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Administrative data

Description of key information

Several acute studies are available by oral route, all of the studies showed a LD50 between 690 and 1400 mg/kg in rodents (rats and mice).
The acute study by inhalation on an analogue of TMTM: TMTD (aerosol) showed a combined LC50 of 4.42 mg/L in rats.
Two reliable acute studies are available by dermal route, one on rats and one on rabbits, showed a LD50 higher than 2000 mg/kg.

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Stamm Wistar TNO W 74, Züchter: Winkenmann, Borchen
- Age at study initiation: 9 week-old
- Weight at study initiation: 182 g
- Fasting period before study: no data
- Housing: 5 per cage
- Diet (e.g. ad libitum): Tiere Atromin R 1324, ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-1.5°C
- Humidity (%): 60+/-5%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: Lutrol
Details on oral exposure:
Volume of administration = 20 ml/kg
Doses:
100, 500, 1000, 2500, 3100 mg/kg
No. of animals per sex per dose:
10 rat/sex/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: twice per day (one time the week end)
- Necropsy of survivors performed: no data
Statistics:
Probit analyse
Sex:
male/female
Dose descriptor:
LD50
Effect level:
690 mg/kg bw
Based on:
test mat.
95% CL:
360 - 1 060
Mortality:
At 100 mg/kg : no mortality (0/10)
At 500 mg/kg : 5/10 died animals
At 1000 and 2000 mg/kg : 7/10 died animals
At 2500 mg/kg: 8/10 died animals
At 3100 mg/kg: all animals died (10/10)
Clinical signs:
No clinical sign was observed at 100 mg/kg.
Narcosis, diarrhea, shaggy coat, hair loss were observed at doses between 500 and 3100 mg/kg.
Body weight:
Decrease of bodyweight was observed at doses between 500 and 3100 mg/kg.
Gross pathology:
no data
Other findings:
no data
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
According to this study, the approximate acute oral rat LD50 is 690 mg/kg for male and female rats.
Executive summary:

Three groups of 10 male and 10 female rats were dosed at 100, 500, 1000, 2500 and 3100 mg/kg. The animals were observed for mortality, body weights and clinical signs though day 14.

No mortalities was observed at 100 mg/kg, 7 -8 animals died at 500, 1000 and 2500 mg/kg bw and all the animals died at 3100 mg/kg. Clinical signs at doses 500 -3100 mg/kg included narcosis, diarrhea, hair loss and shaggy coat ; a a decrease of bodyweight was observed. The dose of 100 mg/kg was asymptomatic.

According to this study, the approximate acute oral rat LD50 is 690 mg/kg for male and female rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
690 mg/kg bw
Quality of whole database:
Löser's study is a reliable study with a klimisch score of 1.

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
Study period:
April-September 1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EPA OPP 81-3 (Acute inhalation toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:Harlan Sprague-Dawley, Inc. Hoston, Texas, USA
- Age at study initiation: yound adult
- Weight at study initiation: 242-350g (male), 178-219g (female)
- Fasting period before study:no data
- Housing: 1-3 per cage, males separate from females
- Diet (e.g. ad libitum): Purina Formulab Chow #5008 ad libitum
- Water (e.g. ad libitum):tap water ad libitum
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
Temperature and humidity were recorded at 30 minutes intervals during the exposure period from a Taylor wet hygrometer located in the exposure room.
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: dried filtered air
Details on inhalation exposure:
The arerosol was generated by passing a stream of dry, filtered air though either two (for the lower exposure concentration) or four (for the higher exposure concentration) glass flasks containing the test material.The concentrated aerosol was then diluted with dried and filtered air and drawn into the exposure cahmber. Air flow into the chamber was maintained through the use of a calibrated critical orifice. Air flow was recorded at 30 minute intervals during the exposure period. The air flow was sufficient to ensure adequate oxygen content of the exposure atmosphere. Temperature and humidity were recorded at 30 minutes intervals during the exposure period from a Taylor wet hygrometer located in the exposure room.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
determined gravimetrically twice per hour (Anderson cascade impactor)
Duration of exposure:
4 h
Concentrations:
Nominal concentrations: 6.9, 14.1, 32.03 mg/L
Analytical concentrations: 2.06, 3.36, 5.04 mg/L (gravimetric)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Observations for mortality and pharmacologic and/or toxicologica effects were made frenquently on the day of exposure and at least one daily thereafter for 14 days (day of exposure considered Day 0). Individual body weights were recorded just prior to the inhalation exposure and on Days 7 and 14 or a time of discovery after death. A gross necropsy examination was conducted on each animal at termination of the study or at the time of discovery after death.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
4.42 mg/L air (analytical)
Based on:
test mat.
95% CL:
3.09 - 6.32
Exp. duration:
4 h
Remarks on result:
other: LC50 calculated
Key result
Sex:
male
Dose descriptor:
LC50
Effect level:
> 5.04 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: One male died at each dose
Key result
Sex:
female
Dose descriptor:
LC50
Effect level:
3.464 mg/L air (analytical)
Based on:
test mat.
95% CL:
2.98 - 4.03
Exp. duration:
4 h
Remarks on result:
other: LC50 calculated
Mortality:
2.06 mg/L: one male died, no female died (10%)
3.36 mg/L: one male and two females died (30%)
5.04 mg/L: one male and five females died (60%)
Clinical signs:
other: Clinical signs were observed at all doses. Prominent in-life observations included activity decrease, constricted pupils, gasping, nasal discharge, piloerection, polyurea, ptosis and salivation.
Body weight:
A decrease of body weight was observed.
Gross pathology:
Treatment related gross necropsy findings: lacrimation, nasal discharge, polyuria, salivation, discoloration of the contents of the stomach, stomach distended with gaz, discoloration of lungs and variations thereof.
Other findings:
no
Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute inhalation LC-50 with 95% confidence limits afor actual thiram technical when administered undiluted as an aerosol to abino rats were calculated: the males LC50 was higher than 5.04 mg/L, the female LC50 was equal to 3.46 [2.96 -4.03] mg/L , and the combined LC50 was equal to 4.42 [3.09 -6.32] mg/L.
Executive summary:

