Potassium iodate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study

Based on the data available from different studies, LOAEL for the test chemical was considered to be 250 mg/kg bw/day, when male and female rats were treated with the test chemical orally. Thus, comparing this value with the criteria of CLP regulation, the test chemical is likely to classify as reproductive toxicant.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

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

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 publication

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Principles of method if other than guideline:

Study 2: The above experiment was performed to examine and analyze the reproductive toxicity of the test chemical in Sprague Dawley Rats.
Study 3: The above experiment was performed to assess and evaluate the effects of the test chemical on female minks.
Study 4: The above experiment was performed to assess and evaluate the effects of the test chemical on Long-Evans rats.
Study 5: Experiment I: One generation study
Lactating females were given a 1.0% (w/v) solution or a 0.1% (w/v) solution of test chemical to drink from Day 0 of pregnancy trough Day 12 or 13 post-partum pregnancy.
Experiment II: Fertility
Females were given 0.1. (w/v) solution of the test chemical to drink from Day 0 of pregnancy. The rats were killed on Day 7.

GLP compliance:

not specified

Justification for study design:

No Data Available

Specific details on test material used for the study:

- Molecular weight (if other than submission substance): 213.995 g/mol
- Substance type: Inorganic
- Physical state: No Data Available
- Impurities (identity and concentrations): No Data Available

Species:

other: Study 2: rat; Study 3: Mink; Study 4: rat and Study 5: rat

Strain:

other: Study 2: Sprague-Dawley, Study 3: Pastel mink; Study 4: Long-Evans; Study 5: Wistar

Details on species / strain selection:

No Data Available

Sex:

female

Details on test animals or test system and environmental conditions:

Study 2: TEST ANIMALS
- Source: Laboratory Supply Co., Indianapolis, IN
- Weight at study initiation: 200-240 g
- Diet (e.g. ad libitum): Purina rat chow meal
- Acclimation period: 5 days

Study 3: TEST ANIMALS
- Age at study initiation: One year old
- Housing: The mink were housed and cared for according to routine commercial mink ranch procedures

Study 4: TEST ANIMALS
- Housing: Animals were housed individually in wire cages. Prior to littering, rats were transferred to 3 X 3 mesh wire cages.
- Diet (e.g. ad libitum): Purina Laboratory Chow were provided ad libitum
- Water (e.g. ad libitum): Tap water was supplied ad libitum

Study 5: No Data Available

Route of administration:

other: Study 2, Study 3 and Study 4: oral: feed; Study 5: Drinking Water

Vehicle:

other: Study 2 and 4:Purina rat chow meal; Study 3:basal diet (consisting of 30% commercial cereal, 30% ocean fish mix, 20% poultry, 7.5% tripe, 7.5% beef trimmings, and 5% beef liver)

Details on exposure:

Study 2: The newborn offspring were exposed through lactating females until weaning.
Study 3: Details on exposure
PREPARATION OF DOSING SOLUTIONS: The test chemical was administered through diet.

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

VEHICLE
- Justification for use and choice of vehicle (if other than water): The test chemical was best miscible in corn oil.
- Concentration in vehicle: 0, 10, 100 and 1000 ppm
- Amount of vehicle (if gavage): No Data Available
- Lot/batch no. (if required): No Data Available
- Purity: No Data Available

Study 4: Details on exposure
PREPARATION OF DOSING SOLUTIONS: The test chemical was administered through diet.

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

VEHICLE
- Justification for use and choice of vehicle (if other than water): The test chemical was best miscible in corn oil.
- Concentration in vehicle: 0, 2500 ppm (150 mg/kg bw)
- Amount of vehicle (if gavage): No Data Available
- Lot/batch no. (if required): No Data Available
- Purity: No Data Available

Study 5: The newborn offspring were exposed through lactating females until weaning

Details on mating procedure:

Study 2: Details of mating
- M/F ratio per cage: No data available
- Length of cohabitation: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: The day on which sperm were found was considered to be day 0 of gestation.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. No Data Available
- Further matings after two unsuccessful attempts: [no / yes (explain)]: No Data Available
- After successful mating each pregnant female was caged (how): No Data Available

Study 3: The females were mated to non-treated males
- Proof of pregnancy: All matings were confirmed by the presence of motile sperm in vaginal smears
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: No difficulties were encountered in mating. Most of the females accepted a second mating either the day following the initial mating or eight days later.

