Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

Several carcinogenicity studies were carried out in rodents prior to the mid-1960s. They described the occurrence of thyroid tumors and tumors at numerous locations other than the thyroid gland, but the distribution of these varied from one study to another. Thyroid tumor development in rats seem to be assiciated with a species specific sensitivity due to a more rapid thyroxine metabolized. The ambiguous results are considered to be driven by endocrine active properties/thyroid effects, not supporting classification of Thiourea as carcinogenic to humans. This is in accordance with the IARC risk assessment from 2001. However, Carc Cat 2 is the current harmonized classification according to CLP.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity
Type of information:
not specified
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Risk assessment conducted by the International Agency for Research on Cancer
Qualifier:
no guideline available
Principles of method if other than guideline:
Risk assessment conducted by the International Agency for Research on Cancer
GLP compliance:
not specified
Dose descriptor:
other: Thiourea is considered not classifiable as to its carcinogenicity to humans (Group 3)
Conclusions:
Thiourea is considered not classifiable as to its carcinogenicity to humans (Group 3)).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The quality of the available data is considered low to medium. Thiourea has not been tested in a standard bioassay of carcinogenicity in rodents.

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Thiourea has not been tested in a standard bioassay of carcinogenicity in rodents. However, several carcinogenicity studies were carried out prior to the mid-1960s (Table). They described the occurrence of tumors at numerous locations other than the thyroid gland, but the distribution of these varied from one study to another. Most of the reports lack important details regarding dosages or the frequencies of spontaneous tumor formation, and the doses administered were often sufficiently toxic to result in 100% mortality (IARC, 1974, 2001). In several studies involving different strains of mice, thyroid hyperplasia, but not thyroid tumors, was reported after oral administration. In rats given thiourea orally, a high incidence of thyroid follicular cell adenomas and carcinomas and increased incidences of hepatocellular adenomas and tumors of the Zymbal or Meibomian gland were reported (IARC, 1974, 2001). Thiourea is negative in a rat liver foci bioassay (Oesterle, 1988).

Administration of thiourea to healthy animals or humans leads to depression of thyroid function. It acts by inhibiting the peroxidase in the thyroid gland, resulting in decreased thyroid hormone production and increased proliferation due to an increase in the secretion of TSH (MAK, 1988; IARC, 2001). This is a well-recognized mechanism of action for non-genotoxic thyroid carcinogens, with rats reported to be especially sensitive to this effect. Enhanced metabolism or clearance of thyroid hormones in rats often trigger a sequence of toxicity events during chronic administration: reduction of thyroxine, elevation of thyroid-stimulating hormone (TSH) levels, and thyroid gland hyperfunction/growth. Hepatocellular hypertrophy and thyroid follicular hyperplasia are often observed with increased liver and thyroid organ weights. This unique toxicity profile seems to be species-specific because the thyroxine in rodents is metabolized rapidly, without thyroid hormone-binding globulin that serves as a reserve, as in humans. Thus, elevations of TSH were not reported in humans for drugs such as delavirdine, fluvastatin, nicardipine, phenobarbital, simvastatin, and spironolactone, all of which produce thyroid hyperplasia or tumors in rats (Wu, 2006). Further, the human thyroid is less sensitive to prolonged TSH stimulation than that of the rat (eg, endemic goiter patients with high TSH due to iodine deficiency do not develop thyroid cancer).

Thiourea is classified as a suspected carcinogen in the European Union (CLP Carc Cat 2). The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) classified Thiourea as a suspected carcinogen (2011; MAK 3B, classification based on insufficient data). In an initial assessment the International Agency for Research on Cancer (IARC) classified Thiourea having “sufficient evidence of carcinogenicity in experimental animals” (IARC 1974). In 2001 the most relevant studies from the 1974 monograph were summarized and re-analysed in greater depth leading to the conclusion that Thiourea is not classifiable as to its carcinogenicity to humans (Group 3) (Mono 79 – 24 (2001)). The assessment in WHO IPCS 2003 (Concise International Chemical Assessment Document 49) is based on IARC 2001 ( “not classifiable as to its carcinogenicity to humans (Group 3)). In the 12th Report on Carcinogens (RoC) from 2011, NTP considers Thiourea as “reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimen­tal animals”. However, this assessment is based on the outdated evaluation reported in the IARC 1974 report.

Conclusion: The ambiguous results on the carcinogenicity of thiourea are considered to be driven by thyroid (endocrine effective) properties, which does not support the classification of Thiourea as carcinogenic to humans. This is in accordance with the IARC risk assessment from 2001. However, Carc Cat 2 is the current harmonized classification according to CLP. [According to Article 37(6) of CLP, it would be possible to submit a proposal to change the harmonised classification to the Competent Authority of a Member State.]

Table 1: Carcinogenicity studies

Species (strain)

Number, sex,aage

Dose, treatment period

Effect

Observations

Reference

Rat (SD)

5♂ + 5♀; 21 d

3 × 200 mg/kg, p.o., after 1 week 2 × 10 mg PCB/kg weekly, 11 weeks

No

no increase in number or size of ATP-free islets in the liver (Rat liver foci bioassay)

Demi 1988 (MAK 1990)

Rat (SD)

4 ♂ + 4♀; 21 d

1 × 8 mg/kg diethylnitrosamine p.o., after 1 week 0.2 % thiourea in the drinking water for 12 weeks

No

70 %-90 % reduction in the number and area of ATP-free islets in the liver (Rat liver foci bioassay)

Demi 1988 (MAK 1990)

Mouse (C3H)
+/– castration

25 m + 25 f;
no controls

0.3% in diet (150 mg/kg body weight per day), 7 months

?

