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Administrative data

Description of key information

Oral route : Repeated dose toxicity LOEL was considered to be 400 mg/kg/day in crossbred (Hampshire x Yorkshire x Landrace) pigs.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Qualifier:
according to
Guideline:
other:
Principles of method if other than guideline:
In a repeated dose study, the toxicity of iodine was assessed in pigs for 111 days.
GLP compliance:
not specified
Limit test:
no
Species:
pig
Strain:
other: Crossbred (Hampshire x Yorkshire x Landrace)
Sex:
not specified
Details on test animals and environmental conditions:
Details on test animal
- Source: No data available
- Age at study initiation: No data available
- Weight at study initiation:
Trial 1: Avg wt 28 kg
Trial 2: Avg wt 17 kg
Trial 3: Avg wt 9 kg
- Fasting period before study: No data available
- Housing: Pigs were housed in individual pens on concrete slotted floors.
- Diet (e.g. ad libitum): Basal diet containing ground shelled corn, soybean oil meal, defluorinated phosphate, ground limestone, trace mineral salt, vitamin supplement and neo-terramycin, ad libitum
- Water (e.g. ad libitum): Ad libitum

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

IN-LIFE DATES: From: To: No data available







Route of administration:
oral: feed
Vehicle:
other: basal diet
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Calcium iodate were mixed with basal diet which contained

INGREDIANT Percent
Ground shelled corn 81.17
Soybean oil meal 15.83
Defluorinated phosphate 1.00
Ground limestone 0.90
Trace mineral salt 0.50
Vitamin supplement 0.50
Neo-Terramycin 0.10

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): Basal diet (contains described above).
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): Basal diet

- Concentration in vehicle:
Trial 1: 0, 10, 20, 40 or 80 ppm/day
Trial 2: 0, 25, 50, 100, 200, 400, 800 or 1600 ppm/day
Trial 3: 0, 800 ppm/day iodine, 800 ppm/day iodine+2140 ppm/day ferrous sulphate or 800 ppm/day iodine+75 mg/pig/week iron dextran

- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Trial 1: 84 days
Trial 2: After 97 or 111 days
Trial 3: 70 days
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
Trial 1: 0, 10, 20, 40 or 80 ppm (mg/kg/day)
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
Trial 2: 0, 25, 50, 100,200, 400, 800 or 1,600 ppm (mg/kg/day)
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
Trial 3: basal + 800 ppm (mg/kg/day) added iodine; basal + 800 ppm (mg/kg/day) added iodine + 2,140 ppm (mg/kg/day) added iron (ferrous sulphate – FeSO4 ,dried powder); or basal + 800 ppm(mg/kg added iodine with 75 mg/pig/week of iron, as iron dextran.
Basis:
nominal in diet
No. of animals per sex per dose:
Trial 1
Control: 12 pigs
10 ppm/day: 12 pigs
20 ppm/day: 12 pigs
40 ppm/day: 12 pigs
80 ppm/day: 12 pigs

Trial 2
Control: 8 pigs
25 ppm/day: 8 pigs
50 ppm/day: 8 pigs
100 ppm/day: 8 pigs
200 ppm/day: 8 pigs
400 ppm/day: 8 pigs
800 ppm/day: 7 pigs
1600 ppm/day: 7 pigs

Trial 3
Control: 6 pigs
800 ppm/day iodine: 6 pigs
800 ppm/day iodine+2140 ppm/day ferrous sulphate: 6 pigs
800 ppm/day iodine+75 mg/pig/week iron dextran: 6 pigs

Control animals:
yes, concurrent vehicle
Details on study design:
Three trials were conducted to investigate the effects of elevated levels of iodine (calcium iodate) in the diets of growing-finishing swine. Crossbred (Hampshire x Yorkshire x Landrace) pigs were used.

Trial 1
Diets were formulated to contain 0, 10, 20, 40 or 80 ppm/day added iodine. Pigs were weighed and feed intake measured at 2-week intervals for 84 days, after which the pigs were sacrificed. Blood serum samples were obtained. At sacrifice, thyroid glands were collected, trimmed of extraneous tissues, blotted and weighed. Samples were taken from the quadrate lobe of the liver and analyzed for iron by atomic absorption spectroscopy.

