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Administrative data

Description of key information

There are three studies on acute oral toxicity of thiourea available. 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:
other: valid without restriction; GLP guideline study
Qualifier:
according to
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:
other: Crl:CD(SD)
Sex:
female
Details on test animals 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
Remarks:
test substance is soluble in 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 (if applicable)
- 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
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:
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, closed eyes)
Body weight:
All surviving animals gained weight in both weeks p.a.
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

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:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
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:
good

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:
other: comparable to guideline study with acceptable restriction
Qualifier:
equivalent or similar to
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 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 (if applicable): Water
- Concentration of test material in vehicle (if applicable): 10 % solution
- Justification of choice of vehicle: Substance was provided by the sponsor as a 10 % solution in water

TEST ATMOSPHERE (if not tabulated)
- 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
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

01)

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:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
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
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:
other: valid with restriction; comparable to guideline study with acceptable restrictions
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
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 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 (if done): The test substance was removed from the skin with water
- Time after start of exposure: 24 h

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

VEHICLE
- Amount(s) applied (volume or weight with unit): 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
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 800 mg/kg bw
Based on:
test mat.
Mortality:
No mortality
Clinical signs:
Slight erythema of the skin of rabbits treated with 2000 or 2800 mg/kg
Body weight:
Comparable to control group
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:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
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

According Regulation (EC) No 1272/2008 LD50-doses of more than 2000 mg/kg are not considered to indicate oral or dermal acute toxicity.

Acute toxicity via inhalation could not be established as the LC50 was above the technical attainable concentration in all available studies.

Thiourea is currently classified as Acute Tox. 4 via the oral route (harmonized classification under CLP), based on outdated study result.