Registration Dossier

Administrative data

Description of key information

Acute oral toxicity: LD50 = 1218 mg/kg bw (males) and 1203 mg/kg bw (females) for rats (similar to OECD 401)
Acute dermal toxicity: LD50 > 500 mg/kg, no effects at this dose were seen in rats (similar to OECD 402)
Acute inhalation toxicity: LC0 ≥ 600 mg/m³ air (rats, dust), LC0 ≥ 24725 mg/m³ air (mice, rats, vapour), LC0 ≥ 24650 mg/m³ air (hamsters, rabbits, vapour) (similar to OECD 403, 4h exposure)
Acute intraperitoneal toxicity: LD50 = 291 mg/kg bw (males) and 253 mg/kg bw (females) (rats, ip injection)

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted prior to GLP similar to OECD guideline 401 on the registered substance itself. The method is to be considered scientifically reasonable with minor deficiencies in documentation.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not applicable
GLP compliance:
no
Remarks:
test conducted prior to GLP implementation
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Wistar-II
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann animal breeder (Kirchborchen, Paderborn district) and Gierlich animal breeder (Bochum)
- Weight at study initiation: 160-210g
- Housing: macrolon cages, Type III
- Diet (e.g. ad libitum): Altromin R Standard diets (Altromin GmbH, Lage/Lippe) ad libitum
- Water (e.g. ad libitum): ad libitum
Route of administration:
oral: gavage
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 1, 2, 5, 10 , 20, 24, 30, 40%
- Amount of vehicle (if gavage): 0.5ml / 100 g bw
Doses:
50, 100, 250, 500, 1000, 1200, 1500, 2000 mg/kg (males; females only 50-1500 mg/kg)
No. of animals per sex per dose:
15
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs
Statistics:
The determination of the average lethal dose (LD50) was made using a Probit analysis (FINK und HUND, Arzneimittelforschung 15, 624, 1965).
Sex:
male
Dose descriptor:
LD50
Effect level:
1 218 mg/kg bw
Based on:
test mat.
95% CL:
1 098 - 1 337
Sex:
female
Dose descriptor:
LD50
Effect level:
1 203 mg/kg bw
Based on:
test mat.
95% CL:
1 086 - 1 331
Mortality:
See 'Any other information on results incl. tables'
Clinical signs:
Appearance of poisoning:
Symptoms of poisoning in the form of reduced general well-being, difficult breathing, reduced reflexes and lying on the stomach began 2 minutes to 24 hours after the application with the rats. The difficult breathing lasted up to 3 days. The reduced reflexes and lying on the stomach were to be observed up to 24 hours and the general well-being was reduced up to 12 days. The occurrence of death took place within 24 hours to 6 days after the application.
Gross pathology:
The livers of the dead animals exhibited a spotty appearance when sectioned.

Table 1: Results

Dose / mg/kg

Conc. in vehicle / %

Toxicol. Results after 14 d*

Symptoms of poisoning

Occurence of Death after

Start

End

Male Rats

50

1

0/0/15

-

-

-

100

2

0/15/15

24 h

2 d

-

250

5

0/15/15

24 h

4 d

-

500

10

0/15/15

1 h

9 d

-

1000

20

3/15/15

16 min

9 d

1 – 6 d

1200

24

7/15/15

10 min

10 d

1 – 2 d

1500

30

12/15/15

4 min

12 d

1 – 2 d

2000

40

15/15/15

2 min

-

1 – 2 d

Female Rats

50

1

0/0/15

-

-

-

100

2

0/15/15

24 h

2 d

-

250

5

0/15/15

24 h

3 d

-

500

10

0/15/15

1.5 h

9 d

-

1000

20

3/15/15

20 min

7 d

1 – 2 d

1200

24

7/15/15

15 min

7 d

1 – 2 d

1500

30

13/15/15

15 min

9 d

1 – 2 d

*1stNumber = Number of dead animals

2ndNumber = Number of animals with symptoms

3rdNumber = Number of animals used

 

Highest dose without finding (m/f): 50 mg/kg

Lowest lethal dose (m/f): 1000 mg/kg

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The study was conducted prior to GLP similar to OECD guideline 401 on the registered substance itself. The method is to be considered scientifically reasonable with minor deficiencies in documentation. Hence, the results can be considered as sufficiently reliable to assess the acute oral toxicity in rats. The determined LD50 values are 1218 mg/kg bw (males) resp. 1203 mg/kg bw (females). The results for both sexes are hence consistant and suitable to determine the classification of N-Methyl-2-thion-thiazolidine. According to Regulation (EC) No. 1272/2008, the substance needs to be classified as acute toxic cat. IV.
Executive summary:

In an acute oral toxicity study similar to OECD guideline 401, groups of Wistar-II rats (15/sex/dose) were given a single oral dose N-Methyl-2-thion-thiazolidine in polyethylene glycol 400 at doses of 50, 100, 250, 500, 1000, 1200, 1500, 2000 mg/kg (males; females only 50-1500 mg/kg) and observed for 14 days. The following oral LD50 were determined:

 

Males = 1218 mg/kg bw (95% C.I. 1098 - 1337)

Females = 1203 mg/kg bw (95% C.I. 1086 - 1331)

 

Symptoms of poisoning were a significant reduction of the general well-being, difficult breathing and reduction of the reflexes. Mortality occurred after 8 minutes to 6 days.

 

N-Methyl-2-thion-thiazolidine is of slight toxicity based on the LD50 in females, leading to the classification as acute toxic Cat. IV according to Regulation (EC) No. 1272/2008.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 203 mg/kg bw
Quality of whole database:
The available data meets fully the tonnage-driven data requirements of REACH. The study and its results are sufficiently reliable due to the applied method, documentation and plausibility compared to the results of the tests of the other application routes. Hence, the database is of good quality.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted prior to GLP similar to OECD guideline 403 on the registered substance itself. The method is to be considered scientifically reasonable with minor deficiencies in documentation.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
not applicable
GLP compliance:
no
Remarks:
test conducted prior to GLP implementation
Test type:
standard acute method
Limit test:
no
Species:
other: mice, rats, hamsters, rabbits
Strain:
other: NMRI mice, Wistar-II rats, Syrian gold hamsters and albino rabbits
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann animal breeder (Kirchborchen, Paderborn district) and Gierlich animal breeder (Bochum)
- Weight at study initiation: 160-210g (rats), 25-31g (mice), 60-75g (hamsters), 3.5-4.3kg (rabbits)
- Housing: macrolon cages, Type III (rats, mice, hamsters), individually in standard rabbit cages (Manufacturer: E. Pluppins, Hamburg) (rabbits)
- Diet (e.g. ad libitum): Altromin R Standard diets (Altromin GmbH, Lage/Lippe) (mice, rats), sniff full diet feed for hamsters (Intermast GmbH, Bockum-Hövel) (hamsters), Höing rabbit feed (rabbits) ad libitum
- Water (e.g. ad libitum): ad libitum
Route of administration:
other: dust or vapour
Type of inhalation exposure:
other: only through breathing (dust), whole body (vapour)
Vehicle:
not specified
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: dusting device (from JÖTTEN) (dust) / electrical heating pot (vapour)
- Exposure chamber volume: 20L cylinder (dust) / 0.4m³ chamber (vapour)

TEST ATMOSPHERE
- Brief description of analytical method used: analysis of the weight (dust) / gas chromatograph with the help of a nitrogen detector (vapour)
Analytical verification of test atmosphere concentrations:
yes
Remarks:
analysis of weight or gas chromatography
Duration of exposure:
4 h
Concentrations:
600 mg/m³ (dust); 137, 207, 24,725, 24,650 mg/m³ (vapour), see results for details
No. of animals per sex per dose:
10 rats/sex (dust)
in total 20 mice, 10 rats, 5 hamsters and 2 rabbits per dose, sex not stated (vapour)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Other examinations performed: clinical signs
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 600 mg/m³ air
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: dust, rats
Sex:
male/female
Dose descriptor:
LC0
Effect level:
>= 600 mg/m³ air
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: dust, rats
Sex:
not specified
Dose descriptor:
LC0
Effect level:
>= 24 725 mg/m³ air
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: vapour, mice and rats, concentration calculated mathematically
Sex:
not specified
Dose descriptor:
LC0
Effect level:
>= 24 650 mg/m³ air
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: vapour, hamsters and rabbits, concentration calculated mathematically
Mortality:
no mortality occurred
Clinical signs:
other: Neither death nor symptoms of poisoning occurred immediately after the 4-hour exposure or in the following 14-day post-observation time with the rats. The vapours formed with the heating of the test item at 100°C and 200°C caused no appearance of poisonin