An acute inhalation toxicity study was conducted on male and female albino rats using test material thiram technical.

The animals were exposed for 4 hours to an aerosol generated from the undiluted test material (fine powder). Five males and five females were exposed to the following levels: 2.06, 3.36 and 5.04 mg/L. One male exposed to 2.06 mg/L died during the study. One male and two females exposed to 3.36 mg/L doed during the study. One male and five females exposed to 5.04 mg/L died during the study. The acute inhalation LC-50 with 95% confidence limits afor actual thiram technical when administered undiluted as an aerosol to abino rats were calculated: the males LC50 was higher than 5.04 mg/L, the female LC50 was equal to 3.46 [2.96 -4.03] mg/L , and the combined LC50 was equal to 4.42 [3.09 -6.32] mg/L. Prominent in-life observations included activity decrease, constricted pupils, gasping, nasal discharge, piloerection, polyurea, ptosis and salivation. Moreover a decrease of body weight was observed in treated animals. Treatment related gross necropsy findings: lacrimation, nasal discharge, polyuria, salivation, discoloration of the contents of the stomach, stomach distended with gaz, discoloration of lungs and variations thereof.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
4 420 mg/m³
Quality of whole database:
Holbert's study is a reliable study with a klimisch score of 1.

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:
30 May 2012 - 05 July 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
no clinical signs were recorded for animal Y23853 on day 4 by mistake. This deviation was considered not to have compromised the validity or integrity of the study
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
yes
Remarks:
no clinical signs were recorded for animal Y23853 on day 4 by mistake. This deviation was considered not to have compromised the validity or integrity of the study
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: approximately 8 weeks old on the day of treatment .
- Mean body weight at study initiation: the males had a mean body weight of 369 g (range: 358 g to 375 g) and the females had a mean body weight of 234 g (range: 224 g to 254 g).
- Fasting period before study: yes, during the night before treatment.
- Housing: the animals were housed by five from the same sex and group in 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: the animals were acclimated to the study conditions for a period of 6 or 9 days before treatment.

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.

IN-LIFE DATES: ---- to ----
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

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Constant volume: no
- For solids, paste formed: no
Duration of exposure:
24h
Doses:
2000 mg/kg.
No. of animals per sex per dose:
5 animals/sex per group
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:
LD0
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No unscheduled deaths occurred during the study.
Clinical signs:
No clinical signs indicative of systemic toxicity were observed in any animals.
A yellow discoloration was observed at application site of all animals between days 2 and 4.
Erythema and scabs were noted in 2/5 females between days 5 and 14. Scabs were also observed in 1/5 males on days 3 and 4.
Body weight:
Lower mean body weight gain was noted between day 1 and day 8 in females. This was mainly related to one female with lower body weight with 5 g, vs. 36 ± 12 g in controls).
Lower mean body weight gain was noted also observed in males between day 1 and day 8. This was mainly related to body weight loss of 1% (corresponding of -3 g and -5 g from day 1) noted respectively in two males during the first week of the observation period. Their body weight gains returned to normal thereafter.
Gross pathology:
Enlarged spleen was seen in one male treated at 2000 mg/kg. In the absence of similar change in females treated at the same dose-level, this observation in a single male was considered to be unlikely test item related.
Other findings:
no
Interpretation of results:
GHS criteria not met
Conclusions:
The dermal LD50 of the test item was higher than 2000 mg/kg in rats.
Therefore, the test item is not classified as toxic by dermal route according to the criteria of CLP Regulation.
Executive summary:

The test item was applied in its original form to the skin of five females and then five males Sprague-Dawley rats at the dose-level of 2000 mg/kg. The application site was covered by a semi-occlusive dressing for 24 hours.

