Thiram

Endpoint summary

Description of key information

Oral

key (EPA OPP 81 -1) rat: LD50 = 1800 mg/kg bw (females) and 3700 mg/kg bw (males)

 

Inhalation

key (EPA OPP 81-3), rat: LC50 = >5.04 mg/L (males) and 3.46 mg/L (females)

 

Dermal

key (EPA OPP 81-2), rabbit: LD50 > 2000 mg/kg bw (males and females)

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:

5 Aug - 2 Oct 1985

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

not specified

Deviations:

not specified

Qualifier:

according to guideline

Guideline:

EPA OPP 81-1 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

The room temperature was on various occasions, for a total of 18 hours, below the protocolled 19°C. This deviation was not considered to has affected the outcome of the study.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Central Institute for the Breeding of Laboratory Animals TNO (CPB), Zeist, The Netherlands
- Age at study initiation: 11-14 weeks (male and female)
- Weight at study initiation: 243-359 g (male), 152-186 g (female)
- Fasting period before study: overnight before dosing till approximately 4 hours after administration of the test substance
- Housing: individually housed in Macrolon cages
- Diet: standard laboratory diet (RMH-B, pellet diameter 10 mm, Hope Farms, Woerden, The Netherlands), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 3-7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-23
- Humidity (%): 50-85
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on oral exposure:

VEHICLE
- Amount of vehicle: 10 mL/kg bw

Doses:

560, 740, 1300, 2400, 4200 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 22 days
- Frequency of observations and weighing: daily for morbitidy, death and clinical signs (except for the day of dosing, were animals were observed 2, 6 and 7.5 h after dosing), animals were weighed on Day 0, 7, 14 and 21
- Necropsy of survivors performed: yes
- Histopathology: At the end of the observation period all surviving animals were scarified and subjected to gross necropsy. Found dead animals were weighed and subjected to gross necropsy.

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

3 700 mg/kg bw

95% CL:

2.3 - 19.8

Remarks on result:

other: Maximum likelihood according to Finney

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

1 800 mg/kg bw

Remarks on result:

other: Maximum likelihood according to Finney

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 600 mg/kg bw

Remarks on result:

other: Maximum likelihood according to Finney

Mortality:

- 560 mg/kg bw: 0/5 males, 1/5 females (Day 1)
- 740 mg/kg bw: 0/5 males, 1/5 females (Day 2)
- 1300 mg/kg bw: 0/5 males, 0/5 females
- 2400 mg/kg bw: 0/5 males, 3/5 females (Day 9, 13 and 22)
- 4200 mg/kg bw: 4/5 males (Day 5, 6, 6 and 7), 5/5 females (Day 3, 7, 8 and 9)

Summarized results can be found in Attachment 1 in the attached background material.

Clinical signs:

bodyweight loss

diarrhoea

lethargy (hypoactivity)

salivation

Body weight:

greater than 10% body weight loss

Remarks:

Please refer to "Any other information on results incl. tables".

Gross pathology:

Please refer to "Any other information on results incl. tables".

Clinical Signs:

- 560 mg/kg bw: Lethargy, (half)-closed eyes, moist eyes reduced respiration in males and females from 1 h to Day 2 post-dosing. In addition, ungroomed appearance (on Day 2) and reduced faecal excretion (on Day 5) was noted in 1/5 females.

- 740 mg/kg bw: Lethargy, (half)-closed eyes, moist eyes, reduced respiration in males and females from 1 h to Day 2 post-dosing. In addition, ungroomed appearance (Day 2, and 8), reduced faecal excretion (Days 4 - 7), and emaciation (Days 6 - 9) was noted in some females.

- 1300 mg/kg bw: Lethargy, (half)-closed eyes, moist eyes, head tremors in males and females from 1 to 6 h post-dosing. In addition, emaciation and pale skin colour was noted in 1/5 females (Day 8).

- 2400 mg/kg bw: Lethargy was noted in all animals of both sexes from 1.5 to 5.5 h after dosing. Males showed lethargy also from day 4 to 7 and Day 12-13. Females shoed lethargy from Day 4 - 13, and Day 18 - 20. Rats of both sexes had closed eyes, moist eyes or salivation within 5.5 h post-dosing. Other signs consisting of bloody eye and nose encrustration, diarrhoea were observed in single animals on some days. In several females bloody eye and nose encrustration, tremors, emaciation, reduced respiration, comatous, ungroomed appearance and reduced faecal excretion were noted throughout the study period.