Table 1: Results of the acute toxicity study with vapour

Test item / g

Concentration of test item / mg/m³ air

Calculated mathematically

Vaporising temperature / °C

Test duration / h

Animals

Toxicol. Results after 14d*

Inserted

Vaporised

4.0

0.055

137

100

4

Mice

0/0/20

Rats

0/0/10

4.0

0.083

207

100

4

Hamsters

0/0/5

Rabbits

0/0/2

10.0

9.892

24725

200

4

Mice

0/0/20

Rats

0/0/10

10.0

9.863

24650

200

4

Hamsters

0/0/5

Rabbits

0/0/2

*1stNumber = Number of dead animals

2ndNumber = Number of animals with symptoms

3rdNumber = Number of animals used

Interpretation of results:
other: EU-GHS criteria not met
Conclusions:
The study was conducted prior to GLP similar to OECD guideline 402 on the registered substance itself. The method is to be considered scientifically reasonable with minor deficiencies in documentation. Hence, the results can be considered as sufficiently reliable to assess the acute oral toxicity in rats. The LC0 for dust was determined as ≥ 600 mg/m³ air in rats, and the LC0 for vapour was determined as ≥ 24725 mg/m³ air (rats, mice) and ≥24650 mg/m³ air (hamsters, rabbits), respectively. The results for both sexes and all species are consistent and suitable to determine the classification of N-Methyl-2-thion-thiazolidine. According to Regulation (EC) No. 1272/2008, the substance does not need to be classified as acute toxic by inhalation.
Executive summary:

In an acute inhalation toxicity study (similar to OECD 403), groups of Wistar-II rats (10/sex) were exposed by inhalation route to dusts of N-Methyl-2-thion-thiazolidine for 4 hours (inhalation only) at a concentration of 600 mg/m³. Further, Wistar-II rats (20/group), NMRI mice (10/group), Syrian gold hamsters (5/group) and albino rabbits (2/group) were exposed by inhalation route to vapours of N-Methyl-2-thion-thiazolidine for 4 hours (whole body) at concentrations of 137 and 24,725 mg/m³ (rats, mice) and 207 and 24,650 mg/m³. Animals then were observed for 14 days.

 

LC50 > 600 mg/m³ (dust, rats, m/f)

LC0 ≥ 600 mg/m³ (dust, rats, m/f)

LC0 ≥ 24,725 mg/m³ (vapour, rats, mice)

LC0 ≥ 24,650 mg/m³ (vapour, hamsters, rabbits)

 

With the dynamic dusting of N-Methyl-2-thion-thiazolidine, an LC50 >600mg/m³ air resulted with a one-time four-hour exposure for male and female rats. With this concentration, no symptoms of poisoning appeared immediately after the exposure or in the following 14-day post-observation time.

When N-Methyl-2-thion-thiazolidine was vaporised (at 100 or 200°C), there were no injuries in the case of rats, mice, rabbits and hamsters through a four-hour exposure.

 

N-Methyl-2-thion-thiazolidine is classified as being of low toxicity based on the results above and does not trigger classification as acute toxic by inhalation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available data meets fully the tonnage-driven data requirements of REACH. The study and its results are sufficiently reliable due to the applied method, documentation and plausibility compared to the results of the tests of the other application routes. Hence, the database is of good quality.

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted prior to GLP similar to OECD guideline 402 on the registered substance itself. The method is to be considered scientifically reasonable with minor deficiencies in documentation, and only one dose (no limit dose) was tested.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
not applicable
GLP compliance:
no
Remarks:
test conducted prior to GLP implementation
Test type:
other: single dose application
Limit test:
no
Species:
rat
Strain:
other: Wistar-II
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann animal breeder (Kirchborchen, Paderborn district) and Gierlich animal breeder (Bochum)
- Weight at study initiation: 160-210g
- Housing: macrolon cages, Type III
- Diet (e.g. ad libitum): Altromin R Standard diets (Altromin GmbH, Lage/Lippe) ad libitum
- Water (e.g. ad libitum): ad libitum
Type of coverage:
occlusive
Vehicle:
polyethylene glycol
Remarks:
400
Details on dermal exposure:
TEST SITE
- Area of exposure: skin of the backs
- Type of wrap if used: aluminium foil and wide ahhesive plaster strip

