thiourea; thiocarbamide

Endpoint summary

Description of key information

There are three studies available on acute oral toxicity of thiourea.

 

These comprise a study according OECD 423 (Seibersdorf, 2010), a study similar to OECD 401 (TNO, 1975) and a study by Korte and Greim (1981).
The acute dermal toxicity was assessed in two studies. One study was conducted by TNO (1978), the other by Korte and Greim (1981).
The acute inhalation toxicity of thiourea was assessed in three studies at maximum attainable concentrations: Two studies by TNO (1977 and 1979) and a study by Korte and Greim (1981).
In addition the intraperitoneal route was assessed by Giri (1979).

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:

2009-11-10 to 2009-12-09

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland GmbH, D-97633 Sulzfeld
- Age at study initiation: Approx. 8 weeks at the time of administration
- Weight at study initiation: Mean 189.7 to 194.0 g
- Fasting period before study: Overnight
- Housing: Individual
- Diet: Ad libitum except fasting period
- Water: Ad libitum
- Acclimation period: At least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.0 °C
- Humidity (%): 30-70 %
- Air changes (per hr): 12 per hour
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 300 mg and 2000 mg per kg body weight
- Amount of vehicle (if gavage): 20 mL per kg body weight
- Justification for choice of vehicle: Thiourea is soluble in water

CLASS METHOD
- Rationale for the selection of the starting dose: No prior information on the toxicity of the test substance was available; starting dose 300 mg/kg body weight was chosen.

Doses:

300 mg per kg bw, 2000 mg per kg bw

No. of animals per sex per dose:

6

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 0-0.5, 0.5-1, 1-2, 2-4 and 4-6 hours after administration and at least once a day for a total of 2 weeks
- Necropsy of survivors performed: Ces
- Other examinations performed: Clinical signs, body weight

Statistics:

None

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 - < 2 500 mg/kg bw

Based on:

test mat.

Mortality:

1/3 animals died 1 day after the administration (300 mg/kg bw)
1/3 animals died 1 day after the administration (2000 mg/kg bw)

Clinical signs:

other: All animals were affected; earliest onset shortly after the administration, lasting until death or up to a maximum of 2 d p.a. in the surviving animals: - Retention of faeces - Signs of reduced well-being (sedation, apathy, piloerection, hunched posture,

Gross pathology:

Abnormal findings in deceased animals: Hydrothorax

Other findings:

None

Table 1: Synopsis of results

Dose mg/kg	Step No.	Animal No.	Numbers of animals
			exposed	affected	deceased
300	1	11, 12, 13	3	3	0
300	2	14, 15, 16	3	3	1
2000	3	21, 22, 23	3	3	1
2000	4	24, 25, 26	3	3	0

 

Table 2: Time of death

Dose mg/kg	Step No.	Animal No.	Time of death (p.a.)
300	1	11, 12, 13	All survived
300	2	14, 15, 16	No. 16 died at day 1
2000	3	21, 22, 23	No. 21 died at day 1
2000	4	24, 25, 26	All survived

 

 

Table 3: Body weights and body weight gain

Dose mg/kg	Animal No.	Body weight (g)			Body weight gain (g)
		Before administration	7 days p.a.	14 days p.a.	death	0-7 days p.a.	7-14 days p.a.
300 (1)	11	189	205	213	-	19	8
	12	190	219	227	-	29	8
	13	193	217	218	-	24	1
	Mean SD	189.7 3.5	213.7 7.6	219.3 7.1	-	24 5	5.7 4
300 (2)	14	199	226	231	-	27	5
	15	179	195	209	-	16	14
	16	191	a	a	188	a	a
	Mean SD	189.7 10.1	210.5 21.9	220 15.6	-	21.5 7.8	9.5 6.4
2000 (3)	21	192	a	a	195	a	a
	22	195	226	229	-	31	3
	23	195	226	237	-	31	11
	Mean SD	194.0 1.7	226 0	233 5.7	-	31 0	7 5.7
2000 (4)	24	183	212	242	-	29	30
	25	202	236	251	-	34	15
	26	185	219	237	-	34	18
	Mean SD	190.0 10.4	222.3 12.3	243.3 7.1	-	32.3 2.9	21 7.9

1. a)animal died spontaneously

 

Due to unspecific symptoms in life no specific mode of action of the test substance could be identified. Circulatory failure may have been the cause of death.

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 of thiourea in rats was estimated to be between 2000 and 2500 mg/kg body weight.

Executive summary:

In an acute oral toxicity study, groups (12 females) of Crl:CD(SD) rats, (approx. 8 weeks, mean weight 189.7 to 194 g) were given a single oral dose of thiourea in deionised water of 300 and 2000 mg/kg bw. Animals were then observed for 14 days.

Oral LD₅₀ (females) = 2000-2500 mg/kg bw.

Thiourea is practically non-toxic.

All surviving animals gained body weight in both weeks p.a. In each case (300 and 2000 mg/kg bw dose) one of three animals died at the first day p.a. All animals were affected. The findings were retention of faeces and signs of reduced well-being, like sedation, apathy, piloerection, hunched posture or closed eyes. Abnormal findings (hydrothorax) were present only in deceased animals.

