Orthoperiodic acid

Endpoint summary

Description of key information

90-Day Study (read-across; Guo et al., 2005)

Under the conditions of the study KIO3 was found to result in lower thyroxine in serum, lipid metabolism disorder and retina dysfunction in rats. The NOAEL of KIO3 in rats was determined to be 3000 μg/L. Serum TC level was found to be a sensitive contacting biomarker of excessive iodine.

Repeat Dose, Reproductive and Developmental Toxicity Screening (read-across; Vorhees et al., 1984)

Under the conditions of the study, dietary doses of up to 0.1 % w/w test material in the diet, equivalent to approximately 90 mg/kg/day, produced only minor effects on parental weight gain and food consumption, and no significant effects on parental mortality. The NOAEL for parental toxicity was therefore determined to be 90 mg/kg/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Remarks:

The study was conducted on the read across substance, potassium iodate. Investigations on the gastric hydrolysis of the registration substance indicate a chemical reaction of periodate to iodate thereby confirming the validity of the read across.

Reason / purpose for cross-reference:

other: read across: target

Principles of method if other than guideline:

Groups of 10 female rats were administered test material, in drinking water, over a period of 13 weeks. At the end of the treatment period, after electroretinogram examination on selected rats, all animals were sacrificed. Haematology and clinical chemistry examinations were performed. Internal organs were weighed and examined histopathologically.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiaion: Weanling
- Source: Hubei laboratory animal center (Hubei, China)
- Weight at study initiation: 50 - 60 g
- Acclimation period: 5 days

Route of administration:

oral: drinking water

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

90 days

Frequency of treatment:

daily

Dose / conc.:

3 000 other: µg/L

Dose / conc.:

6 000 other: µg/L

Dose / conc.:

12 000 other: µg/L

Dose / conc.:

24 000 other: µg/L

Dose / conc.:

48 000 other: µg/L

Dose / conc.:

96 000 other: µg/L

Dose / conc.:

192 000 other: µg/L

No. of animals per sex per dose:

10 females per dose

Control animals:

yes

Details on study design:

- Dose selection rationale: The dose which is 100 times the recommended nutrient intake (RNI) of iodine per adult per day was used in this experiment as the lowest dose, i.e.250 μg/kg. And the dose is 422 μg/kg if converted to KIO3. Daily water intake of rats were estimated to be 160~200 mL/kg. Thus, we can calculate that the lowest dose was 3000μg/L. Acute toxicity test which has been done in this experiment showed that the LD50 value of
KIO3 for female Wistar rats was 667 mg/kg, taking 1/20 of the LD50 value as the highest dose, i.e.33 mg/kg, and the drinking water concentration was 200 000 μg/L. Within the range of 3000~200 000 μg/L, total 7 dose groups were set up using two times the group interval.
- Rationale for animal assignment: the animals were divided into 8 groups according to their weight.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: General conditions were observed twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Weekly

WATER CONSUMPTION : Yes
- Time schedule for examinations: Weekly

OPHTHALMOSCOPIC EXAMINATION: Yes

BLOOD COLLECTION: Yes
The bloods were collected from caudal veins of rats to determine the haematologic parameters (clinical microscopy method). All rats were sacrificed through heart blood collection, and serum was separated for testing the serum biochemical parameters (kits, determined by semiautomatic biochemistry analyser) and thyroid hormone (radioimmunoassay).

URINALYSIS: Yes
For the determination of urine iodine level, acid digestion arsenic cerium catalytic spectrophotometric method was adopted. At the end of the 13th week, 5 rats were randomly selected from the control group and high dose groups, respectively for the ERG examination according to literature methods.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Liver, kidney and spleen were taken and weighed, organ coefficients were calculated and the organs of each group were examined by pathological section (HE staining).

Statistics:

SPSS 12.0 software package was used for data analysis.

Clinical signs:

no effects observed

Description (incidence and severity):

During the experiment, animals of each group showed no obvious toxic reactions.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The weights of rats dosed at concentrations of 3000 and 6000 µg/L increased faster than animals dosed at 48 000 µg/L and above, but there was no significant difference (P > 0.05) when compared to the control group.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

The average daily food intake of rats was not affected by KIO3. The first month’s food utilisation of rats in each group also showed no obvious change trends.

Food efficiency:

not examined

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

effects observed, treatment-related

Description (incidence and severity):

Results show that high doses of KIO3 can affect the water intake of rats. The daily water intake of rats dosed at 48 000 µg/L and above decreased. Rats dosed at 48 000, 96 000 and 192 000 µg/L showed significant differences (P<0.05 or P<0.01) when compared with animals in the control group.