- 4200 mg/kg bw: Lethargy was noted in all animals of both sexes from 2 to 6 h after dosing, and from Day 4 (females) or Day 6 (males) until death of animals. Other signs, which were observed during the study were emaciation, ungroomed appearance, reduced or absent faecal excretion, pale skin colour, bloody nose or eyes encrustration, laboured breathing in animals of both sexes. Males showed also diarrhoe and tremors, whereas females had closed eyes.

 

Summarized results can be found in Attachment 1 in the attached background material.

 

Body weight:

- 560 mg/kg bw: All male and female animals gained weighed during the observation period. In the post-administration period Day 0 – 7, a small weight loss was observed (mean: males -2.7%, females -3.0%), but all animals recovered afterwards. (final mean body weight gain over the observation period: males +18.7%, females +14.3%)

- 740 mg/kg bw: All male and female animals gained weighed during the observation period. In the post-administration period Day 0 – 7, a small weight loss was observed (mean: males -6.5%, females -10.7%), but all animals recovered afterwards (final mean body weight gain over the observation period: males +18.5%, females +16.5%)

- 1300 mg/kg bw: All male and female animals gained weighed during the observation period. In the post-administration period Day 0 – 7, weight loss was observed (mean: males -7.9%, females -5.2%), but all animals recovered afterwards (final mean body weight gain over the observation period: males +12.5%, females +16.6%).

- 2400 mg/kg bw: All male animals gained weighed during the observation period. In the post-administration period Day 0 – 7, weight loss was observed (mean -16.7%), but all animals recovered afterwards (final mean body weight gain over the observation period: +14.7%). Females showed weight loss during the Day 0 – 7 observation period (mean -18.6%), and a partial recovery afterwards (final mean body weight gain over the observation period:-6.3%).  

- 4200 mg/kg bw: Weight loss until deaths in all animals.

Summarized results can be found in Attachment 1 in the attached background material.

 

 

Pathology:

- 560 mg/kg bw: Autolysis of abdominal organs, yellow to white stomach content, and blood clots were observed in 1/5 females. In males no anomalies were observed.

- 740 mg/kg bw: Autolysis of abdominal organs, foamy white stomach content, blood clots in antral lumen were observed in one female. In males no anomalies

- 1300 mg/kg bw: No abnormalities in males and females were observed.

- 2400 mg/kg bw: Autolysis of abdominal organs, enlarged left adrenal, stomach erosive and containing small blood clots were observed in 1/5 females. In another female small spleen and ovaries, pale kidneys and intestine, no intestinal content, damaged stomach containing white granular substance. Histopathology evaluation of these lesions showed local pyelonephritis of kidney and focal erosion of the stomach. In males no anomalies

- 4200 mg/kg bw: In all males and females stomach findings consisting of white discoloration, petechiae, attachment to diaphragm, liver and spleen, white to grey discoloured thick fluid containing blood clots, erosion, speckled fibrosis, hyperemia, bloody stomach fluids, slightly thickened stomach, enlarged stomach, or bedding and mucous substance in stomach. Histopathological evaluation showed gastritis and local erosion, necrosis of the apical mucosa. 4/5 males and 2/5 females had duodenum findings consisting of perforations from 0.5 - 1 cm in length, necrotic areas, greenish mucous fluid with blood clots, or blood clots. Histopathology of one female revealed ulcus, and purulent inflammation in the distal end. Further findings in males were speckled liver lobes (local chronic inflammation with necrosis), testicular atropy (diffuse interstitial and tubular necrosis), and focal peripheral coagulation necrosis of liver, small focal haemorrhages of kidney cortex. In females kidney findings were vacuolisation of proximal tubular cells, increased protein presence in distal tubules and Bowmans space, cortical petechiae, dilatation of distal tubules, diffuse hypertrophy, glomerular necrosis. One female had also enlarged adrenals and a mucous substance in the intestine.