Thyroid hyperplasia

Casas & Koppisch (1952) (MAK 1990)

Mouse (C3H)

21 f
controls: 25 f

0.25% in diet (125 mg/kg body weight per day), 13 weeks; then 0.375% (187.5 mg/kg body weight per day), 3–45 weeks; killed on appearance of tumours

No

Thyroid hyperplasia, no tumours

Dalton et al. (1948) (MAK 1990)

Rat (Osborne-Mendel)

30 m + 30 f
controls: 30 m + 30 f

50 mg/kg in the diet (2.5 mg/kg body weight per day), 26 months

Yes

21 tumours, 4 of them malignant
Controls: 15 tumours not specified in detail

Deichmann et al. (1967) (MAK 1990)

Rat (albino)

18 m/f per group
controls: 18 m/f

0.01–1% in the diet (5–500 mg/kg body weight per day), 24 months

Yes

From 0.25%: thyroid hyperplasia
From 0.1%: liver adenomas in 14/29 survivors

Fitzhugh & Nelson (Science 108; 1948)

Mouse (ICR Swiss)

42 (not specified)
controls: 4 x 50
age: 24–72 h

1 x 2500 mg/kg body weight subcutaneously; killed after 6 months

No

Incidence of lung adenomas: 5%
Controls: 2–14%

Gargus et al. (1969) (MAK 1990)

Mouse (five strains)

4–65 m, f per group controls: 4–51 m, f

2% in diet (1000 mg/kg body weight per day), up to 21 months

No

Thyroid hyperplasia, no carcinomas

Gorbman (1947) (MAK 1990)

Rat (Norway)

9 f

0.25% in drinking-water (350 mg/kg body weight per day), 12–23 months

Yes

Thyroid: 4 carcinomas from month 20, 7 adenomas

Purves & Griesbach (1947)

Rat (Norway)

8 f

0.25% in drinking-water (350 mg/kg body weight per day), 12–24 months

Yes

Thyroid: 3 carcinomas from month 20, 8 adenomas

Purves & Griesbach (1947)

Rat (Wistar)

8 f

0.25% in drinking-water (350 mg/kg body weight per day), 12–22 months

Yes

Thyroid: 6 adenomas

Purves & Griesbach (1947)

Rats from the above three groups

8 f with adenomas

0.25% in drinking-water (350 mg/kg body weight per day), 17–18 months, plus thyroid extract, thyroxine injected from month 16

No

No thyroid gland tumours

Purves & Griesbach (1947)

Rat (Osborne-Mendel)

30 m + 30 f
controls: 50 m + 50 f

80 mg/kg in the diet (4 mg/kg body weight per day), 24 months

no

No increased tumour frequencies

Radomski et al. (1965)(MAK 1990)

Rat (albino)

19 m
controls: 12 m

0.2% in drinking-water (280 mg/kg body weight per day), 13–26 months

Yes

1 nasal tumour, 6 tumours in the ear, 6 orbital tumours; 5 animals with tumours in both of the latter localities

Rosin & Ungar (1957)

Rat (albino)

12 m/f

3–4 ml 10% solution intraperitoneally (857–1142 mg/kg body weight), 3 times per week for 6 months, then 0.2% in drinking-water (280 mg/kg body weight per day) to 15 months

No

6 animals died or were killed after 6 weeks to 8 months: no effects
After 1 year: 6 epidermoid carcinomas in eye and ear region, no hepatic tumours

Rosin & Rachmilewitz (1954)(MAK 1990)

Rat (Wistar)

9 m

0.2% in drinking-water (280 mg/kg body weight per day), 12–23 weeks

Yes

Squamous cell carcinoma of the Zymbal gland and/or Meibomian glands in 8/9 animals

Ungar & Rosin (1960)

Mouse (C3H)

49 f
controls: 33 f

0.1–0.2% in drinking-water (140–280 mg/kg body weight per day), 4–6 months

Yes

No thyroid hyperplasia (1/20 hypertrophy), mammary tumours in 54%, less in controls: 28%

Vasquez-Lopez (1949)

Mouse (R3) with high incidence of mammary tumours

11 f
controls: 7 f

0.2–0.5% in drinking-water (280–700 mg/kg body weight per day), average 10 months

?

Thyroid hyperplasia

Vasquez-Lopez (1949)

 

 


Justification for selection of carcinogenicity via oral route endpoint:
Several carcinogenicity studies were carried out in rodents prior to the mid-1960s. The in depth re-evaluation of available data in 2001 lead to the conclusion, that Thiourea is “not classifiable as to its carcinogenicity to humans (Group 3)” (IARC 2001)

Justification for classification or non-classification

The ambiguous results on the carcinogenicity of thiourea are considered to be driven by thyroid (endocrine effective) properties, which does not support the classification of Thiourea as carcinogenic to humans. This is in accordance with the IARC risk assessment from 2001. However, Carc Cat 2 is the current harmonized classification according to CLP.