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 day 1 and then on days 8 and 15.

On completion of the observation period, the animals were sacrificed and then submitted for a macroscopicpost-mortemexamination.Macroscopic lesions were preservedin buffered formalinthendestroyed at the finalization of the study reportas no microscopic examination was performed.

 

No unscheduled deaths occurred during the study.

No clinical signs indicative of systemic toxicity were observed in any animals.

A yellow discoloration was observed at application site of all animals between days 2 and 4. Erythema and scabs were noted in 2/5 females between days 5 and 14. Scabs were also observed in 1/5 males on days 3 and 4.

When compared to CiToxLAB historical control data, a lower body weight gain was noted in 1/5 females (5 g, vs. 36 ± 12 g in control data base) between day 1 and day 8. In addition, a body weight loss of 1% was noted respectively in 2/5 males during the first week of observation period. Their body weight gains returned to normal thereafter.

No test item-related changes were seen at necropsy.

 

The dermal LD50of the test item,Tetramethylthiurammonosulfide, was higher than 2000 mg/kg in rats.

Therefore, the test item is not classified as toxic by dermal route according to the criteria of CLP Regulation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
The silvano's study is a reliable study with a klimisch score of 1.

Additional information

Oral acute studies

In the key study (Löser 1980), three groups of 10 male and 10 female rats were dosed at 100, 500, 1000, 2500 and 3100 mg/kg. The animals were observed for mortality, body weights and clinical signs though day 14.

No mortalities was observed at 100 mg/kg, 7 -8 animals died at 500, 1000 and 2500 mg/kg bw and all the animals died at 3100 mg/kg. Clinical signs at doses 500 -3100 mg/kg included narcosis, diarrhea, hair loss and shaggy coat ; a a decrease of bodyweight was observed. The dose of 100 mg/kg was asymptomatic.

According to this study, the approximate acute oral rat LD50 is 690 mg/kg for male and female rats.

In the first supporting study (Birch 1973), twenty-five albino rats were ramdomly divided into five groups consisting of five animals, both male and female. The test animals were administered a single dose of the test substance in a 25% suspension in corn oil via oral gavage. Dosages levels were 794, 100, 1260, 1580 and 2000 mg/kg. Initial signs of intoxication were reduced appetite and activity (one to four days in survivors), followed by increasing weakness, collapse and death. One female died at 794 mg/kg (1/5 rats), 2 females died at 1000 mg/kg (2/5 rats) and at 1260 mg/kg (2/5 rats), 3 animals (1 male and 2 females) died at 1580 mg/kg, and all the animals (5/5) died at 2000 mg/kg. Time of mortality was 1 -7 days, with most deaths occurring within four days. Gross autopsy findings on the decedents showed lung hyperemia, slight liver discoloration and gastrointestinal inflammation. Following a 10-day recovery period, the survivors were sacrificed and autopsied. All viscera appeared normal in these animals.According to these study, the approximate oral LD50 was 1320 mg/kg bw in rats.

 

In the Sumitomo study (1977), the test material was suspended in corn oil and orally administered to a group of 10 males and 10 females in one single dose of 100 to 2860 mg/kg. After treatment the animals were observed for signs of intoxication during a 14 -day period, after which autopsies were carried out on the survivors. No mortality was observed at 100, 250 and 385 mg/kg in males and females. Deaths occurred from 500 mg/kg. No toxic symptoms were seen at 100 mg/kg. At 250 and 385 mg/kg: decrease of spontaneous motor activity, piloerection and irregular respiration were developed at 3 and 4 hours after administration and disappeared in 3 -5 days. At 500 mg/kg and above: In addition to the above toxic symptoms, dyspnea, diarrhea and hind limb ataxia were observed. Most death of animals was found 1-5 days after administration. Toxic symptoms in surviving animals disappeared in 7-10 days. No remarkable changes were found in any animals of each group.According to this study, the approximate acute oral rat LD50 is 1090 mg/kg for males and 733 mg/kg for females.