Trial 2
Methods and procedures were similar to those used in Trial 1, with the exceptions noted. The diets were formulated to contain 0, 25, 50, 100,200, 400, 800 or 1600 ppm/day added iodine. The weighing interval was 14 days, except for a 13-day interval between days 84 and 97. Serum samples were obtained and blood samples for hemoglobin analysis were taken.

Trial 3
Pigs were blocked according to body weight and randomly assigned to four treatments to study the effect of dietary and injectable iron in combination with dietary iodate. Two replications of three pigs/pen were allotted to the following treatments: basal diet; basal + 800 ppm added iodine; basal + 800 ppm added iodine + 2,140 ppm added iron (ferrous sulphate - FeSO4 ,dried powder); or basal + 800 ppm added iodine with 75 mg/pig/week of iron, as iron dextran. The ferrous sulphate containing diet was calculated to supply an equal milliequivalent level of iron II and iodate. Iron dextran was injected intramuscularly to meet the estimated physiological requirement of pigs that received this form of iron.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: No
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations:
Trial1: Pigs were weighed at 2-week intervals
Trial 2: The weighing interval was 14 days, except for a 13-day interval between days 84 and 97.
Trial 3: The pigs were weighed every 14 days

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: Yes

FOOD EFFICIENCY: No
- 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

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

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

HAEMATOLOGY: Yes
- Time schedule for collection of blood:
Test 2: Blood samples for hemoglobin analysis were taken at 104 and 111 days.
Test 3: Blood samples for hemoglobin analysis were obtained at 14-day intervals for 70 days.
- Anaesthetic used for blood collection: No
- Animals fasted: No data available
- How many animals: All animals included in trials 2 and 3.
- Parameters examined:
Trial 2: Hemoglobin
Trial 3: Hemoglobin

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
Test 1: Blood serum samples were obtained by jugular puncture on 7, 28, 5 and 84 days.
Test 2: Serum samples were obtained at 14, 42, 70 and 97 days.
Test 3: Blood samples were obtained for total serum iodine analysis at 1, 42 and 70 days.
- Animals fasted: No data available
- How many animals: All animals included in the study.
- Parameters examined:
Trial 1: Serum iodine and liver iron
Trial 2: Serum iodine, serum butanol extractable iodine and liver iron
Trial 3: Serum iodine

URINALYSIS: No
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine:
- Animals fasted:
- Parameters examined:

NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Trial 1: At sacrifice, thyroid glands were collected, trimmed of extraneous tissues, blotted and weighed.
Trial 2: At sacrifice, thyroid glands were collected and weighed.
Trial 3: Animals receiving treatments 800 ppm/day of iodine, 800 ppm/day iodine+2140 ppm/day ferrous sulphate and 800 ppm/day iodine+75 mg/pig/week iron dextran were sacrificed and their thyroid glands were weighed.

HISTPATHOLOGY: Yes
Trial 1: Samples were taken from the quadrate lobe of the liver and analyzed for iron by atomic absorption spectroscopy after wet ashing.
Trial 2: At sacrifice, liver samples were obtained for iron determinations.
Statistics:
Data were analyzed for treatment differences by least squares analysis of variance using a generalized least squares program.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
Clinical signs and mortality:
No clinical signs or mortality observed.

Body weight and weight gain
Trial 1: No significant increased body weight observed.
Trial 2: Decreased body weight observed in pigs treated with 800 or 1600 ppm/day as compared to control.
Trial 3: Decreased body weight observed in pigs treated with 800 ppm/day of iodine, 800 ppm/day iodine+2140 ppm/day ferrous sulphate or 800 ppm/day iodine+75 mg/pig/week iron dextran.

Food consumption and compound intake
Trial 1: No significant increased food consumption observed.
Trial 2: Pigs fed either 800 or 1600 ppm/day of iodine gained significantly slower, consumed significantly less feed and were significantly less efficient in feed conversion than pigs in other treatment groups.
Trial 3: Less daily gain and decreased food consumption observed in pigs exposed to 800 ppm/day of iodine, 800 ppm/day iodine+2140 ppm/day ferrous sulphate or 800 ppm/day iodine+75 mg/pig/week iron dextran.