Study 4: - The sexually mature females were bred to normal males of the breed or strain. Monogamous pairs of rats were mated. When breeding occurred, the time of first copulation was recorded and gestation subsequently calculated from this time to birth of the first young of the litter. Fourteen female rats which had been fed the test chemical and had produced but lost all young in one or more litters were subsequently re-bred after removal from dietary iodine.

- After successful mating each pregnant female was caged (how): Individually

Study 5: - M/F ratio per cage: 1:1 (experiment I), No data available (experiment II)
- Length of cohabitation: Until confirmed pregnancy (Day 0)
- Proof of pregnancy: Presence spermatozoa in vaginal smear or a vaginal plug.
- After successful mating each pregnant female was caged (how): No Data Available
Experiment I: Pregnant females were caged in individual cages together with nine of their litters.
Experiment II: No data available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No Data Available

Duration of treatment / exposure:

Study 2: Males: 28 days
Females: 71 days
Study 3: 18 days (From breeding to lactation phase)
Study 4: 12 days
Study 5:Experiment I: Females were treated until they were killed on Day 12 or 13 post-partum pregnancy and gestation, incl. 9 or 10 days of lactation.
Experiment II: Females were killed on Day 7 after confirmed pregnancy.

Frequency of treatment:

Study 2, 3 and 4: Daily; Study 5: Daily after confirmed pregnancy

Details on study schedule:

Study 2: Males: 14 days before mating and for 1-14 days during breeding
Females: 14 days before mating and for 1-14 days during breeding; during gestation (22 days) and lactation (21 days).

Study 3: Details on study schedule
- F1 parental animals not mated until weeks after selected from the F1 litters: No Data Available
- Selection of parents from F1 generation when pups were [...] days of age: No Data Available
- Age at mating of the mated animals in the study: No Data Available

Study 4: - F1 parental animals not mated until weeks after selected from the F1 litters: No Data Available
- Selection of parents from F1 generation when pups were [...] days of age: No Data Available
- Age at mating of the mated animals in the study: No Data Available

Study 5: No Data Available

Remarks:

Study 2: 0, About 23,45 and 90 mg/kg bw /day
Study 3: 0, 10, 100 or 1000 ppm
Study 4: 0 and 150 mg/kg bw (2500 ppm)
Study 5: (I) 1.0% (w/v) solution or 0.1% (w/v) solution
(II) 0.1% (w/v) solution

No. of animals per sex per dose:

Study 2: No Data Available
Study 3: Control: 10 females
10 ppm: 10 females
100 ppm: 10 females
1000 ppm: 10 females
Study 4: 27 female rats were used
Study 5: Experiment I:
1% (w/v): 9 females
0.1% (w/v): 9 females
Experiment II:
0.1% (w/v): 8 females

Control animals:

yes

Details on study design:

No Data Available

Positive control:

Study 2: Dams were given two i.p. injections of 2 mg/kg of S-azacytidine on day 17 of gestation.

Parental animals: Observations and examinations:

Study 2: BODY WEIGHT: Yes
- Time schedule for examinations: Parental body weights were measured at weekly intervals except during breeding, and food consumption was measured on selected rats during all phases of the experiment.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
The test chemical doses, calculated from food consumption measurements, for the 0.025% test chemical group were 22, 22 and 34 mg/kg/day prior to breeding, during gestation and during lactation, respectively, for females; for the 0.05% test chemical group they were 46, 44 and 66 mg/kg/day; and for the 0.1% test chemical group they were 93, 92 and 140 mg/kg/day respectively.

Study 3: Feed consumption of mink fed the diet that contained the test chemical was examined.
The reproductive performance of the mink on the various treatments is evaluated on the basis of:
• Average no. of matings/female
• No. of females whelped
• Average gestation period
• Average no. kits/female mated

Study 4: Observations were made for length of parturition time and number of young born dead and those born live. Periodic observations were made through the lactation period for mothering instinct, evidence of lactation .

