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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
reproductive toxicity, other
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Chronic maternal dietary iodine deficiency but not thiocyanate feeding affects maternal reproduction and postnatal performance of the rat
Author:
Bala T.S.S., Venu L., Sunita Y., Raghunath M.
Year:
2007
Bibliographic source:
Indian Journal of Experimental Biology, 45(7), p. 603-609 (2007)

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Investigation of effects on reproductive toxicity during maternal dietary iodine deficiency (ID) in comparison to goitrogens (KSCN), including observation of reproductive performance and postnatal performance of off-spring.
GLP compliance:
not specified
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: inbred
- Age at study initiation: weaning
- Housing: individually in polypropylene cages with wire mesh bottom
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22° ± 2°C
- Photoperiod (hrs dark / hrs light): 12/12 light/dark cycle

Administration / exposure

Route of administration:
oral: feed
Details on exposure:
C-Rats fed iodine sufficient control diet through growth, pregnancy and lactation. E1-Rats fed iodine deficient (LIT) diet or control diet with potassium thiocyanate (@ 25 mg/rat/day) as appropriate through growth, pregnancy and lactation. E2-Control rats fed iodine deficient (LIT) diet or control diet with potassium thiocyanate (@ 25 mg/rat/day) from conception through pregnancy and lactation. E3-Control dams fed iodine deficient (LIT) diet or control diet with potassium thiocyanate (@ 25 mg/rat/day) from parturition through lactation. R1-E1 rats fed control, iodine sufficient diet from conception through pregnancy and lactation.
R2-E1 dams fed control, iodine sufficient diet from parturition through lactation.

Schematic representation of the animal feeding protocol is attached as background material
Details on mating procedure:
After confirming their hypothyroidism, rats were subjected to vaginal smear tests to check the regularity of their estrus cycles. At the pro-estrus stage, they were mated with normal adult male rats and the day on which the sperm appeared in vaginal smear was considered as the day one of gestation.
Duration of treatment / exposure:
Schematic representation of the animal feeding protocol is attached as background material
Frequency of treatment:
daily
Doses / concentrations
Dose / conc.:
25 other: mg/rat/day

Examinations

Statistics:
Statistical analysis-Data were analysed statistically by the appropriate use of one-way analysis of variance (ANOVA) coupled with critical difference test.

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Mortality:
no mortality observed
Body weight and weight changes:
no effects observed

Details on results (P0)

Chronic thiocyanate feeding (for eight weeks from weaning) produced a moderate degree of hypothyroidism in the dams comparable to that in ID dams (serum T4 2.31 ± 0.53 µg/dl).
However, unlike in the chronic ID (E1) dams, the urinary excretion of iodine was significantly (P < 0.05) higher (8.90 ± 3.60 µg/mg creatinine) in thiocyanate fed rats than controls (3.31±1.49 µg/mg creatinine) suggesting higher levels of circulating iodide in these rats than controls.
Nevertheless, there was no effect of any of the three dietary thiocyanate feeding regimes, on any of the parameters of maternal reproduction evaluated.

Effect levels (P0)

Key result
Remarks on result:
other: Chronic thiocyanate feeding (for eight weeks from weaning) produced a moderate degree of hypothyroidism in the dams

Results: F1 generation

Details on results (F1)

None of the three thiocyanate feeding regimes had any such effects on the pups' birth-weight, survival and performance till weaning or on the wet weight of their brains per unit body weight at weaning.

Effect levels (F1)

Key result
Remarks on result:
other: thiocyanate feeding (25 mg/rat/day) did not affect reproductive performance and postnatal performance of their offspring.

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Any other information on results incl. tables

Chronic thiocyanate feeding (for eight weeks from weaning) produced a moderate degree of hypothyroidism in the dams comparable to that in ID dams (serum T4 2.31 ± 0.53 µg/dl).

However, unlike in the chronic ID (E1) dams, the urinary excretion of iodine was significantly (P < 0.05) higher (8.90 ± 3.60 µg/mg creatinine) in thiocyanate fed rats than controls (3.31±1.49 µg/mg creatinine) suggesting higher levels of circulating iodide in these rats than controls.

Nevertheless, there was no effect of any of the three dietary thiocyanate feeding regimes, on any of the parameters of maternal reproduction mentioned in the summary table below.

