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Evaluation of health effects

The database is old and insufficient to derive quantitative estimates of tolerable intakes or tolerable concentrations for exposure to thiourea. Species differences in toxicity are large, and there is evidence of tolerance after relatively low exposure, which makes the extrapolation of animal data to humans difficult. In addition, the mechanism of toxic action, which is based on disturbance of hormonal balance and possibly involvement of immune response, may be different in humans and animals.

Hazard identification and dose–response assessment

The critical effect of thiourea is inhibition of thyroid function, which has been shown in humans and in animal studies.

There are only a few reports of adverse effects on health after occupational exposure. Inhibition of thyroid function, as shown by reduction in the concentrations of thyroid hormones T4 and T3, has been reported at a thiourea manufacturing factory in Russia. Thyroid hyperplasia was reported in 17 out of 45 workers exposed to a reported 0.6–12 mg/m3 (Talakin et al., 1985). In other studies, stomach and intestinal disorders as well as blood count changes have also been described.

Thiourea was used in former times as a thyroid depressant in patients with hyperthyroidism. A daily dose of <15 mg (<0.2 mg/kg body weight per day for a 70-kg adult) in adults did not lead to measurable depression of the thyroid gland function, while a dose of 70 mg/day (about 1.0 mg/kg body weight per day) produced a remission of hyperthyroidism (Winkler et al., 1947).

Contact dermatitis and photocontact dermatitis upon dermal exposure have been described during thiourea production and also after handling products containing thiourea, such as diazo copy paper and silver polish. However, thiourea gave a negative result in a guinea-pig sensitization assay.

Administration of thiourea to laboratory animals has caused a reduction in weight gain and enlargement of the thyroid gland and resulting symptoms of hypothyroidism.

Most of the studies in experimental animals were not performed according to current standards and were in some cases not suitable for the overall assessment. There was only one study in which a LOAEL/NOAEL could be derived.

A LOAEL of 27.5 mg/kg body weight per day (reduction of body weight and enlargement of thyroid gland) and a NOAEL of 6.88 mg/kg body weight per day for rats were given for a 2-year drinking-water study (Hartzell, 1942, 1945).

Studies of genotoxicity in vitro and in vivo gave inconsistent results, with the majority being negative. Therefore, thiourea is not considered to be a genotoxic carcinogen.

There are no reports of carcinogenicity due to thiourea exposure in humans.

In several strains of mice, thyroid hyperplasia, but not thyroid tumours, was induced after oral administration of high doses of thiourea. In rats, a high incidence of thyroid follicular cell adenomas and carcinomas or increased incidences of hepatocellular adenomas or tumours of Zymbal or Meibomian glands were observed after oral administration of thiourea. However, there were deficiencies in each of these studies.

Thiourea promoted thyroid tumours in rats initiated by DHPN, but did not show any promoting activity in a rat liver foci bioassay after initiation with diethylnitrosamine or DHPN.

Thiourea passes the placental barrier. In rats, thiourea at maternally toxic doses (0.25% in drinking-water; 350 mg/kg body weight per day) was toxic to the fetuses of the dams.

Hypothyroidism caused by administration of 50 mg thiourea/kg body weight per day to sheep for 2, 4, or 6 months adversely influences somatic development, reproductive/gestational behaviour of animals, and growth of developing fetuses in utero. A similar study with male lambs showed adverse effects on male reproductive development. In limited studies in rodents, no teratogenic effects have been observed.

Criteria for setting tolerable intakes/tolerable concentrations for thiourea

Thyroid hyperplasia was observed in 17 of the 45 workers exposed to air concentrations of 0.6–12 mg/m3. If it is assumed that the workers weighed 70 kg and inhaled 1 m3/h for 8 h/day and that the uptake was complete, this air concentration is equivalent to a dose of 0.07–1.4 mg thiourea/kg body weight per day. At these levels, there was a clear effect. Therefore, tolerable intakes should be much below 0.07 mg thiourea/kg body weight per day.

From data on its use as a thyroid depressant, <15 mg thiourea/day (<0.2 mg/kg body weight per day for a 70-kg adult) had no effect, whereas 70 mg/day (about 1.0 mg/kg body weight per day) showed an effect (Winkler et al., 1947).

Due to a lack of suitable studies and due to the species differences in thyroid gland biochemistry and physiology, it is difficult to set a tolerable intake or tolerable concentration based on animal studies.

Although thiourea has been shown to be a carcinogen in rats, the weight of evidence suggests that rodents are more sensitive than humans to thyroid tumour induction due to hormonal imbalances that cause elevated TSH levels. Up to now, radiation is the only well defined risk factor for thyroid cancer, although an excess risk of thyroid cancer has, in some studies, been associated with goitre (hypothyroidism) (Hill et al., 1998; Franceshi & Dal Maso, 1999).

In occupational settings, dermal contact with thiourea (and resulting sensitization) is a relevant exposure scenario.