This acute oral study is considered to be reliable. It does satisfy the guideline requirement for an acute oral study OECD 423 in the rat.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

reliable study, Klimisch 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:

1979-10-17 to 1979-10-31

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: SPF-reared (Cpb; WU, Wistar random)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Central insitute for the breeding of laboratory animals TNO, Zeist, The Netherlands
- Age at study initiation: No data
- Weight at study initiation: females mean weight: 142 g; males mean weight: 175 g
- Fasting period before study: No data
- Housing: Groupwise (5 per cage)
- Diet: Ad libitum (during exposure no access to food)
- Water: Ad libitum(during exposure no access to water)
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 1°C
- Humidity (%): 50-60%

Route of administration:

other: dispersion of 10 % thiourea to a fine mist

Type of inhalation exposure:

whole body

Vehicle:

not specified

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure chamber volume: 1.5 m³
- Method of holding animals in test chamber: Individually in wire-screen cages to prevent crowding and minimize filtration of the inspired air by animals fur
- Source and rate of air: Airflow rate of nebulizer: 0.9 m³/h; the mist was passed through the exposure chamber with a total airflow of 1.1 m³/h
- System of generating particulates/aerosols: Stainless steel/glass aerodynamic nozzle nebulizer
- Method of particle size determination: Particle Size determination with cascade Impactor (aerosol diameter < 3.3 µm)

TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetrically by passing a measured quantity of the test atmosphere through a Cambridge glass fibre filter;
- Samples taken from breathing zone: No

VEHICLE
- Composition of vehicle: Water
- Concentration of test material in vehicle: 10 % solution
- Justification of choice of vehicle: Substance was provided by the sponsor as a 10 % solution in water

TEST ATMOSPHERE
- Particle size distribution: 100 % of particle counts have a diameter of less than 3.3 µm
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): No data

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetrically; Cambridge glass fibre filter

Duration of exposure:

ca. 4 h

Concentrations:

10 % solution

No. of animals per sex per dose:

5 males and 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Frequently (body weight determination at day 0, 1, 2, 4, 7 and 14)
- Necropsy of survivors performed: No
- Other examinations performed: Clinical signs, body weight

Statistics:

No statistics

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 195 mg/m³ air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: highest attainable concentration

Mortality:

One male died on the first day of the observation period.

Clinical signs:

other: During the first 30 min restlessness; thereafter motionless, eyes half-closed; after exposure the rats were slow in their movement, but otherwise looked normal.

Body weight:

During first day both males and females lost body weight; thereafter body weight gain again.

Gross pathology:

None

Other findings:

None

Table 1: Individual and mean body weights (g) of rats exposed to an aerosol of a 10 % solution of “Thioharnstoff” in rats

Animal code earmarks	0^1)	1	2	4	7	14
Males
Z	176	-	-	-	-	-
R1	176	167	171	183	190	226
R2	166	156	163	172	182	208
L1	180	173	176	186	196	218
L2	176	169	172	182	198	232
Mean body weight	175	166	171	181	192	221
Females
Z	140	130	129	--^2)	140	149
R1	148	141	143	--	152	163
R2	130	126	130	--	139	152
L1	142	133	132	--	144	156
L2	149	143	143	--	151	161
Mean body weight	142	135	135	--	145	156

1)     Day 0: day of exposure

2)     data omitted because unreliable

 

Interpretation of results:

GHS criteria not met

Conclusions:

The 4 h LC50 of thiourea in rats was higher than 195 mg/m³ air. Higher concentrations could not be attained.

Executive summary:

In an acute inhalation toxicity study one dose group (5 males, 5 females) of SPF-reared rats (Cpb; WU, Wistar random) were exposed (whole body) to a fine mist of 10 % thiourea in water for 4 hours. Animals were then observed for 14 days.

One male died on the first day of the observation period. During the first 30 min restlessness was observed. Thereafter the rats were motionless and their eyes were half-closed. After the exposure the rats were slow in their movement, but otherwise looked normal.

The LC₅₀ was determined to be higher than 195 mg/m³ (maximum attainable concentration).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

195 mg/m³ air

Quality of whole database:

consistent; LC50 above maximum attainable concentration; LC10 at 195 mg/m3

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:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data
- Age at study initiation: Young adults
- Weight at study initiation: 2.5 to 3.08 kg
- Fasting period before study: No
- Housing: Individually
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 °C

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: 10 % of total body area
- % coverage: 10 %
- Type of wrap if used: Thin layer of cellulose sheet wrapped in polyethylene foil

REMOVAL OF TEST SUBSTANCE
- Washing: The test substance was removed from the skin with water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount applied: 9 mL/kg body weight
- Constant volume or concentration used: Yes (constant volume: 9 mL/kg body weight)

VEHICLE
- Amount applied: The test substance was applied as solution in water (9 mL/kg)

Duration of exposure:

24 h

Doses:

0, 1.0, 2.0 and 2.8 g/kg body weight

No. of animals per sex per dose:

2 animals per sex and dose (altogether 8 males and 8 females)

Control animals:

yes, concurrent vehicle

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: At day 0, and at the end of week 1 and 2
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical signs, microscopic pathology (treated skin, liver, heart, kidneys), food consumption, water intake, body weights, haematological data, autopsy, histological examination of fixed organs (heart, liver, kidney, spleen).