 

Effect of KSCN feeding/withdrawal on mothers reproductive performance

[Values are mean ± SD]

Parameters

C

E2

E3

E I

Rl

R2

Body weight at mating (g)

154 ± 8.28

154 ±8.28

154 ± 8.28

168 ± 12.3

168 ± 12.3

168 ± 12.3

Body weight during second week of pregnancy

190 ± 15.8

190 ± 15.8

190 ± 15.8

210 ± 13.8

210 ± 13.8

210 ± 13.8

Mated animals conceived (%)

100

 

 

100

 

 

Conceived dams which aborted (%)

ND

ND

ND

ND

ND

ND

Conceived dams dead

during pregnancy (%)

ND

ND

ND

ND

ND

ND

Litter size

7-9

6-9

7-9

6-8

7-8

7-8

 C-Control diet through growth pregnancy and lactation, E1-Control diet with added KSCN (@25 mg/rat/day) through growth pregnancy and lactation, E2-Control diet with added KSCN from conception, E3-Control diet with added KSCN from parturition. R1 -Dietary KSCN withdrawn from E1 rats from conception and R2-Dietary KSCN withdrawn from E1 dams from parturition.

ND-None detected

 

Performance on pubs:

None of the three thiocyanate feeding regimes had any such effects on the pup's birth-weight, survival and performance till weaning or on the wet weight of their brains per unit body weight at weaning.

 

Effect of KSCN feeding/withdrawal on the performance of the pups

[Values are mean ± SE. Figures in parenthesis are no. of observation] 

Parameters

C

E2

E3

EI

RI

R2

Birth weight(g)

5.01±0.70

(28)

4.99 ±0.75

(19)

5.05 ±0.45

(28)

4.74±0.65

(29)

4.85 ±0.38

(10)

4.89 ±0.70

(12)

Liveborn pups dead post-natally (%)

ND

ND

ND

ND

ND

ND

Litter size maintained during lactation

8

8

8

8

8

8

Liveborn pups survived till weaning(%)

100

100

100

100

100

100

Weanling weight(g)

30.8 ±2.95

(20)

23.4 ±2.98

(98)

26.5±2.62

(28)

27.0±3.22

(29)

25.0 ±2.10

(8)

27.6 ±3.55

(8)

Brain weight

(g/100 gbody weightat weaning

4.5 ±0.38

(28) 

5.0±0.53

(14)

4.7±0.62

(28)

4.61±0.09

(10)

4.05 ±0.12

(12)

4.5 ±0.04

(8)

ND - None detected

 

Effect of rehabilitation/thiocyanate withdrawal:

Thiocyanate feeding of any duration from any point of initiation had no effect on maternal mortality, morbidity, reproductive performance or survival/postnatal performance of the offspring.

As such, its withdrawal from the dam's diet, either from conception (Rl) or parturition (R2) had no effect on any of the parameters evaluated.

 

Applicant's summary and conclusion

Conclusions:
It can be stated that based on the results of the present study thiocyanate feeding (25 mg/rat/day) did not affect reproductive performance and postnatal performance of their offspring.
Executive summary:

Iodine deficiency disorders affect reproductive performance in the afflicted populations. Environmental iodine deficiency (ID) and goitrogens are important in their aetiology. We observed earlier that chronic maternal dietary ID but not goitrogen feeding altered the blood-brain barrier nutrient transport in adult rats. Whether similar differences exist in their effects on reproduction of dams and postnatal performance of the offspring has been assessed. Inbred, female, weaning WNIN rats were rendered hypothyroid by feeding for 8-12 weeks, a low iodine test diet or a control diet with added potassium thiocyanate (KSCN) (@ 25 mg/rat/day). Following mating with control males, they continued on their respective diets till their pups were weaned. Indices of reproductive performance such as percentage of conception, mortality of dams during pregnancy and parturition, litter size, and survival of pups till weaning were affected markedly by ID but not thiocyanate feeding. Neither ID nor thiocyanate feeding from conception or parturition affected their reproductive performance. Nevertheless, postnatal weight gain of pups was less in all the three ID groups but not thiocyanate fed dams. Rehabilitation of chronically ID pregnant dams from conception or parturition did not improve their pregnancy weight gain, litter size or birth weight of pups but decreased abortion and mortality of mothers during pregnancy and parturition. Rehabilitation improved the pups' postnatal weight gain but the effect was only moderate. Based on the results of the present study it may be suggested that maternal ID but not thiocyanate feeding affects reproductive performance and postnatal performance of their offspring.