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Description of key information

Acute toxicity of MTSC was evaluated in two reliable studies : by oral and dermal route.
MTSC is toxic by oral route with a LD50 of 15 mg/kg bw on rats (Nelson 1978), and toxic by dermal route with a LD50 comprised between 200 and 1000 mg/kg in rats (Petitpretz 2012).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1977/12/13 - 1977/12/30
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: 2c: comparable to guideline study with acceptable restrictions.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not specified
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
- Source: Holtzman Co. Madison Wisconsin.
- Age: no data
- Weight at study initiation: 256 to 386 g for males 178 to 250 g for females.
-Housing: five per cage
-Diet : Purina lab chow, ad libitum
-Water : ad libitum
-Fasting : yes, 18-hours
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
MTSC is soluble in water and is dissolved in 50 ml of distilled water.
Doses:
4, 8, 12, 16, 23 and 32 mg/kg.
No. of animals per sex per dose:
10 rats/ sex/dose
Control animals:
no
Details on study design:
EXAMINATIONS:
- Clinical signs: yes
- Mortality: was analyzed by the method of Carrol S. Weil , Biometrics.
- Body weight: were taken on days 0, 7 and 14.
- Necropsy: . Macroscopic examination of the main organs: yes
- Microscopic examination: no

- Post dose observation period: 14 days
Statistics:
none
Sex:
male
Dose descriptor:
LD50
Effect level:
16 mg/kg bw
95% CL:
> 13 - < 20
Sex:
female
Dose descriptor:
LD50
Effect level:
14 mg/kg bw
95% CL:
> 11 - < 17
Mortality:
No mortality was observed at 4 and 8 mg/kg bw in female and male rats.
5/10 males and 8/10 females died at 16 mg/kg bw.
10/10 males and 9/10 females died at 32 mg/kg bw.
Clinical signs:
Signs of toxicity for males were the following: diarrhea, salivation, tremors, increased activity, decreased activity, rough coat, and increased aggressiveness. At the level of 4 and 12 mg/kg, the onset of observable diarrhea was delayed to days 7 and 8 respectively. The level of 8 mg/kg showed no observable signs of toxicity throughout the 14-day period. The increased aggressiveness (seen only at the two highest dose levels) included vicious attacks on other rats in the cage.
During the first four hours following administration of this test material, males and females at the levels of 12, 16, 23 and 32 mg/kg generally reacted according to the following pattern: 1. decreased activity; sluggish 2. squealing; paralytic-like stance 3. increased activity; sometimes increased aggressiveness 4. tetanic convulsions; squealing.
Body weight:
See table of results enclosed
Gross pathology:
Necropsies at the time of death or on day 14 showed: only congested lungs at the two lowest levels; animals also had lung adhesions not believed to be related to the test material. Congested lungs, dark liver, hemorrhagic enteritis and evidence of diarrhea and salivation were seen in the next three dose levels; also one rat in the 32 mg/kg level had lung adhesions and abscesses not necessarily compound related. For females, also at the lowest two levels, only congested lungs were observer at gross necropsy. Other gross finding were: congested lungs, congested or dark liver, dark spleen, evidence of diarrhea and salivation, and hemorrhagic enteritis.

Table 1: MTSC Acute oral rat

 

sex

Dose (mg/kg)

Observa-ions (no. death/ no. exposed)

Signs

Time of death within (hour)

Average body weights (g)

LD50 (95% confidence limits) (mg/kg)

Begin within (hour)

End within (hour)

Day 0

Day 7

Day 14

males

4

0/10

Day 7

Day 8

-

317

343

382

 

16

(13 to 20)

8

0/10

-

-

-

309

345

286

12

5/10

3

3*

3

305

340

374

16

5/10

2

2

18

320

350

388

23

10/10

1

3

4

324

-

-

32

10/10

1

2

18

306

-

-

females

4

0/10

-

-

-

237

266

274

14

(11 to 17)

8

0/10

2

2

-

223

251

258

12

4/10

1

3

18

204

240

257

16

8/10

2

3

18

230

268

278

23

10/10

1

4

18

215

-

-

32

9/10

1

2

18

224

231

266

 

* Signs of toxicity also seen on Day 18

Interpretation of results:
Toxicity Category II
Remarks:
Migrated information Criteria used for interpretation of results: other: Regulation EC n°1272/2008 (CLP)
Conclusions:
The acute oral LD50 values for male and female rats were 14 and 16 mg/kg bw.
Executive summary:

The purpose of this study was to determine the acute oral toxicity of MTSC when administered to male and female rats.