Statistics:

none

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 800 mg/kg bw

Based on:

test mat.

Mortality:

No mortality

Clinical signs:

other: Slight erythema of the skin of rabbits treated with 2000 or 2800 mg/kg

Gross pathology:

No gross changes that could be related to the treating

Other findings:

None

Table 1: Individual body weights of male and female rabbits after a single dermal application of thiourea

Animal number and sex	Dose g/kg	Condition of skin	Body weights (in kg)
			At day 0	At the end of week 1	At the end of week 2
6336 M	0	Abraded	3.08	3.00	3.24
6338 M	0	Intact	2.80	2.83	2.93
6348 F	0	Abraded	2.83	2.82	3.00
6352 F	0	Intact	2.50	2.57	2.84
6337 M	1	Abraded	3.07	2.96	3.24
6343 M	1	Intact	2.84	2.85	2.97
6346 F	1	Abraded	2.6	2.35	2.50
6353 F	1	Intact	2.78	2.55	2.90
6340 M	2	Abraded	2.81	2.73	2.88
6341 M	2	Intact	3.05	3.04	3.12
6349 F	2	Abraded	2.66	2.68	2.94
6351 F	2	Intact	2.75	2.35	2.78
6334 M	2.8	Abraded	2.93	2.94	3.04
6339 M	2.8	Intact	2.88	2.86	3.00
6345 F	2.8	Abraded	2.70	2.60	2.91
6350 F	2.8	Intact	2.70	2.43	2.70

 

Interpretation of results:

GHS criteria not met

Conclusions:

Thiourea is practically non-toxic in rabbits, when applied dermally at a single dose of up to 2.800 mg/kg.

Executive summary:

In an acute dermal toxicity study, groups of young adult New Zealand White albino rabbits (8/sex) were dermally exposed to thiourea in water for 24 hours, covering 10 % of body surface area at doses of 0, 1000, 2000 and 2800 mg/kg bw. Animals were subsequently observed for 14 days. No mortality occured at the highest dose of 2800 mg/kg bw.

Thiourea is practically non-toxic when applied in a single dose to the skin of rabbits.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 800 mg/kg bw

Quality of whole database:

consistent

Additional information

The oral LD50 value of thiourea was determined in three studies in rats.

The key study reports the LD50 (females) to be between 2000 and 2500 mg/kg. A study by TNO (1975) reports an LD50 of 1750 mg/kg bw/d. As there was no dose-response-relationship the study is not considered to be reliable.

The low oral toxicity is supported by the Korte and Greim (1981) study, reporting an LD50 of 6300 mg/kg bw for females and 6200 mg/kg bw for males. Thiourea is therefore considered to be not acutely toxic via the oral route according to the CLP rules.

In two dermal toxicity studies LD50 > 2800 mg/kg bw (TNO 1975) and > 6810 mg/kg bw (Korte and Greim, 1981) were reported in rabbits. Therefore, thiourea is considered to be practically non-toxic when applied in a single dose to the skin.

Studies on acute toxicity via inhalation are limited in that the tests were conducted with the maximum attainable concentration that is below CLP classification criteria. In a study by TNO (1979) the LC50 was determined to be higher than 195 mg/m³ (maximum attainable concentration). Similarly, the LC50 was above 170 mg/m³ in a second study (TNO 1977). Based on these results classification is not warranted.

Justification for selection of acute toxicity – oral endpoint
most recent OECD 423/GLP study

Justification for selection of acute toxicity – inhalation endpoint
reliable study; supported by TNO 1977 and Korte&Greim 1981

Justification for selection of acute toxicity – dermal endpoint
key study; supported by Korte & Greim 1981

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008.

 

Oral Toxicity:

Based on the results of an outdated acute oral toxicity study Thiourea is currently classified as Acute Tox. 4 via the oral route (harmonized classification under CLP, according to the Regulation (EC) No 1272/2008 (CLP), as amended for seventeenth time in Regulation (EU) No 2021/849).

 

Dermal Toxicity:

Based on the results of the acute toxicity dermal study on Thiourea, LD50-doses of more than 2000 mg/kg are not considered to indicate dermal acute toxicity. Therefore Thiourea is not classified as for dermal acute toxicity according to the Regulation (EC) No 1272/2008 (CLP), as amended for seventeenth time in Regulation (EU) No 2021/849.

 

Inhalation Toxicity:

As the LC50 was above the technical attainable concentration in all available studies, Thiourea is not classified for acute inhalation toxicity according to the Regulation (EC) No 1272/2008 (CLP), as amended for seventeenth time in Regulation (EU) No 2021/849.