Registration Dossier

Administrative data

Description of key information

Several repeated dose studies are available. Key study is Hartzell (1945/1942), a chronic (1y/3y) study in mice and rats. The effects level is supported by a 90day study in rats (Hazelton, 1987). In addition, data on short term exposure (Astwood, 1943; 1945), a 28-day dose range feeding study conducted by TNO (1979), a 28-day oral toxicity study by Korte and Greim (1981) and two sub-chronic drinking water studies conducted by TNO (1984a and b) are available. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, sufficient documentation and acceptable for assessment.
Reason / purpose:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
In a chronic toxicity study, thiourea was administered daily in drinking-water at concentrations of 1.72, 6.88, or 27.5 mg/kg body weight to mice for 2 years and to rats for the duration of their lifetimes or a maximum of 3 years.
GLP compliance:
not specified
Limit test:
no
Species:
other: rat and mice
Strain:
not specified
Sex:
not specified
Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
Administration of thiourea in drinking water at concentrations of In a chronic toxicity study, thiourea was administered daily in drinking-water at concentrations of 1.72, 6.88, or 27.5 mg/kg body weight to mice for 2 years and to rats for the duration of their lifetimes or a maximum of 3 years.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
Duration of exposure:
mice for 2 years
rats for the duration of their lifetimes or a maximum of 3 years
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
1.72 mg/kg bw/day
Basis:
nominal in water
Remarks:
Doses / Concentrations:
6.88 mg/kg bw/day
Basis:
nominal in water
Remarks:
Doses / Concentrations:
27.5 mg/kg bw/day
Basis:
nominal in water
No. of animals per sex per dose:
no data
Control animals:
not specified
Details on study design:
no data
Positive control:
no data
Observations and examinations performed and frequency:
no data
Sacrifice and pathology:
no data
Other examinations:
no data
Statistics:
no data
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
A reduction in body weight gain and an enlargement of the thyroid gland were observed only in the rats in the highest dose group, and no other changes were detected, either macroscopically or microscopically.
Dose descriptor:
LOAEL
Effect level:
27.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: reduction of body weight and enlargement of thyroid gland
Dose descriptor:
NOAEL
Effect level:
6.88 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Critical effects observed:
not specified
Conclusions:
In a chronic toxicity study a LOAEL of 27.5 mg/kg bw and a NOAEL of 6.88 mg/kg bw was established for thiourea in rats.
Executive summary:

In a chronic toxicity study, thiourea was administered daily in drinking-water at concentrations of 1.72, 6.88, or 27.5 mg/kg body weight to mice for 2 years and to rats for the duration of their lifetimes or a maximum of 3 years. A reduction in body weight gain and an enlargement of the thyroid gland were observed only in the rats in the highest dose group, and no other changes were detected, either macroscopically or microscopically. A LOAEL of 27.5 mg/kg body weight per day (reduction of body weight and enlargement of thyroid gland) and a no-observed-adverse-effect level (NOAEL) of 6.88 mg/kg body weight per day for rats was established. The results of the publication by Hartzell (1945) are also cited in the "Concise International Chemical Assessment Document 49" (WHO, 2003).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
6.88 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In a chronic toxicity study, thiourea was administered in drinking-water at concentrations of 1.72, 6.88, or 27.5 mg/kg/d to mice for 2 years and to rats for the duration of their lifetimes or a maximum of 3 years. A reduction in body weight gain and an enlargement of the thyroid gland were observed in the highest dose group. No other changes were reported, either macroscopically or microscopically (Hartzell, 1942, 1945; WHO, 2003).Thus, a NOAEL of 6.88 mg/kg bw/day was concluded. This result was supported by a subchronic (90d) drinking water study (Oserhof/Hazelton, 1987). Thiourea was administered to 10 Sprague-Dawley rats/sex/dose at 0, 0.02 ppm, 0.1 ppm, 0.5 ppm, and to 20 rats/sex/dose at 2.5 ppm. Nine males and 10 females of the 2.5 ppm group served as recovery group over 4 weeks. A full complement of qualitative and quantitative parameters was evaluated after 7 and 13 weeks. Animals were observed for mortality and moribundity and for overt signs of toxicity. Detailed physical examinations and individual body weight and food consumption measurements were performed. Clinical pathology parameters (haematology, clinical chemistry, urinalysis, triiodothyronine [T3], T4, and TSH levels in blood) were evaluated. There was no evidence of substance-related clinical or histopathological effects at levels up to 2.5 ppm of thiourea. Thus, the NOAEL in this study is considered to be at least 2.5 ppm, or approximately 1.73 mg/kg bw/d for males, and 2.65 mg/kg b.w./d for females. A LOAEL was not determined.

In a 28d dose range finding study groups of 10 albino rats/sex/dose were fed stock diet supplemented with 0, 300, 1000 or 3000 ppm thiourea (Beek/TNO 1979). After 4 weeks five rats/sex/dose were killed for interim observations of haematology, thyroid function, organ weights and histopathology. The remaining rats were killed and examined after 8 weeks. Growth, food intake, and food efficiency were decreased in all dose groups. Haemoglobin levels and packed cell volume were decreased in males and females of all dose groups after 4 weeks and in males of the two higher dose groups after 8 weeks. The relative weight of the liver was increased at all dose levels both after 4 and 8 weeks. The relative weight of the thyroid was increased only at the two high dose levels both after 4 and 8 weeks. In the mid- and low-dose group the T3-uptake and T4-concentration were generally somehow lower than in controls, especially in males. No relevant changes were seen upon gross examination. Microscopically, treatment-related changes occurred in the thyroid of rats in the mid­ and high-dose group and in the liver of rats in all dose groups. It was concluded that the LOAEL in the present study was 300 mg/kg diet, which is equivalent to 30 mg/kg bw/d. A NOAEL has not been determined.