Sample risk characterization

An occupational exposure study giving measured data from the production and packing of thiourea in a German factory reported an average air concentration (thiourea in total dust) of 0.085 mg/m3 (maximum 0.32 mg/m3) (BUA, 1995). From the data reported in the Russian study, it is likely that at least at these maximum levels, a health risk may exist if no hygienic precautions are taken.

Uncertainties in the hazard characterization

The accuracy of the occupational exposure data (Talakin et al., 1985) is uncertain.

Although the clinical experience from the use of thiourea as an antithyroid drug is rather extensive, the estimate of the no-effect level is based on very limited information from rather old studies, where the assessment of thyroid function was not performed with the sensitive methods of today. Furthermore, these were patients with hyperthyroidism and not healthy workers.

High doses of thiourea have induced hypothyroidism and thyroid tumours and promote nitrosamine-induced carcinogenesis in the thyroid in rats and hypothyroidism without thyroid tumours in mice. Although these tumours are likely to be induced by the hypothyroidism, thiourea has also, in some studies, shown weak genotoxic potential, and the mechanism of carcinogenesis is not fully settled. There are no studies on the possible carcinogenic effect of thiourea in exposed humans.

There are possible species differences in thyroid gland biochemistry and physiology, which indicate that the rodent thyroid gland is more active and operates at a higher level with respect to thyroid hormone turnover compared with the human gland.

The estimation of workplace exposure is based on very limited data.

Evaluation of environmental effects

Evaluation of effects in surface waters

The main environmental target compartment of thiourea from its physicochemical properties and its uses is expected to be the hydrosphere.

The calculated Henry’s law constant indicates that thiourea is not expected to volatilize from aqueous solution. In water, thiourea is resistant to hydrolysis. Whereas direct photolysis is not to be expected, thiourea undergoes photochemical oxidation via reaction with hydroxyl radicals. Half-lives of 17 days and 2.4 h can be calculated for the hydrosphere and the atmosphere, respectively. According to the available data, thiourea will be biodegraded by an adapted microflora only after extended acclimation periods. Thus, under conditions not favouring biotic or abiotic removal, thiourea may be present in surface waters and sediments over longer time periods. Adsorption to sediment particles, however, is not to be expected.

The available experimental data on bioaccumulation as well as the measured n-octanol/water partition coefficients indicate no bioaccumulation potential for thiourea in aquatic organisms.

A sample risk characterization with respect to the aquatic environment may be performed by calculating the ratio between a (local or regional) predicted environmental concentration (PEC; based on measured or model concentrations) and a predicted no-effect concentration (PNEC) (EC, 1996).

A quantification of the thiourea releases from all the different industrial sources is not possible with the available data. Furthermore, there are no present-day monitoring data available. Thus, a PEC for thiourea in the hydrosphere could not be defined.

A PNEC for surface waters may be calculated by dividing the lowest valid NOEC obtained in chronic studies by an appropriate uncertainty or characterization factor:

PNEC = (0.25 mg/litre)/50 = 0.005 mg/litre


0.25 mg/litre is the lowest valid NOEC from a 21-day reproduction test with Daphnia magna

50 is the uncertainty factor; according to EC (1996), this factor should be applied when long-term toxicity data are available for at least two trophic levels (algae and daphnia).

In European Union jurisdiction, for substances exhibiting PEC/PNEC ratios of less than or equal to one, further information and/or testing as well as risk reduction measures beyond those that are already being applied are not required. Therefore, measured or calculated thiourea concentrations in surface waters below 0.005 mg/litre will not lead to any regulatory actions.

The lack of current monitoring data for relevant aquatic compartments does not allow a quantitative risk assessment to be performed; however, from the reliable data available on environmental fate, bioaccumulation, and ecotoxicity, a significant risk of thiourea to aquatic organisms is not to be expected (except in the case of an accidental spill).

Evaluation of effects on terrestrial species

Due to the measured soil sorption coefficients and the observed (slow) biodegradation in soil, accumulation of thiourea in the geosphere is not to be expected. A leaching of residual thiourea from soil into groundwater cannot be excluded.

For the terrestrial compartment, toxicity tests on microorganisms, higher plants, earthworms, nematodes, and insects are available. The lowest effect value is reported for turnip (Brassica rapa; 14-day EC50 = 15 mg/kg soil dry weight). No studies on the toxicity of thiourea to terrestrial vertebrates or effects on ecosystems are available.

As no measured soil concentrations of thiourea are available, a quantitative risk characterization could not be performed. However, according to the experimental data available for toxicity to terrestrial species, the low bioaccumulation potential, and the expected environmental fate when released to soil, thiourea is not expected to pose a significant risk for terrestrial species (except in the case of an accidental spill).

Uncertainties in the evaluation of environmental effects

Due to the lack of measured thiourea concentrations in surface waters and soil, a quantitative risk assessment for these environmental compartments could not be performed.

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