Details on dermal exposure:

TEST SITE
- Area of exposure: The closely clipped skin.
- Type of wrap if used: The test chemical was held under an impervious cuff.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The cuffs were removed and the application sites were gently wiped to remove the test substance.
- Time after start of exposure:24-hr

TEST MATERIAL
- For solids, paste formed: yes, the test substance, prepared as a paste in saline (1:1)

Duration of exposure:

24 hours

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

Total = 2

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Other examinations performed: Animals were observed for mortality and clinical signs.
- Necropsy of survivors performed: yes

Statistics:

not specified

Preliminary study:

not specified

Sex:

male

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed at the dose concentration of 5000 mg/kg bw.

Clinical signs:

other: Well defined erythema and very slight edema was observed.

Gross pathology:

No gross changes were observed in either rabbit.

Other findings:

not specified

Interpretation of results:

other: Not classified

Conclusions:

The acute dermal LD50 value was considered to be >5000 mg/kg bw, when 2 male New Zealand White rabbits were treated with the given test chemical by dermal application occlusively.

Executive summary:

The acute dermal toxicity study was conducted by using the given test chemical in 2 male New Zealand White rabbits at the dose concentration of 5000 mg/kg bw.

The test substance, prepared as a paste in saline (1:1), was held under an impervious cuff in continuous 24 hr contact with the closely clipped skin. After the 24-hr exposure, the cuffs were removed and the application sites were gently wiped to remove the test substance. Animals were observed for mortality and clinical signs. Necropsy of survivors performed.

No mortality was observed at the dose concentration of 5000 mg/kg bw. Well defined erythema and very slight edema was observed. No gross changes were observed in either rabbit.

Hence, the LD50 value was considered to be >5000 mg/kg bw, when 2 male New Zealand White rabbits were treated with the given test chemical by dermal application occlusively.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and handbook.

Acute oral toxicity:

In different studies, the given test chemical has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents, i.e. most commonly in rats for test chemical. The studies are summarized as below -

The reported study was mentioned in publication and secondary database and conducted to determine acute oral toxicity dose for the given test chemical. The study was conducted in 10 male and 10 female Sprague-dawley rats at the dose concentration of 0 and 2000 mg/kg bw.

The given test chemical was dissolved in sterile water and administered as 10 ml/kg via oral gavage route. The control animals received sterile water only.

Animals were checked for clinical signs and mortality twice a day. Each rat was weighed on days 1, 5, 8, 12 and 15. Necropsy of survivors performed. Rats were sacrificed on day 15 by CO2 asphyxiation. Necropsy examinations included a thorough inspection of all external surfaces, organs and orifices. The following organs and tissues were examined: adrenals, aorta, brain, cecum, colon, duodenum, epididymides, esophagus, eyes, heart, ileum, jejunum, kidneys, larynx, liver, lungs, lymph nodes (mesenteric, mandibular), mammary glands, ovaries, pancreas, parathyroid, prostate, rectum, salivary glands, skeletal muscle, skin, spleen, stomach (fundic area), testes, thyroid, tongue, trachea, urinary bladder, uterus and vagina.

No mortality was observed at the dose concentration of 2000 mg/kg bw. No adverse effects or clinical signs of toxicity were observed for any animals dosed during the study. No discernible differences in weight gain were noted between treatment groups. No gross lesions were noted in any rats on necropsy.

Under the condition of the study, the LD50 value was considered to be >2000 mg/kg bw, when 10 male and 10 female Sprague-dawley rats were treated with the given test chemical via oral gavage route.

The above study is supported with the study available in different handbooks, authoritative databases and secondary sources and conducted by using the given test chemical in group of 3 male Sprague-dawley rats at the dose concentration of 500 and 5000 mg/kg bw.

The given test chemical was dissolved as 20 % (W/V) dispersion in 0.5% solution of Methocel in water and administered via oral gavage route. Animals were observed for mortality and clinical signs for 14 days. Necropsy of survivors performed.

No mortality was observed at the dose concentration of 5000 mg/kg bw. No toxic signs observed. No gross changes were observed in any animal.

Therefore, the LD50 value was considered to be >5000 mg/kg bw, when group of 3 male Sprague-dawley rats were treated with the given test chemical via oral gavage route.

Both the above studies are further supported by the study mentioned in secondary databases for the test chemical. The acute oral toxicity study was conducted by using the given test chemical in group of 4 male and female Albino rats at the dose concentration of 10250 and 15380 mg/kg bw.

The given test chemical was prepared as 25% (w/v) aqueous solution and administered via oral gavage route. Initial and final body weights as well as all mortalities and /or reactions displayed were recorded. Necropsy of survivors performed. Arrangements were made to autopsy any animal which might succumb during the study as well as all surviving animals at the end of the 14 days. At the end of the observation period, all data were collected and arrangements were made to calculate, if possible, the acute median lethal dose (LD50) of the test material using the technique of Weil, Thompson and Thompson and Weil.

No mortality was observed in treated animals. Body weight gain was observed in treated animals. Necropsy of the animal which died during the study as well as all animals sacrificed at the end of the 14-day observation period did not reveal any gross pathologic, alterations in the tissues and organs examined.

Therefore, the LD50 value was considered to be ≥17020 mg/kg bw, when group of 4 male and female Albino rats was treated with the given test chemical via oral gavage route.

Thus, based on the above summarised studies on the given test chemical, it can be concluded that LD50 value is >2000 mg/kg bw, for acute oral toxicity. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute oral toxicity.

Acute Inhalation Toxicity:

The toxicity study was conducted to evaluate the acute toxic effects of administration of the given test chemical in Crl:CD(SD)BR rat (n = five per sex) by the inhalation route.

The given test chemical was administered as a 16% solution in water by the intranasal route at a dose of 0.6 ml/kg to six male rats. Clinical observations, body weight determinations and gross pathology examinations were conducted. A detailed post-mortem examination, including gross pathology and histology was performed on nasal turbinate.

No deaths or general/local clinical changes or body weight growth abnormalities were noted. At the post-mortem examinations, no treatment-related changes were noted. It is concluded that intranasal administration of test chemical did not induce mortality, signs of toxicity or local irritation reactions.

Thus, based on the results obtained from present investigation, it can be concluded that test compound is acutely non toxic to rats at the tested concentration of 600 mg/L. The acute lethal concentration (LC50) of test chemical was considered to be >600 mg/L.

Thus, according to CLP criteria for acute toxicity rating for the chemicals, the test compound can be classifying under acutely non toxic compound at the tested dose levels.

Acute Dermal toxicity:

The acute dermal toxicity study was conducted by using the given test chemical in 2 male New Zealand White rabbits at the dose concentration of 5000 mg/kg bw.

The test substance, prepared as a paste in saline (1:1), was held under an impervious cuff in continuous 24 hr contact with the closely clipped skin. After the 24-hr exposure, the cuffs were removed and the application sites were gently wiped to remove the test substance. Animals were observed for mortality and clinical signs. Necropsy of survivors performed.

No mortality was observed at the dose concentration of 5000 mg/kg bw. Well defined erythema and very slight edema was observed. No gross changes were observed in either rabbit.

Hence, the LD50 value was considered to be >5000 mg/kg bw, when 2 male New Zealand White rabbits were treated with the given test chemical by dermal application occlusively.

Based on the above studies on test chemical, it can be concluded that LD50 value is >2000 mg/kg bw, for acute oral and acute dermal toxicity; and LC50 value is >5 mg/L air, for acute inhalation toxicity. Thus, comparing these values with the criteria of CLP regulation, the given test chemical cannot be classified for acute oral, acute dermal and acute inhalation toxicity.