 

Summarized results can be found in Attachment 1 in the attached background material.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The study was conducted according to EPA-OPP 81-1 and under GLP conditions. Under the conditions of this study, the acute oral LD50 of thiram was 3700 mg/kg bw for males and 1800 mg/kg bw for female rats.
In accordance with Regulation (EC) No 1272/2008 the test susbtance should be classified as acute toxic category 4 and the hazard statement H302 “harmful if swallowed" should be assigned.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 800 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study, and is thus sufficient to fulfill the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

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:

8 Apr - 3 Sep 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

not specified

Deviations:

yes

Remarks:

methodological deficiencies (whole body exposure)

Qualifier:

according to guideline

Guideline:

EPA OPP 81-3 (Acute inhalation toxicity)

Version / remarks:

not specified

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Remarks:

HSD:(SD) BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Sprague-Dawley, Inc. Houston, Texas, USA
- Age at study initiation: young adult
- Weight at study initiation: 242 - 350 g (male), 178 - 219 g (female)
- Housing: 1 - 3 per cage, males seperate from females, suspended wire bottom stainless steel cages
- Die: Purina Formulab Chow # 5008 ad libitum
- Water: tap water ad libitum
- Acclimation period: at least one week

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

other: dried filtered air

Mass median aerodynamic diameter (MMAD):

>= 3.9 - <= 4.5 µm

Geometric standard deviation (GSD):

>= 1.5 - <= 3

Remark on MMAD/GSD:

Please refer to "Any other information on materials and methods incl. tables"

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel dynamic flow inhalation chamber
- Exposure chamber volume: 200 L
- Method of holding animals in test chamber: not reported
- System of generating particulates/aerosols: A stream of dry, filtered air was passed through either two (for thee 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 chamber.
- Method of particle size determination: Andersen cascade impactor
- Treatment of exhaust air: not reported
- Temperature, humidity, pressure in air chamber: Temperature: 8.9 - 20 °C, Humidity: 67 - 71%

TEST ATMOSPHERE
- Brief description of analytical method and equipment used: particle size was determined gravimetrically twice per h
- Samples taken from breathing zone: yes

Analytical verification of test atmosphere concentrations:

yes

Remarks:

The concentration of the test atmosphere was determined gravimetrically twice per h, the particle size determination was performed using an Andersen cascade impactor.

Duration of exposure:

4 h

Concentrations:

Nominal concentrations: 6.90, 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:

- Duration of observation period following administration: 14 days
- Frequency of observations: Observations for mortality and pharmacological and/or toxicological effects were made frequently on the day of exposure and at least once daily thereafter for 14 days on all animals. Due to chamber design, only four animals (two males, and two females) could be observed during the exposure period.
- Necropsy of survivors performed: yes
- Body weight: Individual body weights were recorded prior to dosing and on day 7 and 14 or at the time of discovery of death.

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: According to Litchfield and Wilcoxon

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: According to Litchfield and Wilcoxon

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: According to Litchfield and Wilcoxon

Mortality:

- 2.06 mg/L: 1/5 males (Day 1), 0/5 females
- 3.36 mg/L: 1/5 males (Day 2), 2/5 females (both Day 2)
- 5.04 mg/L: 1/5 males (Day 1), 5/5 females (Day 1, 2, 2 and 3)

Clinical signs:

other: Please refer to "Any other informations incl. tables"

Body weight:

Reduced body weight was observed at Day 7 in all dose groups. However, body weight of the surviving animals recovered till the end of the observation period.
Summarized results can be found in Attachment 1 in the attached background material.

Gross pathology:

The gross macroscopic examination of animals found dead between Day 1 and Day 3 after exposure revealed nasal discharge , salivation, lacrimation, polyuria, mottled red lungs and stomachs filled with gas and green-yellow paste. Except one male that showed mottled red lungs, no gross pathological abnormalities were noted in the animals sacrificed at the end of the post exposure observation period.

Summarized results can be found in Attachment 1 in the attached background material.

Clinical signs of toxicity included decreased activity, constricted pupils, gasping, lacrimation, nasal discharge, piloerection, polyuria, ptosis and salivation during the exposure period and were further observed thereafter until Day 7 (2.06 mg/mL), Day 9 (3.36 mg/mL) and Day 10 (5.04 mg/mL) after treatment. No abnormalities were detected in surviving animals during the post exposure observation period from Day 11 onwards.

Summarized results can be found in Attachment 1 in the attached background material.