 

In the Latven study (1977), Groups of 5 male rats were dosed at 442, 625, 884, 1250, 1768 and 2500 mg/kg. The animals were observed for mortality, body weights and clinical signs though day 10. No mortality was observed at 442 mg/kg. Two, three and four animals died at 625, 884 and 1250 mg/kg respectively. All the animals died at 1768 and 2500 mg/kg. General depression and continuous losses in body weight were observed until death. Survivors showed daily losses in bodyweight for 3 to 5 days, these were recovered 7 to 10 days after treatment. Autopsies revealed a possible renal pathology.According to this study, the approximate acute oral LD50 of TMTM is 801 mg/kg for male rats.

 

In the Alani’s publication (1982), TMTM was given by gavage in an aqueous solution containing 0.5% (v/v) Tween 80 as solubilising agent. Groups of 10 -20 mice were treated with doses between 500 and 2500 mg/kg. Mortality was observed at all doses. Death occurred at different time intervals during 24 hours after administration of TMTM. Intoxication of mice became manifest by tachypnea, tachycardia, and miosis and, more rarely, by a convulsive tendency and paralysis of the extremities.The acute LD50 value after oral administration of TMTM to adult female mice was found to be 818 (583 -995) mg/kg.

Inhalation acute study (read-across)

An acute inhalation toxicity study was conducted on male and female albino rats using test material thiram technical.

The animals were exposed for 4 hours to an aerosol generated from the undiluted test material (fine powder). Five males and five females were exposed to the following levels: 2.06, 3.36 and 5.04 mg/L. One male exposed to 2.06 mg/L died during the study. One male and two females exposed to 3.36 mg/L died during the study. One male and five females exposed to 5.04 mg/L died during the study. The acute inhalation LC-50 with 95% confidence limits for actual thiram technical when administered undiluted as an aerosol to albino rats were calculated: the males LC50 was higher than 5.04 mg/L, the female LC50 was equal to 3.46 [2.96 -4.03] mg/L , and the combined LC50 was equal to 4.42 [3.09 -6.32] mg/L. Prominent in-life observations included activity decrease, constricted pupils, gasping, nasal discharge, piloerection, polyurea, ptosis and salivation. Moreover a decrease of body weight was observed in treated animals. Treatment related gross necropsy findings: lacrimation, nasal discharge, polyuria, salivation, discoloration of the contents of the stomach, stomach distended with gaz, discoloration of lungs and variations thereof.

Dermal acute studies

In the key study (Silvano 2012), the test item was applied in its original form to the skin of five females and then five males Sprague-Dawley rats at the dose-level of 2000 mg/kg. The application site was covered by a semi-occlusive dressing for 24 hours. No unscheduled deaths occurred during the study. No clinical signs indicative of systemic toxicity were observed in any animals. A yellow discoloration was observed at application site of all animals between days 2 and 4. Erythema and scabs were noted in 2/5 females between days 5 and 14. Scabs were also observed in 1/5 males on days 3 and 4. When compared to historical control data, a lower body weight gain was noted in 1/5 females (5 g,vs.36 ± 12 g in control data base) between day 1 and day 8. In addition, a body weight loss of 1% was noted respectively in 2/5 males during the first week of observation period. Their body weight gains returned to normal thereafter. No test item-related changes were seen at necropsy. The dermal LD50 of the test item,TMTM, was higher than 2000 mg/kg in rats.

In the supporting study (Latven 1977), group of 6 rabbits were dosed with a single dose of 2000 mg/kg. Individual doses were applied to the pre-moistened fur-clipped skin of the drunk, covered with a two-ply layer of wet gauze, and overcovered with an impervious sleeve. These dressings were removed 24 hours later and the animals were observed for seven days. No mortalities was observed. All of the animals remained asymptomatic and gained body weight during the observation period. According to this study, the acute dermal LD50 is higher than 2000 mg/kg in rabbits.

Justification for classification or non-classification

 Mandatory classification / Regulation (EC) No 1272/2008


Oral acute Tox. 4, H 302(Harmful if swallowed). Justification: LD50(oral) is between 300 and 2000 mg/kg bw.


  


 Self classification / Regulation (EC) No 1272/2008:


Oral acute Tox. 4, H 302(Harmful if swallowed). Justification: LD50 (oral) is between 300 and 2000 mg/kg bw.


Inhalation acute Tox. 4, H 332 (Harmful if inhaled). Justification: LC50 (aerosol) is between 1 and 5 mg/L.


No classification is required by dermal route because the dermal LD50 of TMTM is higher than 2000 mg/kg.