Ammonium iodide

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from peer reviewed publication

Data source

Reference

Reference Type:

publication

Title:

Repeated dose oral toxicity study of the test chemical

Author:

Pitsiavas et al

Year:

1997

Bibliographic source:

European Journal of Endocrinology

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

15 weeks repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Sodium iodide

EC Number:

231-679-3

EC Name:

Sodium iodide

Cas Number:

7681-82-5

Molecular formula:

INa

IUPAC Name:

sodium iodide

Details on test material:

- Name of test material: Sodium iodide
- Molecular formula :I Na
- Molecular weight : 149.89427 g/mol
- Substance type:Inorganic
- Physical state:Solid
- Impurities (identity and concentrations):N/A

Test animals

Species:

rat

Strain:

Wistar

Details on species / strain selection:

No data

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data
- Age at study initiation: 4 weeks
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: No data
- Diet (e.g. ad libitum): Rat chow
- Water (e.g. ad libitum): No data
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%):No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: To: No data

Administration / exposure

Route of administration:

oral: drinking water

Details on route of administration:

No data

Vehicle:

water

Remarks:

Sterile drinking water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: The test chemical at dose level of 0 or 10mg/Kg bw was dissolved in sterile distilled water to produce iodide water

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): Sterile drinking water
- Concentration in vehicle: 0 or 10 mg/Kg/day
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

15 weeks

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

0 or 10 mg/Kg/bw

No. of animals per sex per dose:

Total: 17
0 mg/Kg/bw: 8
10 mg/Kg/bw: 9

Control animals:

yes, concurrent vehicle

Details on study design:

No data

Positive control:

No data

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. No data

DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: No data

BODY WEIGHT: No data
- Time schedule for examinations: No data

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

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: No data
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. Total thyroxine (T4) and total tri-iodothyronine (T3) were analysed, Thyrotrophin (TSH), Reverse T3

URINALYSIS: No data
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, thyoid gland was examined

HISTOPATHOLOGY: Yes, After washing out red blood cells, the
thyroid gland was removed and stored in Karnovsky fixative (2.5% glutaraldehyde, 2.5% pure formalin in 0.1M MOPS buffer, pH7.4) for 3 h and then cut into
1mm3 blocks. Both lobes were diced and processed using a Polaron E9000 EM Tissue Processor. On average 20 diced sections were prepared from each rat thyroid gland and 6 were selected randomly for block preparation. For histological assessment sections were cut at 0.5 mm thickness and stained with methylene blue; they were photographed using Kodak Technical Pan
Film (black and white; magnification X 399). For EM assessment resin-embedded ultra-thin sections were stained with uranyl acetate and lead citrate and examined using a Phillips EM 201S transmission electron microscope. Photographs of sections were recorded on Kodak SO-281 electron microscope film (35mm) and developed in Kodak D19 developer. The observed changes were graded by two of the authors (VP and LM) independently without knowledge of the treatment groups. The changes were graded as follows: (a) follicular disruption, ER dilatation and lymphocytic infiltration: 0, none observed; 1, low; 2, moderate; 3, marked; (b) lysosomal numbers: 1, low; 2, moderate; 3, marked; (c) lipofuscinogenesis: 1, low;
2, moderate; 3, marked.

Other examinations:

No data

Statistics:

The thyroid function results are expressed as means±S.E. Analysis of difference was performed using analysis of variance (ANOVA) followed by Scheffes test for significance of differences among multiple experimental groups.

Results and discussion

Results of examinations

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

Iodide had no effect on reverse T3

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Macroscopically the thyroid gland appeared small and white in colour.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

In the 15-week-old Wistar rat controls fed sterile water, the thyroid follicles were morphologically intact, microvilli were regular in shape at the apical surface and the colloid was evenly stained. Nuclei were regular in shape with evenly stained chromatin and regular nucleoli. Under higher magnification the ER was of normal appearance and mitochondria also appeared normal with oval and rod shapes present. Lysosomes were present with low numbers of lipofuscin bodies. There was no evidence of tissue damage, apoptosis or inclusion bodies.

The Wistar rats on iodide water gave similar results to the Wistar controls. Under EM examination the follicles appeared intact with cuboidal cells. The colloid was evenly stained with regular microvilli at the apical surface. Nuclei were regularly shaped with evenly stained chromatin. Both ER and mitochondria appeared normal. Lysosomes were present in greater numbers than in the control groups. Tissue damage and apoptosis were not observed in this group, nor were inclusion bodies.

Folicular architecture in the Iodide treated groups was essentially normal. Lysosomes were increased and there was no lymphocytic infiltration.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

No data

Effect levels

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: No significant effects were noted at the mentioned dose level

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1 Thyroid function test results and weights of 15-week-old W rats on sterile water, iodide water. Results are reported as mean±S.E. with n indicating the number in each group.

	Control group	Test group
Total T4	663.3 2.3	62.1 4.0
Total T3	1.04 0.08	0.84 0.04
Reverse T3	0.090 0.018	0.057 0.02
TSH	0.729 0.2	5.76 0.76*
Weight (g)	331 32	365 39

*P < 0:05 compared with control groups

Table 2 Results of thyroid ultrastructural changes in 15-week-old W rats treated with sterile water (Control) and iodide water.

	Control	Test group
Macroscopic gland appearance	Small, white colour	Small, white colour
Follicles	Morphologically intact	Morphologically intact
Follicular disruption	0	0
Colloid	Evenly stained	Evenly stained
Microvilli	Regular	Regular
Nucleus	Regular shape, evenly stained	Regular shape, evenly stained
Apoptosis	None observed	None observed
ER dialation	0	0
Lysosomal numbers	1	3
Lipofuscinogenesis	1	2
Inclusion bodies	0	0
Lymphocytic infiltration	0	1

 

Results were graded as follows: follicular disruption, ER dilatation, lymphocytic infiltration: 0 – none observed, 1 – low, 2 – moderate, 3 – marked; lysomomal numbers: 1 – low, 2 – moderate, 3 – marked; lipofuscinogenesis: 1 – low, 2 – moderate, 3 – marked.

Applicant's summary and conclusion

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for the test chemical using Wistar rats for 15 weeks repeated oral toxicity study is considered to be 10 mg/Kg bw.

Executive summary:

15 weeks repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical. The study was performed using 8-10/group Wistar rats for 15 weeks. The test chemical at dose level of 0 or 10 mg/Kg bw was dissolved in sterile distilled water to produce iodide water. Blood was collected for thyroid function analysis prior to removal of the thyroid. The thyroid gland was further removed for microscopic examination.Iodide had no effect on reverse T3. Macroscopically the thyroid gland appeared small and white in colour. The Wistar rats on iodide water gave similar results to the Wistar controls. Under EM examination the follicles appeared intact with cuboidal cells. The colloid was evenly stained with regular microvilli at the apical surface. Nuclei were regularly shaped with evenly stained chromatin. Both ER and mitochondria appeared normal. Lysosomes were present in greater numbers than in the control groups. Tissue damage and apoptosis were not observed in this group, nor were inclusion bodies. Follicular architecture in the Iodide treated groups was essentially normal. Lysosomes were increased and there was no lymphocytic infiltration. Based on the observations made, No Observed Adverse Effect Level (NOAEL) for the test chemical using Wistar rats for 15 weeks repeated oral toxicity study is considered to be 10 mg/Kg bw.