In two subsequent 90 day studies thiourea was administered to 10 Wistar rats/sex/dose at concentrations of 0, 10, 25 and 250 ppm (Lina/TNO 1984(a)), and 10 female rats/dose at 0, 0.02, 0.1, 0.5, 2.5 ppm (Lina/TNO, 1984 (b)), respectively, in drinking water. Growth reduction, a decrease in the number of neutrophilic granulocytes and a decrease in the relative weight of the thymus was observed in the females of all test groups. In males similar changes were observed in the mid- and top-dose group, but not in the low-dose group. It was concluded that the NOAEL of thiourea when administered in drinking water to rats for 13 weeks, is 10 ppm (0.9 mg/kg/d) for males and below 10 ppm (1.3 mg/kg/d) for females (Lina/TNO 1984(a)). In the corresponding study the same author concluded an effect level in females below 0.2 ppm (0.02 mg/kg/d) (Lina, TNA 1984 (b)). However, these effect level are based on missing dose-response relationship or transient effects. Only the change in absolute/relative thymus weight are considered to be substance related. This may be attributed to two factors. First, very young rats (3.5 w ) were tested, which is not recommended in OECD 408 and could result in a pronounced effect of the developing immune system. Second, the concentration of folic acid in the diet was very low, especially in the second study diet contains 0.5 ppm folic acid, compared to 3.5 ppm in the standard diet. Thioles are known to increase folic acid demands. As folic acid is needed to maintain the immune system, a deficiency is a known cause of increased thymus weight. Thus, it is questionable that this effect is relevant for human risk assessment.

Supporting data is provided in a couple of other studies from 1940ies. Daily ingestion of 131 mg thiourea/kg body weight in drinking-water by female rats for 10 consecutive days led to hyperplasia of the thyroid, which could be demonstrated both macroscopically and microscopically. No such effect resulted from treatment with 12 mg thiourea/kg body weight (Astwood, 1943). In addition, the iodine level of the thyroid gland was reduced from 73 to 13 mg/100 g tissue upon the oral administration of thiourea at 70 mg/kg body weight for 10 days (Astwood et al., 1945). McKenzie 1943 reported a slight increase in thyroid weight in rats administered 25 mg/kg bw/day, however, no statistical analyses were presented. Mice appear to be less sensitive to thiourea than rats, in that daily subcutaneous administration at 500 mg/kg body weight for 10 days resulted in only a slight reduction in the colloid content of the thyroid (Jones, 1946).

Some non-rodent data provide effect levels of 50 mg/kg/d, but no NOAELs. Twenty-seven female, 2 -3 month old lambs were orally administered 0 or 50 mg/kg bw/day thiourea over a time period of 2, 4, or 6 month (6 animals per exposure group, 3 animals per control group) (Nasser, 1987). The lambs suffered from slight to moderate facial oedema, significant reduction in weight gain, stunted growth, weakness, profound depression, loss of appetite, alopecia, a moderately to severly enlarged thyroid gland, muscular weakness, hypoglycaemia, hyperlipidaemia/hypercholesterolaemia, and a significant fall in serum T4 were related to length of treatment. In another study on sheep, eight male lambs aged 3–3.5 months were orally administered 50 mg /kg/d for 3.5 months together with four control lambs (Sokkar et al., 2000; see section 8.7.2). The dosed animals became weak, emaciated, anaemic, and significantly reduced in body weight, with facial oedema and alopecia at thigh, legs, and abdomen. Clinical analysis showed significant reduction in erythrocyte and leukocyte numbers and in levels of T3 and testosterone at the end of the experiment. Histopathology of the thyroid gland revealed hyperplasia of the follicle-lining epithelial cells that project into the lumen. The lumina were devoid of colloid. The testes showed ill developed, small, empty seminiferous tubules. Hepatocytes in the liver showed degeneration and vacuolation with proliferation of Kupffer cells. The kidney showed glomerular lipidosis with accumulation of haemosiderin pigment in the cytoplasm of the renal tubules. Hyperkeratosis of the epidermis was associated with excessive keratin formation within the hair follicles.

Human Data: Several case studies have been reported from the therapeutic treatment of hyperthyroidism. For example, a female patient was treated for hyperthyroidism with 85g Thiourea for 5 weeks (1-3g/person/d; 20-50 mg/kg/d) without adverse effects. After 5 weeks significant side effects were reported (blood count, hemorrhage, granulocytopenia), which showed a gradual return to normal within 12 days after the end of the treatment (Newcomb, 1944). From these data it can be concluded that there is a risk of cumulative exposure, most likely due to a saturable biotransformation/elimination process.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Study meets generally accepted scientific standards, provides a dose response relationship and the NOAEL/LOAEL is supported by several other repeat dose studies.

Justification for classification or non-classification

Thiourea does not elicit specific target organ toxicity. The impairment of the thyroid function results in a disturbance of the hormonal balance which is accounted for by classifying thiourea as toxic to reproduction (Repro Cat 2, CLP).