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EC number: 200-543-5
CAS number: 62-56-6
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.
The NOAEL for oral repeated dose toxicity was concluded to be 6.88 mg/kg bw/d, based on the key chronic toxicity study.
Further investigation will be conducted according to ECHA decision No. CCH-D-2114539794-36-01/F (19th January 2021).
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).
In a subchronic toxicity study thiourea was administered daily in
drinking water to 60 male and 60 female Sprague-Dawley rats (10
rats/sex/dose) in the dose groups 1–4 (0, 0.02 ppm, 0.1 ppm, 0.5 ppm)
and 20 rats/sex/dose in group 5 (2.5 ppm). Nine males and 10 females of
group 5 served as recovery group over 4 weeks. The objective of this
study was to determine a no-observed effect level of thiourea when
administered daily via drinking water to male and female Sprague-Dawley
rats for at least 13 weeks. A full complement of qualitative and
quantitative parameters was evaluated after 7 and 13 weeks, and data
generated from this study indicated that levels up to 2.5 ppm of
thiourea in the drinking water failed to elicit a demonstrable
biological effect. It may therefore be concluded that the no-observed
effect level of thiourea administered via drinking water to rats for 13
weeks is at least 2.5 ppm, or approximately 1.73 mg/kg b.w./d for males
and 2.65 mg/kg b.w./d for females.
Table 1: Mean body weights in week 1-4 of 10 animals per group; in week 6 and 8 of 5 animals/group
Thiourea (ppm) in the diet
Mean body (in g) at end of week
* P<0.05; ** 0.001<P<0.01; ***P<0.001
Table 2: Mean food intake and food efficiency
Food intake in g/rat/day in week
Food efficiency during week 1-4
Table 3: Mean hematological values in 5 rats/group
At week 4
At week 8
WBC x 109/L
*0.01<P<0.05; **0.001<P<0.01; *** P<0.001
PCV= packed cell volume
RBC= red blood cells
WBC= white blood cells
PT= prothrombin time
Table 4: Mean values of T3-uptake and T4-concentration in blood plasma of 5 rats/group, unless otherwise indicated by figure in parentheses
T3-uptake (% of Calibration standard)
*0.01<P<0.05; **0.001<P<0.01; *** P<0.001
Table 5: Mean relative organ weights (in g/100 g body weight) of 5 rats/sex/group
After 4 weeks
After 8 weeks
1) BW = body weight (in g)
Groups of 10 male and 10 female weanling rats were fed stock diet supplemented with 0 (control), 300, 1000 or 3000 ppm thiourea. After 4 weeks five rats/sex/ group 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 no-toxic-effect level of thiourea in the present study was lower than 300 mg/kg diet, which is equivalent to 30 mg/kg bw/d.
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.
Dose Range Finding
In the first Dose Range Finding study, the toxicity of thiourea, when administered daily via drinking water to rats, was investigated over a period of 2 consecutive weeks. Three groups of 4 male and 4 female Sprague Dawley SD rats each received the test item at nominal dose levels of 1, 5 and 15 mg/kg/day. A fourth similarly constituted group received untreated drinking water and acted as a control. No mortality occurred and no clinical signs were seen during the study.A slight but treatment-related decrease in body weight was observed in high dose treated males (statistically significant when compared to controls) and in high dose females from Day 5 of treatment. Food consumption did not show relevant changes through the study. Water consumption was not affected by treatment. The calculated mean daily achieved dosages for the 2 week period of treatment were 1, 6, 21 mg/kg/day for the males and 1, 9 and 20 mg/kg/day for the females, in terms of test item as supplied. At the end of the treatment period a statistically significant decrease in terminal bodyweight was observed in treated males when compared to the controls.A statistically significant decrease in absolute and relative mean thymus weight was observed in high and mid-dose treated males and females and in low dose males. The decreased terminal body weight and thymus weight of treated animals of both sexes were considered to be most likely treatment related. No treatment-related changes were noted following gross pathology examination at the end of treatment period.