Study 5: Test substance intake, Body weights, Feed Consumption and Organ weights were observed.

Oestrous cyclicity (parental animals):

No Data Available

Sperm parameters (parental animals):

No Data Available

Litter observations:

Study 2: PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring:
Incisor eruption was observed daily from day 8 until all incisors were visible. Eye opening was observed daily from day 10 until both eyes were fully open in all rats. Testicular development was checked each day from day 10 until both testes could first be seen as two small nodules in the scrotum. 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.
.
Study 3: The kits were counted, sexed and weighed the day of birth and at 2 and 4 weeks of age.

Study 4: Survival of young animals was observed.

Study 5: No Data Available

Postmortem examinations (parental animals):

No Data Available

Postmortem examinations (offspring):

No Data Available

Statistics:

Study 2: 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. Adjustments of Duncan's test for un-equal group sizes were made using the procedure of Kramer.
Study 3: Dunnett’s t-test
Study 4: The data was subjected to statistical analysis. The analytical methods included Analysis of Variance (ANOVA).
Study 5: No Data Available

Reproductive indices:

No Data Available

Offspring viability indices:

Study 2: Pup Viability Index
Study 4: Pups Viability Index.

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Study 2: A reduction in male (P < 0.01), but not female, body weight was found in the 0. 1% test chemical group prior to breeding. Although, these cases were considered as sporadic.

Study 3: No effects were observed in body-weight gain at all the dose groups.

Study 4 and 5: Body weight changes related to the test chemical administration was observed.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Study 2: A reduction in male (P < 0.01), but not female, feed consumption was found in the 0. 1% test chemical group prior to breeding. Although, these cases were considered as sporadic.

Study 3: No effects were observed in feed consumption at all the dose groups.

Study 4 and 5: Changes in feed consumption related to the test chemical administration was observed.

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:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Description (incidence and severity):

Study 3: Average gestation period: The gestation periods of the iodine treated mink were shorter than the controls. Average no. kits/female mated: 10 ppm supplemental dietary test chemical had no observable detrimental effects on litter size or kit survival. Only 2.1 kits/female mated were whelped by mink fed 100 ppm of the test chemical and none of females that received 1000 ppm test chemical whelped.

Study 5: Test chemical intake: Test chemical was mixed into the drinking water at concentrations of 1% (w/v) or 0.1% (w/v).

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

Study 2: No significant effects on parental mortality, fertility, pregnancy parameters, or gestation length were observed at any dose groups.

Study 3: None of females that received 1000 ppm of the test chemical whelped.

Study 4: Gestation time for rats was not affected by the test chemical; however, prolonged parturition was observed in rats.No signs of the beginning of lactation were observed.

Study 5: Treatment with 1% (w/v) of the test chemical prevented implantation in female rats.

Dose descriptor:

LOAEL

Effect level:

ca. 90 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

organ weights and organ / body weight ratios

reproductive performance

Critical effects observed:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

no effects observed

Description (incidence and severity):

Study 2: Upper and lower incisor eruption and eye opening were unaffected by treatment with the test chemical.

Dermal irritation (if dermal study):

not specified

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

Study 2: The test chemical produced significant increases in offspring mortality in the 90 mg/kg group at birth and up to day 24 after birth.
Study 3: 10 ppm supplemental dietary test chemical had no observable detrimental effects on litter size or kit survival. A dose of 100 ppm supplemental dietary test chemical caused a marked reduction in litter size and kit survival
Study 4: Average mortality was slightly greater of young from those fed with the test chemical.
Study 5: There were many deaths among the litters whose body weight were low when their mothers were treated with 1% of the test chemicals.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Study 2: The test chemical decreased preweaning body weights in both the 90 and 45 mg/kg groups.
Study 3: No effects were observed in body-weight gain at all the dose groups.
Study 4: Weaning weight was significantly less than that of controls.
Study 5: Experiment I Mean body weight: 1% (w/v): 11±1g, 0.1% (w/v): 14±1g ;
Experiment II: No data available

Food consumption and compound intake (if feeding study):

no effects observed

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:

not specified

Urinalysis findings:

not specified

Sexual maturation:

no effects observed

Description (incidence and severity):

Study 2: Testicular development was unaffected by treatment with the test chemical.

