Thiram

Acute Toxicity: oral

Administrative data

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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1985

Report date:

1985

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

not specified

Deviations:

not specified

Test guideline 2

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

Test material

Test material information

Constituent 1

Reference substance name:

Thiram

EC Number:

205-286-2

EC Name:

Thiram

Cas Number:

137-26-8

Molecular formula:

C6H12N2S4

IUPAC Name:

thiram

Test animals

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

Administration / exposure

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.

Results and discussion

Effect levels

Effect levels 1

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

Effect levels 2

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

1 800 mg/kg bw

Remarks on result:

other: Maximum likelihood according to Finney

Effect levels 3

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".

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.

Applicant's summary and conclusion

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.