In a second dose range finding study, the toxicity of thiourea, when administered daily via drinking water, was investigated in Sprague Dawley rats after daily oral administration for 2 weeks, in order to select dose levels for subsequent toxicological studies.The study was performed in 3 phases:During the first phase of the study (Phase 1), three groups of 4 male and 4 female rats were treated for 1 day only with the test item at nominal doses of 60, 180 and 240 mg/kg/day. A fourth similarly constituted group received untreated drinking water (sterile water) and acted as a control. Due to the mortality observed on Day 1 (1 male of Group 2 and 1 male of Group 4) the treatment was suspended on the same day. A one-week wash-out period was allowed before restarting treatment at different nominal doses. In the second phase of the study (Phase 2), 3 groups of 7 or 8 rats each were treated for a period of two weeks at 3 nominal ascending dose levels (30, 60 and 180 mg/kg/day). A 1-week interval was allowed between the start of each treatment. One additional group was treated with untreated drinking water and acted as a control. Due to a severe reduction in bodyweight in both male and female rats in Group 4, treatmentwas discontinued after 8 days. During the third phase of the study (Phase 3), Group 3 (4 males and 4 females) was treated again after a 1-week wash-out period for 2 consecutive weeks at nominal dose level of 120 mg/kg/day.
Phase 1On Day 1 of Phase 1 two cases of premature death occurred in one male treated at nominal dose level of 60 mg/kg/day (low dose) and in one male treated at nominal dose level of 240 mg/kg/day (high dose). The findings observed at post mortem examination were pale areas in lungs in both animals,whereas red mucosa of duodenum, jejunum and ileum, dark red areas in the adrenal glands were also noted in the high dose male. The observed findings are associated with the death of the animals and therefore are considered treatment-related.
Phase 2No mortality occurred in Groups 1, 2 and 3 during Phase 2 of study. For Group 4 due to the marked reduction in body weight it was decided to discontinuetreatment on Day 8, therefore they were prematurely sacrificed on Day 9.
Phase 3No mortality occurred in Group 3 during Phase 3 of the study.
Clinical signsPhase 1Dyspnoea was the main treatment-related clinical sign observed on Day 1 in the majority of treated males.
Phase 2No clinical signs were observed for animals in Groups 2 and 3. Decreased activity, decreased muscle tone, hunched posture and semiclosed eyes wereobserved during the study in a single male animal of Group 4.
Phase 3No clinical signs were observed in male and female rats in Group 3.
Phase 2Dose-related body weight losses were observed in males from all treated groups from Day 1to Day 5, but a progressive recovery of body weight was observed from Day 8.
Phase 3Animals of both sexes inGroup 3 showed a bodyweight losses fromDay 1 toDay 5. Recovery was observed from Day 8 onwards.
Phase 2Dose-related body weight losses were observed in males from all treated groups from Day 1 to Day 5, but a progressive recovery of body weight was observed from Day 8.
Food consumptionPhase 2Food consumption inGroup 2, in both males and females, was not affected by the treatment. A slight decrease in food consumption was observed in Group 3 males from Day 1 to Day 5 with a recovery from Day 8. Treatment-related reduction in food consumption was observed in Group 4, which was more pronounced in males than in females.
Phase 3Group 3 showed a decrease in food consumption in both sexes, with a recovery in males from Day 12 and in females from Day 8.
Water consumptionPhase 2Males in Group 2 and males and females in Group 3 showed very low water intake in the first 3 or 4 days of treatment, gradually increasing until the end of treatment period. Water consumption of the animals in Group 4 was highly compromised by the treatment throughout the administration period.
Phase 3Reductions in water consumption were observed in both sex animals during the first week of treatment, achieving normal values during the second week of administration.
The calculated mean daily achieved dosages for Groups 2 and 3 over a 2-week treatment period were 36 and 59 mg/kg/day for the males and 44 and 55 mg/kg/day for the females, in terms of test item as supplied. The calculated mean daily achieved dosages for Group 3 over a 2-week treatment period were 152 mg/kg/day for the males and 143 mg/kg/day for the females, in terms of test item as supplied. Any organ weight changes were within the range of occasionally observed and expected spontaneous changes in rats of the same age and considered unrelated to treatment. No treatment-related changes were noted following gross pathology examination at the end of treatment period for animals of Groups 2 and 3. In all males and one female of Group 4, only a small thymus was noted.
A subchronic oral toxicity study in the rat according to OECD No. 408 is on-going. After finalization of this test, this section will be updated accordingly.
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), but further investigations are on-going (see above).
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