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EC number: 200-543-5
CAS number: 62-56-6
Further investigation on toxicity to reproduction and developmental toxicity will be conducted according to ECHA decision No. CCH-D-2114539794-36-01/F (19th January 2021). This section will be updated after finalization of these studies.
Effects observed in young lambs orally administered thiourea daily for 2, 4, or 6 months include hypothyroidism, reduction of testosterone levels, small and empty seminiferous tubules and “ill developed testes” in males and infantile and stunted external genitalia and an absence of estrus and retarded mammary development in females at 50 mg/kg bw/day. In addition to general signs of toxicity the thyroid gland was moderately to severely enlarged, although there was no direct correlation with length of dosing. Muscular weakness and difficulty standing and walking were noted with increased dosing. Hypoglycaemia, hyperlipidaemia/hypercholesterolaemia, and a significant fall in serum T4 were related to length of treatment. (Sokkar et al., 2000; Nasseri and Prassad, 1987a [7.5.1], Nasseri & Prasad, 1987b [7.8.2]). In addition, effects on reproductive organs observed in female lambs following subchronic oral administration include non-significantly reduced size and weight of ovaries, uterine horn and vagina when administered orally at a dose of 50 mg/kg/d to four female lambs for 80 days. Follicles in the ovaries were atretic and endometrial cells were shorter than the controls, indicating that hypothyroidism probably suppresses the ovarian and other reproductive functions of female lambs (Alavi Shoushtari & Safaii 1993). Oral administration of greater than 35 mg/kg bw/day thiourea to male rats produced a reduction or cessation of spermatogenesis (Fitzhugh & Nelson 1948). Reddy et al. (1998) verified the impairment on male fertility in a one-generation study treating male animals only followed by an artificial insemination of untreated females. The available data suggest that effects on reproductive organs in adult and developing animals are related to the inhibition of thyroid function. Thus, Thiourea is considered to affect fertility as a result of hypothyroidism This conclusion supports the current harmonized classification under CLP (Repro Cat 2).
Short description of key information: Effects on the male and female reproductive organs have been described in subchronic studies in sheep and rodents. Reddy (1998) reported on a one-generation study with dosing of male goats, only. Justification for selection of Effect on fertility via oral route: None of the available studies provide data on full dose response relationship. However, the adverse effects on reproductive organs in developing animals are considered to be related to an impairment of the thyroid function. Thus it is expected that these effects can be extrapolated form repeated dose toxicity studies. Sokkar 2000 has been selected as it provides the lowest LOAEL value for reproductive effects.
Table 1: The mean values SEM of body weights (kg) of control and hypothyroid lambs
Control group (kg)
Treated group (kg)
22.00 ± 0.20
** Highly significant at P < 0.01
Eight male lambs aged 3 to 3.5 months were orally administered 50 mg
thiourea/kg body weight daily for 3.5 months. There were four control
lambs. Hypothyroidism was caused by thiourea adminsitration and which
led to retardation of growth and interfered with the sexual maturity of
the growing male lambs. The treated males did not show any sexual desire
when introduced to ewes in estrus compared with control animals.
Palpation of the testes of treated lambs revealed hydrocoele with small
testes. The average weight of the testes of the hypothyroid lambs was
significantly reduced (3.2 ± 0.255 g) compared with that of control
lambs (8.9 ± 1.00 g). The testes showed underdeveloped, small, empty
seminiferous tubules with thick basement membranes. The Sertoli cells
were primitive and nonfunctional. The level of testosterone in the
plasma of these hypothyroid lambs was not detectable. The results of
this publication are summarized in the " Concise International Chemical
assessment Document 49 - Thiourea" (WHO, 2003).
Developmental effects have been observed in young lambs orally administered thiourea at one dose, only (Nasseri and Prassad, 1987b), and in rodents (Kern, 1980; Teramoto, 1981; Ruddick, 1976). Effects on the thyroid and the passage of the blood-placenta barrier are summarized in section 7.1.
Administering 0.2% Thiourea in drinking water to pregnant rats on gestation days 1–14 results in malformation of the foetuses, i.e. of the central nervous system and skeleton . Thyroid hyperplasia was found in the rat foetuses and newborn animals. Data on maternal toxicity were not provided in this study (Kern 1980). Hypothyroidism caused by the administration of 50 mg thiourea/kg bw to 66 female sheep for 2, 4, or 6 months adversely influences somatic development, reproductive/gestational performance of animals, and growth of developing fetuses in utero. The growing lambs did not show signs of estrus and mammary development was retarded. Thiourea administered to pregnant ewes induced abortion, stillbirth, birth of weak/low-weight lambs, dystokia, and retention of placenta. The severity of changes was dependent upon the stage of gestation when hypothyroidism was induced. (Nasseri and Prassad, 1987b). Studies with 35S-thiourea in rats and mice demonstrate that the substance crosses the placenta and, depending on the stage of development of the thyroid gland, is stored in particular in this organ where it affects iodine metabolism (Shepard, 1963). Maternally toxic oral doses of 1000 mg/kg given to mice on day 10 or to rats on day 12 or day 14 of gestation were embryotoxic. Absorption frequency was increased without malformations in the foetuses living on day 18 (mice) or 20 (rats) (Teramoto, 1981). Thiourea had neither a maternally toxic nor a teratogenic effect when administered to rats on the 12th or 13th day of gestation as a single oral dose of 480 mg/kg body weight (Ruddick et al., 1976).
The embryotoxic effects of thiourea can be attributed to the depressing action of thiourea on thyroid activity. The effect of Thiourea on the thyroid is well known and has been used in the 1940ies to treat hyperthyroidism in human patients (IUCLID 7.10.3). It is not to be expected that such effects would occur at levels of thiourea that do not result in an inhibition of thyroid function. This conclusion is in line with the risk assessment conducted by the MAK commission (1990) and WHO (IPCS, 2003). Therefore, the dose-response data from repeated dose toxicity studies can be used to predict maternal and foetal toxicity.
Justification for selection of Effect on developmental toxicity: via oral route: Teratogenic effects have been reported at dose levels eliciting maternal toxicity. None of the available studies provide data on full dose-response relationship. However, the adverse effect is considered to be related to an impairment of the thyroid function. Thus it is expected that teratogenicity occurs at dose levels that also cause maternal toxicity.
66 female sheep (18 growing lambs, 18 maiden ewes, 9 pregnant ewes;
controls: 9 growing lambs, 9 maiden ewes, 3 pregnant ewes) were
administered orally 0 and 50 mg thiourea/kg body weight daily for 2, 4,
or 6 month. External genitalia were infantile and stunted in growing
lambs and pale anaemic and dry in maiden ewes. The growing lambs did not
show signs of estrus and mammary development was retarded. Thiourea
administered to pregnant ewes induced abortion, stillbirth, birth of
weak/low-weight lambs, dystokia, and retention of placenta. The severity
of changes was dependent upon the stage of gestation when hypothyroidism
The effects on reproductive organs in adult and developing animals are considered to be related to inhibition of thyroid function. Thus, Thiourea is considered to affect fertility and development as a result of hypothyroidism. This conclusion supports the current harmonized classification as toxic to reproduction (Repro Cat 2, CLP), but further investigations are on-going (see above).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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