Haematology
Trial 1: No data available.
Trial 2: Hematocrit was low for pigs fed 800 or 1600 ppm/day of added dietary iodine prior to sacrifice of the four heavier replications.
On both day 104 and 111 the hemoglobin levels of pigs fed either the 800 or 1600 ppm/day diets were significantly lower.
Trial 3: Pigs receiving added iodine with no added iron had a gradual decrease in hemoglobin levels with time.

Clinical chemistry
Trial 1: Serum iodine values were significantly increased by adding iodine to the diets of pig.
Trial 2: Serum iodine values were markedly increased due to the addition of iodine to the diet. The mean serum BEI of pigs receiving the 1600 ppm/day diet was higher as compared to control.
Trial 3: Serum iodine also appeared to be greater in pigs in Trial 3 than in pigs fed 800 ppm added iodine in Trial 2.

Organ weights
Trial 1: Thyroid weights were significantly increased by adding iodine to the diets of pigs.
Trial 2: Thyroid weights were significantly increased by adding iodine to the diets of pigs.
Trial 3: Pigs receiving no added iodine gained significantly faster than pigs receiving added iodine and no supplemental iron. The pigs receiving added iodine and iron were intermediate in their rate of gain. Supplemental iron, in either form, tended to increase feed consumption over that observed when 800 ppm added iodine was fed with no added iron.

Feed:gain ratio tended to increase when iron was added. These results indicate that the availability of and/or interference with the metabolism of iron may be partially responsible for the decreased performance of pigs fed the two higher levels of iodine during Trial 2. Thyroid weights tended to be increased with the addition of iodine to the diet, and were not affected by iron injection.

Gross pathology
Trial 1: No external signs of iodinism were noted during Trial I. However, submaxillary salivary glands were enlarged to the point that they were easily palpated in some pigs on all elevated iodine diets.
Trial 2: The pigs fed either the 800 or 1600 ppm/day level of dietary iodine and several fed lower levels developed an encrustation around the eyes. This appeared to be due to lacrimal secretion and dust accumulation. In addition, one pig in both the 800 and 1600 ppm/day treatments of Trial 2 developed eye lesions.
Trial 3: No data available

Histopathology
Trial 1: No data avilable
Trial 2: Eye lesions were confined to the cornea and were characterized by opacity and hyperplasia of the corneal epithelium.
Trial 3: No data available
Dose descriptor:
LOEL
Effect level:
400 other: mg/kg/day
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: Body weight, iodine concentration, thyroid gland development and liver iron concentration.
Critical effects observed:
not specified
Conclusions:
LOEL was considered to be 400 mg/kg/day in crossbred (Hampshire x Yorkshire x Landrace) pigs.
Executive summary:

In a study investigating the toxicity of iodine three trials were conducted to study the effects of elevated dietary iodine (calcium iodate) intake on the performance, thyroid gland development, liver iron concentration and certain blood constituents in pigs. No differences in performance measures were noted at iodine levels of 400 mg/kg/day or lower, however, all levels of added iodine increased serum iodine levels and thyroid gland weights. The feeding of diets containing 400 to 1600 mg/kg/day added iodine significantly depressed liver iron concentration. Growth rate, feed intake and hemoglobin levels were depressed when pigs received diets containing either 800 or 1600 mg/kg/day added iodine. Therefore, LOEL was considered to be 400 mg/kg/day when crossbred (Hampshire x Yorkshire x Landrace) pigs were exposed to iodine on a daily basis.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
400 mg/kg bw/day
Study duration:
chronic
Species:
pig
Quality of whole database:
The data is K2 level as the data has been obtained from the experimental study from the reliable journal .Based upon this available data it is expected that the test chemical Calcium iodate does not exhibit repeated oral toxicity to pig.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxicity: Oral

Based on the various studies available with Klimish rating 2 for the target as well as read across substances for CAS NO 7789-80-2, also from category based on organic functional group along with similar mechanistic approach and having structural similarities defined by QSAR toolbox. The results for target as well as analogues are summarized as follows