Ophthalmological findings:

effects observed, treatment-related

Description (incidence and severity):

- ERG: The mechanism of KIO3’s damage to retina was not clear and possibly related to its own oxidation. The appropriate amount, and high doses, of potassium iodide and KIO3 were administered to iodine deficient rats for 22 weeks. The antioxidant capacity of the normal iodine group was better than that of the 2 high iodine groups, and the total retina antioxidant capacity of rats in potassium iodide group was higher than that of the KIO3 group. Therefore, the doses and dosage forms of iodine all have significant effects on the retina antioxidant capacity of iodine deficient rats.
To test the theory that the retina toxicity of iodate is related to its interference on the metabolism of amino acid inside retina and damage of the blood retinal barrier, the ERG method was used in this study. The method found that the amplitude of a and b waves of ERG both decreased significantly in the highest dose group rats, but there was no obvious abnormity in retina pathological sections, which means high KIO3 doses can possibly damage the functions of retina at first.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Blood of rats in each group was tested at the end of the experiment, the leukocytes amount of rats dosed at 6000 µg/L and above increased (P<0.01) while that of other groups was within normal ranges, and there was no significant difference (P>0.05) observed for other indexes among the groups.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

The test results of blood biochemical index at the end of the experiment suggested that KIO3 has an effect on the metabolism of sugar, lipid and protein, especially TC. The results of variance analysis showed that TC values of animals dosed at 6000 µg/L and above were all higher than that of control group, and the differences were significant (P<0.05) except for the group dosed at 96 000 µg/L. TC values tended to increase at first and then decreased, and the values of the 96 000 and 192 000 µg/L dose groups were the lowest. TP values of the two groups also declined and significant differences (P<0.05) were observed when compared to the controls. Glucose (Glu) values were also increased first and then decreased, but there was no significant difference among the groups. Other blood biochemical indexes were not significantly affected by KIO3.
- Changes of serum thyroid hormone level: The levels of serum TT4, TT3 and rT3 went up with increasing doses of KIO3 .
- ERG: The results of ERG examination suggested that the amplitude of a (18.8 ± 4.4 μv) and b (79.7 ± 18.2 μv) waves of ERG were significantly lower (P < 0.05) in rats dosed at 192 000 µg/L compared to that of other groups.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

- Terminal urine iodine: The urine iodine levels of each dose group were significantly different (P < 0.01) compared with the control group. The higher the dose of KIO3, the higher the level of urine iodine.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

The kidney/weight value of rats dosed at 192 000 µg/L and the spleen/weight value of rats dosed at 24 000, 96 000 and 192 000 µg/L increased and showed significant differences (P<0.05) compared to animals in the control group. The other organ coefficients (including ovary/weight, liver/weight and lung/weight) were not apparently affected by KIO3.

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Pathological sections of each organ (thyroid, retina, liver, kidney, gastrointestinal, spleen, lung and ovary) were observed by microscopy, and there were no significant pathologic changes.

Histopathological findings: neoplastic:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

3 000 other: µg/L

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical biochemistry

ophthalmological examination

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

6 000 other: µg/L

System:

endocrine system

Organ:

thyroid gland

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

Effects of KIO3 on the serum thyroid hormone level of rats

KIO3 doses of 48 000 μg/L and above can decrease the serum thyroid hormone level of rats. In the study, values of TT4, TT3 and rT3 all decreased with increasing KIO3 doses, which means that high dose of KIO3 may result in hypothyroidism of rats. There were, however, no colloid goiter of rats observed in any dose group.

 

Effects of KIO3 on the lipid metabolism of rats

Higher doses of KIO3 can increase the serum TC level. Indeed, during the study, as the KIO3 dose increased, the serum TC first increased and then decreased; serum TC was the most sensitive to high iodine. In this experiment, lipid disorder of rats was likely to be related to high iodine and hypothyroidism.

The study revealed that the TC values of groups dosed at 6000 μg/L and above were significantly higher than that of the control group. Meanwhile, the study also showed that serum TC level was more sensitive than crowd goiter rate when used as the contacting biomarker of excessive iodine.

Conclusions:

Under the conditions of the study KIO3 was found to result in lower thyroxine in serum, lipid metabolism disorder and retina dysfunction in rats. The NOAEL of KIO3 in rats was determined to be 3000 μg/L. Serum TC level was found to be a sensitive contacting biomarker of excessive iodine.

