Copper iodide

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Published literature data

Data source

Reference

Reference Type:

publication

Title:

Developmental toxic effects of chronic exposure to high doses of iodine in the mouse.

Author:

Yang, X.F., Xu, J., Hou, H. H., Guo, H.L., Hao, L.P., Yao, P., Liu, L.G., Sun, X.F.

Year:

2006

Bibliographic source:

Reproductive Toxicology 22: 725-730

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Animals were randomly assigned to six groups of 15 animals each according to body weight and given different doses of iodine at the levels of 0, 1500, 3000, 6000, 12,000 and 24,000 µg/L by using sterile water as the vehicle. Four months later, female mice were placed into the metabolic cages of five mice each and urine samples over 3 h in the morning were collected for 3 days to measure urinary iodine concentration. Females were then paired overnight and examined for a vaginal plug the following morning. Dams were euthanized on day 19 of gestation.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Iodine

EC Number:

231-442-4

EC Name:

Iodine

Cas Number:

7553-56-2

Molecular formula:

I2

IUPAC Name:

iodine

Details on test material:

- Name of test material (as cited in study report): Iodine
- Analytical purity: Not reported
- Impurities (identity and concentrations): Not reported
- Lot/batch No.: Not reported
- Expiration date of the lot/batch: Not reported
- Stability under test conditions: Not reported
- Storage condition of test material: Not reported

Test animals

Species:

mouse

Strain:

Balb/c

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Laboratory Animal Center of Hubei Provincial Center for Disease Control and Prevention (Wuhan, China)
- Age at study initiation: Not reported
- Weight at study initiation: Not reported
- Fasting period before study: No
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: One week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 ºC
- Humidity (%): Not reported
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Not reported

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Iodine concentration in diet and water was measured by Cer-Arsenite colormetric method as modified by Fisher et al. (Anal Chem. 69:687-689, 1986).

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 2 females: 1male
- Length of cohabitation: Overnight
- Further matings after two unsuccessful attempts: No
- Proof of pregnancy: vaginal plug referred to as [day 0 of pregnancy

Duration of treatment / exposure:

Animals were treated 4 months before and during gestation.

Frequency of treatment:

Daily (drinking water)

Duration of test:

Dams were euthanized on day 19 of gestation

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
1,500 µg/L
Basis:
nominal in water

Doses / concentrations 2

Remarks:

Doses / Concentrations:
3,000 µg/L
Basis:

Doses / concentrations 3

Remarks:

Doses / Concentrations:
6,000 µg/L
Basis:
nominal in water

Doses / concentrations 4

Remarks:

Doses / Concentrations:
12,000 µg/L
Basis:
nominal in water

Doses / concentrations 5

Remarks:

Doses / Concentrations:
24,000 µg/L
Basis:
nominal in water

No. of animals per sex per dose:

10 female and 5 males per group

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: Not reported, but presumibly necessary to obtain high iodine exposure.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: Not reported

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: Yes
- Time schedule for examinations: Statistic up to termination

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 19
- Organs examined:

OTHER: Urine samples over 3 h in the morning before mating to measure iodine to creatinine ratio. Thyroxine and triiodothyronine were also measured in day 19 of gestation. Histological examinaton of the thyroid was also performed as part of the maternal observations.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- gravid uterus weight: Yes
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:

Fetal examinations:

- External examinations: Yes:, all per litter
- Soft tissue examinations: Yes, all per litter
- Skeletal examinations: Yes, one-half to two-thirds per litter
- Head examinations: Yes, all per litter

Statistics:

Because of its skewed distribution, the median was used to describe the central tendency of urinary iodine concentration. The Kruskal–Wallis method was used to test the differences in ranking of urinary iodine concentration. One-way analysis of variance (ANOVA) was used to analyze thyroid hormone levels, maternal food and water consumption, maternal body weight gain, placental weight. Two-way ANOVA with factors = treatment and sex was performed to analysis the gender difference in fetal weight. When significant effects were observed by ANOVA, the data for the treated groups were compared statistically with the control group by Duncan’s multiple range test. The ratios of live, resorbed and dead fetuses were analyzed by variance and Duncan’s test after arcsine transformation. The incidence of skeletal anomalies was analyzed by χ2-test. Significance was set at the 0.05 probability level.

Indices:

Dams
Implants/litter

Fetuses
Live fetuses/implants
Resorbed fetuses/implants
Dead fetuses/implants
Ratio of males/total

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Compared to control group, serum TT4 level increased and serum TT3 decreased significantly in dams when iodine dose reached 3000 µg/L.

Effect levels (maternal animals)

1

Dose descriptor:

LOAEL

Effect level:

3 000 other: µg/L

Based on:

other: Test substance in drinking water

Basis for effect level:

other: developmental toxicity

2

Dose descriptor:

NOAEL

Effect level:

1 500 other: µg/L

Based on:

other: test substance in drinking water

Basis for effect level:

other: developmental toxicity

3

Dose descriptor:

NOAEL

Effect level:

1 500 other: µg/L

Based on:

other: Test substance in drinking water

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
The results of fetal observation showed that high doses of iodine exposure induced a decrease in the incidence of live fetuses and an increase in the incidence of reabsorbed fetuses (Table 1). Excess iodine-associated reduction in fetal body weight was observed only in female fetuses of 6000, 12,000 or 24,000g/L groups. Neither obvious external alternations nor visceral malformations were found in fetuses in any treated groups.
Exposure to high doses of iodine resulted in an increase in the incidence of skeletal variations dose-dependently (r = 0.80, p < 0.05), and this increase was statistically significant in the high doses of iodine groups except 1500g/L group compared to control group (Table 2). Skeletal alterations included supernumerary ribs, agenesis of sternbrae, poor ossification of metacarpals and metatarsals, abnormal fusion of supraoccipital and malaligned vertebral centra. No multiple defects found in the same fetus. The form of ectopic or supernumerary ribs (SNR) was commonly observed (Table 2).