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 500 mg/kg bw
- Concentration (if solution): 25% emulsion
Duration of exposure:
24 h
Doses:
500 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Other examinations performed: clinical signs
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 500 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LD0
Effect level:
>= 500 mg/kg bw
Based on:
test mat.
Mortality:
No cases of death occurred.
Clinical signs:
No symptoms of poisoning appeared with the rats in the first 24 hours after the application or during the 14-day post-observation time.
Interpretation of results:
study cannot be used for classification
Conclusions:
The study was conducted prior to GLP similar to OECD guideline 402 on the registered substance itself. The method is to be considered scientifically reasonable with minor deficiencies in documentation, and only one dose (no limit dose) was tested. Hence, the results can be considered at least as sufficiently reliable to assess the dermal oral toxicity in rats. Since the test item was only tested at a dose of 500 mg/kg, which does not correspond to the limit dose, and no effects were seen, there can no absolute conclusions be made regarding the substances definitive classification under the CLP Regulation. It can only be stated that the substance is relatively harmless as does not trigger classification as acute toxic Cat. III or higher.
Executive summary:

In an acute dermal toxicity study similar to OECD 402, two groups of each five male and female rats were dermally exposed to the test item in polyethylene glycol 400 for 24 hours to the skin on the backs at a dose of 500 mg/kg bw. Animals then were observed for 14 days.

 

No cases of death occurred and no symptoms of poisoning appeared with the rats in the first 24 hours after the application or during the 14-day post-observation time. A dermal LD50 >500 mg/kg therefore results for both sexes.

 

The test item is hence of low Toxicity.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available data meets fully the tonnage-driven data requirements of REACH. The study and its results are sufficiently reliable due to the applied method, documentation and plausibility compared to the results of the tests of the other application routes. Hence, the database is of good quality.

Additional information

There are four acute toxicity studies available on 3-methylthiazolidine-2-thione, which are mostly conducted similar to the recent respective OECD guidelines, conducted prior to GLP implementation:

Acute oral toxicity: The following oral LD50 were determined:

Males = 1218 mg/kg bw (95% C.I. 1098 - 1337)

Females = 1203 mg/kg bw (95% C.I. 1086 - 1331)

Symptoms of poisoning were a significant reduction of the general well-being, difficult breathing and reduction of the reflexes. Mortality occurred after 8 minutes to 6 days.

N-Methyl-2-thion-thiazolidine is of slight toxicity based on the LD50 in females, leading to the classification as acute toxic Cat. IV according to Regulation (EC) No. 1272/2008.

 

Acute dermal toxicity: No cases of death occurred and no symptoms of poisoning appeared with the rats in the first 24 hours after the application or during the 14-day post-observation time. A dermal LD50 >500 mg/kg therefore results for both sexes.

The test item is hence of low Toxicity.

 

Acute inhalation toxicity: The following inhalative LC50/LC0 were determined:

LC50 > 600 mg/m³ (dust, rats, m/f)

LC0 ≥ 600 mg/m³ (dust, rats, m/f)

LC0 ≥ 24,725 mg/m³ (vapour, rats, mice)

LC0 ≥ 24,650 mg/m³ (vapour, hamsters, rabbits)

With the dynamic dusting of N-Methyl-2-thion-thiazolidine, an LC50 >600mg/m³ air resulted with a one-time four-hour exposure for male and female rats. With this concentration, no symptoms of poisoning appeared immediately after the exposure or in the following 14-day post-observation time.

When N-Methyl-2-thion-thiazolidine was vaporised (at 100 or 200°C), there were no injuries in the case of rats, mice, rabbits and hamsters through a four-hour exposure.

N-Methyl-2-thion-thiazolidine is classified as being of low toxicity based on the results above and does not trigger classification as acute toxic by inhalation.

 

Acute intraperitoneal toxicity: The following ip LD50 were determined:

Males = 291 mg/kg bw (95% C.I. 266 - 318)

Females = 253 mg/kg bw (95% C.I. 233 - 274)

Symptoms of poisoning were a reduction of the general well-being, difficult breathing and cramps. Death occurred within 24 hours after the application.

 

All required routes of application are covered, no data gaps were identified, as all data is considered sufficiently reliable. The relative magnitude of the results derived from the different routes of application are in the expected range when taking into account the sensitivity of the routes and the possible differences in absorption, making the results plausible and sufficient for human risk assessment. 3-methylthiazolidine-2-thione is to be considered slightly toxic.

Justification for classification or non-classification

Both the inhalation and dermal study did not reveal any signs of toxicity. The only available LD50 values are via the oral and intraperitoneal route. The ip route is not relevant for classification according to Regulation (EC) No. 1272/2008, leaving only the oral LD50 in female rats (more sensitive sex) to assess the need for classification. The oral LD50 of 1203 mg/kg bw lies between the boundary values of 300 and 2000 mg/kg bw, triggering the classification of 3-methylthiazolidine-2-thione as acute toxic Cat. IV according to Regulation (EC) No. 1272/2008.