Rats were exposed by gavage at 4, 8, 16 and 32 mg/kg bw. Mortality, clinical signs, body weight were observed during 14 days after administration. Mortalities were observed at 16 and 32 mg/kg in male and females rats. This study also reported neurobehavioral signs such as salivation, tremors, increased activity, aggressiveness and tetanic convulsions.

Under the conditions of this study, the acute oral LD50 values for male and female rats were 14 and 16 mg/kg bw respectively.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
15 mg/kg bw
Quality of whole database:
The oral acute toxicity study is reliable with a klimisch score of 2.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 August 2011 - 02 December 2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Compliant to GLP and testing guidelines; adequate consistence between data, comments and conclusions.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: breeder: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: on the day of treatment, the animals were approximately 8 weeks old (except group five males which were 10 weeks old
- Mean body weight at study initiation: the males had a mean body weight of 377 g (range: 345 g to 423 g) and the females had a mean body weight of 234 g (range: 217 g to 249 g)
- Fasting period before study: yes, during the night before treatment
- Housing: polycarbonate cages with stainless steel lids
- Diet: SSNIFF R/M-H pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h (7:00 - 19:00)

IN-LIFE DATES: 30 August 2011 to 02 December 2011.
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 10% of body surface, dorsal site
- Type of wrap if used: hydrophilic gauze pad + adhesive hypoallergenic aerated semi-occlusive dressing + restraining bandage

REMOVAL OF TEST SUBSTANCE
- Removal of dressing: 24h post-exposure
- Washing: at 24h post-exposure, with a moistened cotton pad
Duration of exposure:
24 hours.
Doses:
200, 1000 and 2000 mg/kg.
No. of animals per sex per dose:
Groups 1 to 3: one female per group
Groups 4 and 6: 4 females
Groups 5 and 7: 5 males
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Clinical observations: frequently during the hours following treatment; then, at least once a day.
- Body weight: just before treatment on day 1; then on days 8 and 15.
- Necropsy of survivors performed: yes (macroscopic).
Statistics:
no
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 200 - < 1 000 mg/kg bw
Based on:
test mat.
Mortality:
During the first step, the female given 2000 mg/kg died on day 3. No mortality was observed at 200 mg/kg (one female) and at 1000 mg/kg
(one female).
During the confirmatory step at 1000 mg/kg, 2/4 females and 4/5 males died on day 3. Except for chromodacryorrhea in one male on day 2,
no pre-death clinical signs were observed in any animal.
There were no deaths during the confirmatory step at 200 mg/kg (four females and five males).
In summary, 1/1 female died at 2000 mg/kg, 6/10 rats (2/5 females and 4/5 males) died at 1000 mg/kg and 0/10 rats died at 200 mg/kg.
Clinical signs:
No clinical signs indicative of systemic toxicity were observed in any animal during the study.
No cutaneous reactions were observed in any animal, except for scabs at the application site on days 7 to 10 in 1/5 males given 200 mg/kg.
Body weight:
The mean body weight changes (g) recorded in animals during the confirmatory step at 200 mg/kg and in historical control data.
Body weight was considered to be unaffected by the test item treatment at 200 mg/kg, when compared to historical control data.
Gross pathology:
Macroscopic enlargement of the spleen was noted at the end of the 14-day observation period in 5/5 males and 2/4 females given 200 mg/kg. In the absence of microscopic examination, the cause of this enlargement could not be determined and a relationship to treatment could not be excluded.
Interpretation of results:
Toxicity Category III
Remarks:
Migrated information Criteria used for interpretation of results: other: Regulation EC n°1272/2008
Conclusions:
The dermal LD50 of the test item was comprised between 200 and 1000 mg/kg in rats.
According to the criteria of CLP Regulation, the test item should be classified category 3 and assigned the signal word "danger" and the hazard statement "H311: Toxic in contact with skin".
Executive summary:

The objective of this study was to evaluate the potential toxicity of the test item following a single dermal application to rats (OECD 402).

 

Methods

The test item was applied in its original form to the skin of Sprague‑Dawley rats.The application site was covered by a semi‑occlusive dressing for 24 hours.