Effect levels (fetuses)

Dose descriptor:

LOAEL

Effect level:

1 500 other: µg/L

Based on:

other: test substance in drinking water

Basis for effect level:

other: fetotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Table 1: Pregnancy outcome following chronic high doses of iodine exposure.

Dose groups ( µg/L)	0	1500	3000	6000	12000	24000
Dams
Number of dams pregnant (%)	10 (100)	9 (90)	9 (90)	8 (80)	9 (90)	9 (90)
Number of examined litters	7	8	8	7	7	8
Implants/litter	5.6 ± 2.4	6.6 ± 1.3	7.3 ± 2.1	5.7 ± 1.3	7.6 ± 1.3	7.6 ± 1.5
Average daily food consumption (g)	4.8 ± 0.4	4.6 ± 0.3	4.7 ± 0.3	4.5 ± 0.5	4.3 ± 0.4*	4.3 ± 0.3
Average daily water consumption (mL)	4.9 ± 0.8	4.8 ± 0.9	4.8 ± 1.2	4.5 ± 1.3	4.2 ± 0.7	4.2 ± 1.2
Body weight gain (g)	11.386 ± 3.339	10.762 ± 2.058	11.363± 3.531	10.840 ± 1.705	11.243 ± 2.651	11.138 ± 3.673
Mean placenta weight (g)	0.126 ± 0.019	0.113 ± 0.014	0.106 ± 0.009*	0.104 ± 0.011*	0.109 ± 0.019*	0.102 ± 0.012*
Fetuses
Live fetuses/implants (%) (a)	92.3 ± 7.2	72.5 ± 9.4*	69.8 ± 14.6*	67.9 ± 17.5*	64.4 ± 10.0*	63.2 ± 17.4*
Resorbed fetuses/implants (%) (a)	7.7 ± 7.2	27.5 ± 9.4*	26.2 ± 10.8*	28.1 ± 13.5*	28.6 ± 13.1*	27.0 ± 15.3*
Dead fetuses/implants (%) (a)	0 ± 0	1.6 ± 4.4	4.1 ± 5.7	4.1 ± 7.0	7.0 ± 9.0	9.9 ± 15.1
Fetal body weight (g)
Males	1.21 ± 0.12	1.13 ± 0.29	1.14 ± 0.11	1.21 ± 0.12	1.21 ± 0.06	1.18 ± 0.11
Females	1.20 ± 0.13	1.09 ± 0.16	1.11 ± 0.11	1.05 ± 0.09*	1.05 ± 0.11*	1.05 ± 0.18*
Ratio of males/total	0.48	0.47	0.50	0.46	0.44	0.46

Data represented mean ± S.D.

(a) data were analyzed after arcsine transformation.

* p < 0.05 compared with the control group by χ2-test Table 2: Skeletal variations by chronic high doses of iodine exposure

Table 2: Skeletal variations by chronic high doses of iodine exposure

Dose groups ( µg/L)	0	1500	3000	6000	12000	24000
Dams
Number of examined litters	7	8	8	7	7	8
Number of fetuses examined (a)	22	23	19	18	22	28
Number of skeletal malformation (%) (b)	2 (9.1)	6 (26.1)	8 (42.1)*	8 (44.4) *	11 (50.0)*	15 (53.6)*
Supernumerary ribs	2	5	6	6	8	11
Agenesis of sternbrae	0	1	0	1	2	0
Poor ossification of metacarpals and metatarsals	0	0	0	0	0	1
Abnormal fusion of suppraoccipital	0	0	0	1	1	2
Malaligned vertebral centra	0	0	2	0	0	1

(a) One-half or two-thirds of the live fetuses were used for skeletal examination

(b) No multiple defects found in the same fetus

* p < 0.05 compared with the control group by χ2-test.

Applicant's summary and conclusion

Conclusions:

Based on study results, embryotoxicity and teratogenicity were mainly indicated by the reduced body weight in female fetuses, the decreased number of live fetuses, and the increased incidence of resorptions, and especially skeletal variations. A NOAEL for fetotoxicity could not be obtained. Fetotoxicity LOAEL was 1500 µg/L.

Executive summary:

To evaluate the effects of chronic exposure to high amounts of iodine on pregnancy and fetal outcome, Balb/C mice were given different doses of iodine at the levels of 0, 1500, 3000, 6000, 12,000 and 24,000 µg/L by using sterile water as the vehicle. Four months later, female mice were placed into the metabolic cages of five mice each and urine samples over 3 h in the morning were collected for 3 days to measure urinary iodine concentration. Females were then paired overnight and examined for a vaginal plug the following morning. Dams were euthanized on day 19 of gestation. Animals were examined daily and after euthanization thyroid was examined as well as thyroidal hormones levels were measured. The gravid uterus of the pregnant mice were weighed, the number of positions of the live or dead fetuses, together with resorptions, were recorded. Live fetuses were examined for external abnormalities and for skeletal examination.

Based on study results, embryotoxicity and teratogenicity were mainly indicated by the reduced body weight in female fetuses, the decreased number of live fetuses, and the increased incidence of resorptions, and especially skeletal variations. A NOAEL for fetotoxicity could not be obtained. Fetotoxicity LOAEL was 1500 µg/L.