Executive summary:

The repeated dose toxicity of the test material was investigated in a study in which groups of 10 female rats were administered test material, in drinking water, over a period of 13 weeks. Animals were dosed at 3000, 6000, 12 000, 24 000, 48 000, 96 000 and 192 000 µg/L, a concurrent control group was administered with plain drinking water. At the end of the treatment period, after electroretinogram examination on selected rats, all animals were sacrificed. Haematology and clinical chemistry examinations were performed. Internal organs were weighed and examined histopathologically.

 

The levels of serum TT4, TT3 and rT3 increased with increasing doses of KIO3, while total cholesterol (TC), triglyetide (TG) in serum and white blood cell (WBC) rose significantly in animals dosed at 6000 μg/L and above (P < 0.05). In addition, the amplitude of a and b waves of ERG were significantly lower in the highest KIO3 group rats compared to the control rats (P < 0.05).

Under the conditions of the study, KIO3 was found to result in lower thyroxine in serum, lipid metabolism disorder and retina dysfunction in rats. The NOAEL of KIO3 in rats was determined to be 3000 μg/L. Serum TC level was found to be a sensitive contacting biomarker of excessive iodine.

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted on read-across material.

Justification for type of information:

A read-across justification report (RAAF) will be added to Section 13 as soon as possible.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

3 000 other: µg/L

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical biochemistry

ophthalmological examination

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

6 000 other: µg/L

System:

endocrine system

Organ:

thyroid gland

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

Reference 3

Endpoint:

repeated dose toxicity: oral, other

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted on read-across material.

Justification for type of information:

A read-across justification report (RAAF) will be added to Section 13 as soon as possible.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

0.1 other: % w/w

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects

Critical effects observed:

no

Reference 4

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Remarks:

As the study was conducted on the read-across substance, potassium iodide, it has been assigned a reliability score of 2.

Reason / purpose for cross-reference:

other: read across: target

Principles of method if other than guideline:

Test material was fed to male and female rats before and during breeding, to females only during gestation and lactation, and to their offspring after weaning (day 21 after birth) through to day 90, at levels of 0, 0.025, 0.05 or 0.1 % (w/w) in the diet. To investigate the repeated dose toxicity of the test material to parental animals, body weights and food consumption was measured; animals were also checked regularly for mortality.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Laboratory Supply Co., Indianapolis, USA
- Weight at study initiation: 200 - 240 g
- Diet: Purina rat chow meal, ad libitum
- Acclimation period: 5 days

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Mixing appropriate amounts with (Type of food): Purina rat chow meal was supplemented with 0 (two control groups), 0.025, 0.05 or 0.1 % (w/w) potassium iodide.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

- Parents (males and females): 14 days before mating; 1-14 days during breeding.
- Female only (mother): during gestation (22 days) and lactation (21 days)
- Offspring: given dietary potassium iodide, at the level their parents had received, throughout the remainder of the experiment (up to 90 days of age for most animals and somewhat longer for those in avoidance testing).

Frequency of treatment:

Continuously (in diet)

Dose / conc.:

0.025 other: (w/w) potassium iodide nominal in diet

Dose / conc.:

0.05 other: % (w/w) potassium iodide nominal in diet

Dose / conc.:

0.1 other: % (w/w) potassium iodide nominal in diet

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Parental animals were checked for mortality

BODY WEIGHT: Yes
- Time schedule for examinations: weekly (except during breeding)

FOOD CONSUMPTION: Yes
- Time schedule for examinations: measured on selected rats during all phases of the experiment.

Other examinations:

The date of birth (postnatal day 0) of all litters and the length of gestation were recorded.
On the day following birth, all litters were examined and data collected on litter size, sex distribution, weight, and number of dead and/or malformed offspring. At this time, two males and two females from each litter were designated for pre-weaning testing. In addition to these four, two other males and two other females from each litter were later designated for post-weaning testing. The testing procedure was conducted blind with respect to treatment.

Statistics:

Analysis of variance (ANOVA) was performed on the majority of data (general linear model), and Duncan's pairwise comparisons made between individual groups in the event of significant treatment F-ratios. On all tests litter was used as the unit of analysis. On preweaning tests this was done by averaging scores together from all tested littermates. On post-weaning tests this was done by testing only one male and one female from each litter on each test. An exception was vaginal patency which was analysed as though it were a preweaning test. Frequency data were analysed using Fisher's test for uncorrelated proportions (Guilford, 1965).

