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Description of key information

Two oral studies of 7 weeks in rats and mice are available, there are two range finding tests for carcinogenicity tests. The aim of these studies was to establish the maximum tolerated concentrations of DETU for administration to dosed animals in the chronic studies. Animals were exposed to DETU in diet during seven weeks to 147, 215, 316 and 464 ppm for rats, and 680, 1000, 1470, 2160 and 3150 ppm for mice. 
The target organ of DETU is the thyroid of rat. The LOAEL for thyroid toxicity is 6.25 mg/kg bw in rat (= 125 ppm).
No target organ is showed in the mice.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
6.25 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Reliable study (klimish score of 2)
System:
endocrine system

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

Range finding test for carcinogenicity test (rat and mice).

Rats were exposed to DETU in diet during seven weeks to 147, 215, 316 and 464 ppm.

- At 316 ppm concentration: Mean body weight gain increased by 3 % among male rats compared to control group while it decreased by 11% in female rats. 1 female rat died and another had an arched back and rough coat.

- At 215 ppm concentration: Mean body weight gain decreased by 10 % among male rats compared to control group while it decreased by 1% in female rats.

=> The maximum tolerated concentration was around 250 ppm, and the NOAEL is 147 ppm (7.35 mg/kg bw/d).

Mice were exposed to DETU during seven weeks to 680, 1000, 1470, 2160 and 3150 ppm in diet.

At 680 ppm, the mean body weight gain was decreased among males (-10%) and females (-8%) compared to control group.

=> The high concentration selected for administration to dosed mice in the main study was 500 ppm (=NOAEL).

Carcinogenicity tests on rats and mice.

Rats were exposed to DETU in diet during 103 weeks at 125 and 250 ppm (6.25 and 12.50 mg/kg bw/d respectively).

No mortality, no clinical signs and no change of body weight gain were observed during this study.

This study shows that thyroid is a target organ of DETU at the higher dose (250 ppm). A relatively high incidence of thyroid tumors (in particular thyroid follicular-cell carcinomas and follicular-cell adenomas) was noted and appeared to be related to the dietary administration of N,N'-diethylthiourea.The LOAEL for carcinogenicity and thyroid toxicity is 125 ppm (6.25 mg.kg bw/d).

Mice were exposed to DETU in diet during 103 weeks at 250 and 500 ppm (12.5 and 25 mg/kg bw/d respectively).

No mortality, no clinical signs were observed during this study, but decrease of body weight gain was observed at each dose.

No effects on thyroid were observed in this study at any dose.

The NOAEL for general toxicity is smaller than 12.5 mg/kg bw/d.

Thyroid toxicity in rats of DETU

In the carcinogenicity test, a thyroid toxicity was observed on rats :

1/ the incidence of follicular-cell carcinomas was significantly increased in male rats exposed to high dose (11 animals among 48 examined histologically),

2/ the incidence of follicular-cell adenomas and carcinomas was significantly increased too in female rats exposed to high dose (follicular-cell adenomas: 9/46, follicular-cell carcinomas: 8/48),

3/ moreover few C-cell carcinomas and C-cell adenomas were observed too in males and females exposed to high dose.

Thyroid hyperplasia (cystic and follicular-cell) was commonly recognized and appeared to be related to dietary administration and dosage compound.

=>The LOAEL of thyroid toxicity was 125 ppm (6.25 mg.kg bw/d) in rat.

This thyroid toxicity was confirmed in the study of Hasegawa (1991) :

DETU was administered in the diet to male rats at 200 ppm for 52 weeks. The incidence of liver tumors was observed.

No significant changes were observed for mortality, clinical signs, food consumption or bodyweight in the treated group (DETU) in comparison to the control group. Thyroid weight was significantly increased as compared to control group (p < 0.05: 0.16 ± 0.01g vs 0.13 ± 0.01g). Thyroid follicular cell carcinomas were only induced in 1 of 21 DETU-treated rats (5%). A significant increase of T4 level serum was observed after 52 weeks of exposure (3.67 ± 0.58 µg/dl in treated group vs 2.93 ± 0.55 µg/dl in control group). An apparent correlation between the T4 levels and thyroid weight was noted: the lower the serum T4 level with the greater the thyroid weight.

=> The NOAEL of thyroid toxicity was smaller than 200 ppm.

Study of Astwood (1945) : Effects of DETU on thyroid function (section 7.9.3.)

DETU was tested in rats for capacity to interfere with the endocrine function of the thyroid gland. Test substance was administered to young rats by mixing it with the food at 37 mg/kg bw. At the end of ten days the thyroid glands were examined grossly and microscopically, and the relative activities of the compounds were then roughly compared on the basis on the minimal dose required to produce a noticeable effect.

The weight of thyroid was increased in rat treated with DETU compared to control rats. Thyroid iodine concentration in treated rats was smaller than concentration of control rats. Therefore, an antithyroid activity of DETU was observed in the rats treated with DETU compared to the control rats (treated with thiouracil) at 37 mg/kg bw.

Justification for classification or non-classification

Proposed self-classification (Regulation (EC) No 1272/2008):

STOT RE 1 (thyroid) - H372 "Causes damage to organs through prolonged or repeated exposure".

Justification: the LOAEL for thyroid toxicity (hyperplasia, antithyroid activity) is 6.25 mg/kg bw/d (<10 mg/kg bw/d).