 

Summarized results (tabulated):

Dose [mg/L]	Toxicological results*		Duration of clinical signs	Time of death	Mortality (%)
Males
2.06	1/5/5		1/2h - day 7	day 1	20
3.36	1/5/5		1/2h - day 9	day 2	20
5.04	1/5/5		1/2h - day 10	day 1	20
LC50 < 5.04 mg/L
Females
2.06	0/5/5		1/2h - day 7	day 1	0
3.36	2/5/5		1/2h - day 8	day 2	40
5.04	5/5/5		1/2h - day 3	day 1, 2, 3	100
LC50 = 3.464 mg/L
Combined
2.06	1/10/10	--		--	10
3.36	3/10/10	--		--	30
5.04	6/10/10	--		--	60
combined LC50 = 4.42 mg/L

 

* first number = number of dead animals, second number = number of animals with signs of toxicity, third number = number of animals used

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The study was a guideline-conform study and conducted under GLP conditions.
Under the conditions of this study, the acute inhalation LC50 for 4-hour exposure was determined at 4.42 mg/L (371 mg/kg bw) for males and females combined, 5.04 mg/L (424 mg/kg bw) for males and 3.46 mg/L (290 mg/kg bw) for females.
In accordance with Regulation (EC) No 1272/2008 the test substance should be classified as acute toxic category 4 and the hazard statement H332 “harmful if inhaled” should be assigned.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

3.46 mg/L air

Physical form:

inhalation: aerosol

Quality of whole database:

The available information comprises an adequate and reliable study, and is thus sufficient to fulfill the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

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:

14 - 28 May 1985

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

not specified

Deviations:

not specified

Qualifier:

according to guideline

Guideline:

EPA OPP 81-2 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

room temperature was twice increased for 12-14 hours above 20 2°C, due to a technical failure. This deviation was considered not to has affected the outcome of the study.

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Broekman Institute, Someren, the Netherlands
- Age at study initiation: 18 weeks (male and female)
- Weight at study initiation: 2.7 - 2.9 kg (male), 2.8 - 3.0 kg (female)
- Housing: induvidually housed in metal cages
- Diet: standard laboratory animal diet
- Water: tap water ad libitum
- Acclimation period: 13 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 27
- Humidity (%): 60 - 85
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: mid-dorsal area
- % coverage: 10 (body surface)
- Type of wrap: surgical gauze fixed to aluminum foil


REMOVAL OF TEST SUBSTANCE
- Washing: with a wet paper tissue
- Time after start of exposure: 24 h

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations for death or overt signs of toxicity were made during exposure and the following 14-day observation period. Body weights were noted prior to application of the test material on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes
- Erythema and Eschar Formation / Oedema Formation: After removal of the dressings and during the 14-day observation period.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

No mortality was observed.

Clinical signs:

other: No signs of systemic toxicity were noted throughout the study.

Body weight:

other body weight observations

Remarks:

Body weight development was not affected by the treatment.

Gross pathology:

No abnormalities were noted.

Other findings:

In the beginning of the study the treated skin surface generally showed slight erythema. Some areas revealed well-defined and moderate erythema. These signs were resolved one week after administration of the test susbtance.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study, the acute dermal LD50 of thiram was greater than 2000 mg/kg bw for both male and female rabbits.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study, and is thus sufficient to fulfill the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

To assess acute toxicity of the test substance, data after oral, inhalation and dermal exposure to the test substance are considered. All three studies were GLP-compliant, and performed in accordance with appropriate guidelines (EPA OPP 81-1, EPA OPP 81-3, EPA OPP 81-2)

 

Acute oral exposure to the test substance led to massive body weight loss, apathy, reduced locomotive activity, laboured breathing, ungroomed appearance, reduced faecal excretion, (half) closed and moist eyes, and tremors of the head. The acute oral LD50 of the test substance in the rat was 3700 mg/kg bw for male and 1800 mg/kg bw for female animals.

By dermal application the test substance showed only very low toxicity. No mortality was observed. The acute dermal LD50 of the test substance was > 2000 mg/kg bw in male and in female animals.

After whole body inhalation exposure to the test substance, observed toxicological effects consisted of activity decrease, constricted pupils, gasping, lacrimation, nasal discharge, piloerection, polyuria, ptosis, and salivation. The median lethal concentration (LC50) for the test substance in the rat was > 5.04 mg/L in male rats and 3.46 mg/L in female rats.

Justification for classification or non-classification

The available data on acute oral toxicity and acute inhalation toxicity meet the criteria for classification according to Regulation (EC) 1272/2008 and are therefore sufficient for classification of the test substance for acute oral toxicity category 4 (Acute Tox. 4, H302) and acute inhalation toxicity category 4 (Acute Tox. 4, H332). Based on the available data on acute dermal toxicity, no classification of the test substance for acute dermal toxicity is required.

The substance is listed in Annex VI of Regulation (EC) 1272/2008 (006-005-00-4). Harmonised classification in regard to minimum classification was adapted according to the available experimental data if appropriate.