Clinical signs:

no effects observed

Description (incidence and severity):

There were no significant effects.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

A reduction in male food consumption was found in the group dosed at 0.1 % w/w test material prior to breeding, but this reduction resulted in only a marginal decease in body weight (p < 0.09). No effects were found on maternal body weight during gestation. During lactation in the group dosed at 0.025 % w/w test material maternal body weight was reduced (P < 0.05) during lactation.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

A reduction in male (P < 0.01), but not female, food consumption was found in the group dosed at 0.1 % w/w test material prior to breeding. No effects were found on maternal food consumption during gestation. Maternal food consumption was reduced during lactation in the group dosed at 0.025 % w/w test material.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Dose descriptor:

NOAEL

Effect level:

0.1 other: % w/w

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects

Dose descriptor:

NOAEL

Effect level:

ca. 90 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects

Critical effects observed:

no

Dose Levels

The test material doses, calculated from food consumption measurements, for the 0.025 % w/w group were 2, 22 and 34 mg/kg/day prior to breeding, during gestation and during lactation, respectively, for females; for the 0.05 % w/w dose group they were 46, 44 and 66 mg/kg/day; and for the 0.1 % w/w group they were 93, 92 and 140 mg/kg/day, respectively.

Conclusions:

Under the conditions of the study, dietary doses of up to 0.1 % w/w test material in the diet, equivalent to approximately 90 mg/kg/day, produced only minor effects on parental weight gain and food consumption, and no significant effects on parental mortality. The NOAEL for parental toxicity was therefore determined to be 90 mg/kg/day.

Executive summary:

The repeated dose toxicity of the test material was investigated in a study in which the test material was fed to male and female rats before and during breeding, to females only during gestation and lactation, and to their offspring after weaning (day 21 after birth) through to day 90, at levels of 0, 0.025, 0.05 or 0.1 % (w/w) in the diet. To investigate the repeated dose toxicity of the test material to parental animals, body weights and food consumption was measured; animals were also checked regularly for mortality.

Under the conditions of the study, dietary doses of up to 0.1 % w/w test material in the diet, equivalent to approximately 90 mg/kg/day, produced only minor effects on parental weight gain and food consumption, and no significant effects on parental mortality. The NOAEL for parental toxicity was therefore determined to be 90 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

90 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

90-Day Study (read-across; Guo et al., 2005)

The repeated dose toxicity of the test material was investigated in a study in which groups of 10 female rats were administered test material, in drinking water, over a period of 13 weeks. Animals were dosed at 3000, 6000, 12 000, 24 000, 48 000, 96 000 and 192 000 µg/L, a concurrent control group was administered with plain drinking water. At the end of the treatment period, after electroretinogram examination on selected rats, all animals were sacrificed. Haematology and clinical chemistry examinations were performed. Internal organs were weighed and examined histopathologically.

The levels of serum TT4, TT3 and rT3 increased with increasing doses of KIO3, while total cholesterol (TC), triglyetide (TG) in serum and white blood cell (WBC) rose significantly in animals dosed at 6000 μg/L and above (P < 0.05). In addition, the amplitude of a and b waves of ERG were significantly lower in the highest KIO3 group rats compared to the control rats (P < 0.05).

Under the conditions of the study, KIO3 was found to result in lower thyroxine in serum, lipid metabolism disorder and retina dysfunction in rats. The NOAEL of KIO3 in rats was determined to be 3000 μg/L. Serum TC level was found to be a sensitive contacting biomarker of excessive iodine.

Repeat Dose, Reproductive and Developmental Toxicity Screening (read-across; Vorhees et al., 1984)

The repeated dose toxicity of the test material was investigated in a study in which the test material was fed to male and female rats before and during breeding, to females only during gestation and lactation, and to their offspring after weaning (day 21 after birth) through to day 90, at levels of 0, 0.025, 0.05 or 0.1 % (w/w) in the diet. To investigate the repeated dose toxicity of the test material to parental animals, body weights and food consumption was measured; animals were also checked regularly for mortality.

Under the conditions of the study, dietary doses of up to 0.1 % w/w test material in the diet, equivalent to approximately 90 mg/kg/day, produced only minor effects on parental weight gain and food consumption, and no significant effects on parental mortality. The NOAEL for parental toxicity was therefore determined to be 90 mg/kg/day.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to repeated dose toxicity.