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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
fertility, other
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards; well documented and acceptable for assessment.

Data source

Reference
Reference Type:
publication
Title:
Pathological and biochemical studies on experimental hypothyroidism in growing lambs.
Author:
Sokkar, S. et al.
Year:
2000
Bibliographic source:
Journal of Veterinary Medicine, Series B 47(9):641-652

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Eight male lambs aged 3 to 3.5 months were orally administered 50 mg thiourea/kg body weight daily for 3.5 months. The aim of the study was to induce secondary iodine deficiency in lambs to clarify the biochemical and pathological changes, especially in the male reproductive organs.
GLP compliance:
not specified
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
no details on test material are available

Test animals

Species:
other: Lamb
Strain:
other: Rahmani
Sex:
male
Details on test animals and environmental conditions:
The study was conducted on 12 Rahmani immature growing male lambs 3±3.5 months old. The animals were apparently healthy and free from internal and external parasites. The animals were offered balanced rations and were raised on the National Research Center farm.

Administration / exposure

Route of administration:
oral: unspecified
Type of inhalation exposure (if applicable):
other: not applicable
Vehicle:
not specified
Details on exposure:
- daily oral administration of 50 mg/kg bw of thiourea for 3.5 month (from June to September).
Details on mating procedure:
- The animals were not mated; the development of the male reproductive organs under the influence of thiourea administration was monitored.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
3.5 month
Frequency of treatment:
daily
Details on study schedule:
3.5 month (14 weeks)
Doses / concentrations
Remarks:
Doses / Concentrations:
50 mg/kg bw/day
Basis:
nominal conc.
No. of animals per sex per dose:
8 of 12 male animals were administered thiourea
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
Positive control:
no

Examinations

Oestrous cyclicity (parental animals):
- no female lambs were included in the study
Litter observations:
- The animals were not mated; the development of the male reproductive organs under the influence of thiourea administration was monitored.
Postmortem examinations (parental animals):
SACRIFICE
- All animals were sacrified
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations

HISTOPATHOLOGY / ORGAN WEIGHTS
- histopathological examination of the thyroid gland, testis, liver, renal tubuleskidney, spleen, skin.
- determination of organ weight of testis and the thyroid gland
Postmortem examinations (offspring):
n.a.
Statistics:
Statistical analyses used Student's t-test according to Snedecor and Cochran (1976)
Reproductive indices:
n.a.
Offspring viability indices:
n.a.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Description (incidence and severity):
only male animals were administered thiourea
Reproductive function: sperm measures:
not specified
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
no sexual desire when introduced to ewes in oestrus compared with control animals

Details on results (P0)

- facial oedema and variable degrees of alopecia
- the wool became rough, lustreless and easily pulled, with thick keratinized skin
- by the 8th week, the appetite of the treated lambs decreased gradually until the lambs were off their food
- gradual decrease in body weight in treated lambs with significant (P<0.01) reduction by weeks 13 and 14 (Table 1)
- no sexual desire when introduced to ewes in oestrus compared with control animals
- palpation of the testes of treated lambs revealed hydrocele with small testes
- significant decrease in the mean values of erythrocyte count, leucocyte count and haemoglobin concentration during the last weeks of treatment (10±12 weeks) as compared with the control group
- the treated lambs showed significant (P<0.05) hypoalbuminemia, significant (P<0.05) hyperlipidemia and significant (P<0.01) hypercholesterolemia at the end of the experiment
- macroscopic examination of the testes revealed hydrocoele in two cases with small testes
- the average weight of the testes of hypothyroid lambs showed a significant reduction in comparison with those of control lambs, weight being 3.2 +/- 0.255 g for treated and 8.9 +/- 1.00 g for control lambs
- microscopically, the seminiferous tubules were underdeveloped, small in size, having an empty lumen with thick basement membrane; degenerative changes; most Sertoli cells were primitive and nonfunctional; infiltration of mononuclear cells, mainly lymphocytes, with oedema was noticed in interstitial tissue
- degeneration of hepatocytes
- hyperplasia of follicular cells of thyroid gland

Effect levels (P0)

Dose descriptor:
LOEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: hypothyroidism; retardation of growth; weight loss; lack of sexual desire; Hydrocoele; small testes; hyperplasia of follicular cells of thyroid gland; degenerative changes of liver; alopecia

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
not examined
Body weight and weight changes:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined

Details on results (F1)

There were only male lambs included in the study. No offspring.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Table 1: The mean values SEM of body weights (kg) of control and hypothyroid lambs

Time

Control group (kg)

Treated group (kg)

Day 2

16.00±0.10

17.00±1.15

Week 3

16.00±0.20

17.33± 1.45

Week 4

15.25± 1.25

17.33± 0.88

Week 5

16.25± 1.25

18.00± 0.88

Week 6

16.25± 1.25

17.66± 1.20

Week 8

17.00± 0.99

17.60± 1.20

Week 9

17.50± 1.50

17.83±1.16

Week 11

20.00± 1.00

18.33± 0.88

Week 13

22.00 ± 0.20

17.00± 0.10**

Week 14

23.25± 0.25

16.50± 0.29**

** Highly significant at P < 0.01

Applicant's summary and conclusion

Conclusions:
Secondary iodine deficiency induced by thiourea administration caused clinical and pathological lesions in different organs, especially in the male gonad of growing male lambs.
Executive summary:

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).