 

Sr. No

End point

Value

Species

Route

Effects

Remarks

1

LOEL

400 mg/kg/day

 

Pig

Oral feed

serum iodine levels and thyroidgland weights increased,depressed liver iron concentration, 

 

Publication data for target chemical

2

NOAEL

225 mg/kg bw/day

Dog

Oral Capsule

 

Predicted data for target chemical

3

LOEL

 

 

 

 

 

NOAEL

714.285 mg/kg bw/day

 

 

 

357.142 mg/kg bw/day

mice

Oral drinking water

Body weight, water consumption and increased hemolysis.

 

water consumption and increased hemolysis.

Publication data for CAS NO 7758-05-6

4

LOEL

 

 

 

 

 

NOAEL

90 mg/kg/day

 

 

 

 

 

60 mg/kg/day

Dog

Oral

weight gain, hemosiderin in the spleen, liver, and kidneys,mild anemia

 

Emesis and vomating was observed

Publication data for CAS NO 7758-05-6

5

LOAEL

100 mg/l drinking water

Rat

Oral drinking water

modifications of thyroid function was observed

Publication data for CAS NO 7681-82-5

 

Based on the studies summarized in the above table it is observed that NOAEL values vary from 60 – 357.142 mg/kg bw/day. Whereas the lowest effect observed value (LOEL) values varies from 90 -714.285 mg/kg bw/d. The effects observed on these doses was listed as follows

 

·        serum iodine levels and thyroidgland weights increased,depressed liver iron concentration

·        Body weight, water consumption and increased hemolysis.

·        weight gain, hemosiderin in the spleen, liver, and kidneys,mild anemia was also observed

·        modifications of thyroid function was observed

·        Emesis and vomiting was observed

 

Thus based on above values it can be concluded that substance CAS NO 7789-80-2 is expected to show the similar toxicological effect based on the effects observed on the other category members. Since no effective dose value (NOAEL) is 60 mg/Kg bw/d thus based on this value it can be concluded that substance CAS NO 7789-80-2 is considered to be not toxic to repeated dose via oral route for the above mentioned dose. Also there are no known evidence of adverse effect to Human of CAS NO 7789-80-2 as well as mechanistic trigger does not indicates any concern of CAS NO 7789-80-2 on toxicity to human.

 

 

Repeated dose toxicity: Inhalation

This end point was considered for waiver since calcium iodate has negligible vapour pressure and therefore exposure via the inhalation route is will not take place, justifying this end point for waiver.

Repeated dose toxicity: Dermal

A waiver is proposed for this data requirement; adequate data are available to assess the toxicity of TPA by the oral and inhalation routes.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
In a study investigating the toxicity of iodine three trials were conducted to study the effects of elevated dietary iodine (calcium iodate) intake on the performance, thyroid gland development, liver iron concentration and certain blood constituents in pigs. No differences in performance measures were noted at iodine levels of 400 mg/kg/day or lower, however, all levels of added iodine increased serum iodine levels and thyroid gland weights. The feeding of diets containing 400 to 1600 mg/kg/day added iodine significantly depressed liver iron concentration. Growth rate, feed intake and hemoglobin levels were depressed when pigs received diets containing either 800 or 1600 mg/kg/day added iodine. Therefore, LOEL was considered to be 400 mg/kg/day when crossbred (Hampshire x Yorkshire x Landrace) pigs were exposed to iodine on a daily basis.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
This end point was considered for waiver since calcium iodate has negligible vapour pressure and therefore exposure via the inhalation route is will not take place, justifying this end point for waiver.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
The acute toxicity value for calcium iodate (as provided in section 7.2.1) is 1300mg/kg body weight. which is relatively non toxic. Thus, it is expected that calcium iodate shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that calcium iodate shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Justification for classification or non-classification

Based on the above information, these are effects which adversely alter human function for a short duration after exposure and from which humans may recover in a reasonable period without leaving significant alteration of structure or function. thus the substance will qualify for STOT - SE 3 category classification as per the regulation.