A first step was performed to determine the appropriate dose-level to be administered in a confirmatory step. In this first step, three females received the dose-level of 200, 1000 or 2000 mg/kg, respectively. As the female given 2000 mg/kg died and as no mortality occurred at 200 and 1000 mg/kg,four other females and then five males received 1000 mg/kg in the confirmatory step. As mortality was observed in males and females at 1000 mg/kg, four females and then five males received 200 mg/kg.

Each animal was observed at least once a day for mortality and clinical signs for 15 days. From day 2, any local reactions at the treatment site were also noted. Body weight was recorded on days 1, 8 and 15. On completion of the observation period, the animals were sacrificed and submitted for a macroscopicpost-mortemexamination. Macroscopic lesions were preserved but no microscopic examination was performed.

 

Results

The female given 2000 mg/kg and 2/5 females and 4/5 males given 1000 mg/kg died on day 3, without pre‑death clinical signs. No deaths occurred at 200 mg/kg (five females and five males).

No clinical signs indicative of systemic toxicity were observed in any animals, regardless of the dose-level. No cutaneous changes, which could be related to the test item treatment, were noted during the observation period.

Body weight was considered to be unaffected by the test item treatment at 200 mg/kg.

A test item-related enlargement of the spleen at 200 mg/kg could not be ruled out.

Conclusion: The dermal LD50 of the test item was comprised between 200 and 1000 mg/kg in rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
200 mg/kg bw
Quality of whole database:
The oral acute toxicity study is reliable with a klimisch score of 1; the study was performing according to the OECD 402 guideline and GLP compliance.

Additional information

Acute oral (Study of Nelson 1978) :

The purpose of this study was to determine the acute oral toxicity of MTSC when administered to male and female rats.

Rats were exposed by gavage at 4, 8, 16 and 32 mg/kg bw. Mortality, clinical signs, body weight were observed during 14 days after administration. Mortalities were observed at 16 and 32 mg/kg in male and females rats. This study also reported neurobehavioral signs such as salivation, tremors, increased activity, aggressiveness and tetanic convulsions.

Under the conditions of this study, the oral LD50 values for male and female rats were 14 and 16 mg/kg bw respectively.

Acute dermal (Petitpretz 2012):

The objective of this study was to evaluate the potential toxicity of the test item following a single dermal application to rats (OECD 402).The test item was applied in its original form to the skin of Sprague-Dawley rats.The application site was covered by a semi-occlusive dressing for 24 hours.

A first step was performed to determine the appropriate dose-level to be administered in a confirmatory step. In this first step, three females received the dose-level of 200, 1000 or 2000 mg/kg, respectively. As the female given 2000 mg/kg died and as no mortality occurred at 200 and 1000 mg/kg,four other females and then five males received 1000 mg/kg in the confirmatory step. As mortality was observed in males and females at 1000 mg/kg, four females and then five males received 200 mg/kg.

The female given 2000 mg/kg and 2/5 females and 4/5 males given 1000 mg/kg died on day 3, without pre‑death clinical signs. No deaths occurred at 200 mg/kg (five females and five males).

No clinical signs indicative of systemic toxicity were observed in any animals, regardless of the dose-level. No cutaneous changes, which could be related to the test item treatment, were noted during the observation period. Body weight was considered to be unaffected by the test item treatment at 200 mg/kg. A test item-related enlargement of the spleen at 200 mg/kg could not be ruled out.

The dermal LD50 of MTSC was comprised between 200 and 1000 mg/kg in rats.


Justification for selection of acute toxicity – oral endpoint
Only one reliable study is available for this endpoint.

Justification for selection of acute toxicity – inhalation endpoint
No reliable acute study is available by inhalation.

Justification for selection of acute toxicity – dermal endpoint
Only one reliable study is available for this endpoint.

Justification for classification or non-classification

Proposed self-classification

- Regulation (EC) No 1272/2008

Oral acute Tox. 2, H 300 (Fatal if swallowed). Justification: LD50(oral) is comprised between 5 and 50 mg/kg bw.

Dermal acute Tox. 3, H 311 (Toxic in contact with skin). Justification: LD50(dermal) is comprised between 200 and 1000 mg/kg bw.

 

- Directive 67/548/EEC

T+, R28 (Very toxic if swallowed).

Xn, R21 (Harmful in contact with skin)