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Study 2: No significant effect was found on absolute or relative thyroid and testes weights at 90 days of age.
Study 5: Experiment I: Thyroid weight (mg/100 g of young): 1% (w/v): 14.0±1.3g; 0.1% (w/v): 14.6±0.6g
Experiment II: No data available

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

LOAEL

Generation:

F1

Effect level:

ca. 45 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

mortality

body weight and weight gain

Critical effects observed:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

From all the above observations, it was concluded that the LOAEL for the test chemical was found to be 45 mg/kg bw.

Executive summary:

Reproductive toxicity study:

Data available from different studies were reviewed to determine the reproductive toxicity of the test chemical. The studies are as mentioned below:

Reproductive Toxicity Study 2:

The above experiment was performed to study the effect of ingestion of the test chemical by parental examinations on the behavioural competence of developing animals is studied.The test chemicalwas administered in diet to male and female Sprague-Dawley rats before and during breeding, to females only during gestation and lactation, at levels of 0, about 23,45 and 90 mg/kg bw [0, 0.025, 0.05 or 0.1% (w/w)]. Dams in a positive control group were given 4 mg/kg ip of the anti-mitotic/cytotoxic drug 5-azacytidine on day 17 of gestation.The LOAEL value for the test chemical in rats is found to be about 90 mg/kg/day (0.1%). At this dose level, the test chemical did not produce any significant reduction in parental body weight or food consumption, though it significantly reduced litter size and increased offspring mortality.The LOAEL value for the test chemical is found to be about 45 mg/kg/day (0.05%) for the F1 generation based on the effect of decreased pre-weaning body weights in the offspring, delay in auditory startle and delayed olfactory orientation from the home-cage scent.Overall, the data in this experiment support the view that the test chemical at doses of up to 0.1% in the diet of growing rats produces evidence of developmental toxicity.

Reproductive Toxicity Study 3:

The effect of the test chemical on the reproductive performance of female minks was investigated.Female minks were administered with 0, 10, 100, or 1000 ppm of the test chemical, in diet for 18 days, from breeding through lactation. A total of 60 animals were used in the study. The animals were grouped in to 4 test groups 10 animals per group. The test animals were observed for , In litter observations, the kits were counted, weighed and sexed. From all the observations, it was found that, the gestation periods of the test chemical-treated mink were shorter than the controls. Kit birth weights were not significantly different from the controls. The average number of kits whelped per female mated in the control group was 5.0. Only 2.1 kits per female mated were whelped by the mink fed 100 ppm supplemental test chemical and none of the females that received the 1000 ppm supplemental test chemical diet whelped. Body weights of kits whelped and nursed by the females that received the 100 ppm supplemental test chemical diet were significantly lighter at 4 weeks of age.No detrimental effects were observed on litter size or kit survival in the group fed 10 ppm supplemental test chemical, and hence the NOAEL for reproductive toxicity in female minks is determined to be 10 ppm of the test chemical in the diet.

Reproductive Toxicity Study 4:

A study was conducted with rats to determine the effects of intake of the test chemical. A total of 27 animals were used in this study. Females were bred to normal males, wherein the test chemical was added to the diet during the latter portion of gestation and the females were permitted to litter normally. The effect of the treatment on gestation period, lactation and survival of the young was observed.It was observed that, gestation time for rats was not affected ; however, prolonged parturition was observed in rats. In fetal parameters, average mortality was slightly greater of young from those fed with the test chemical, while the weaning weight was significantly less than that of controls.In other experiment, the female rats were re-bred after removal of dietary intake of the test chemical. It was observed that the females gave birth and nursed litters normally. Thus, from all the oabove observations,LOAEL was found to be150 mg/kg bw andit is likely to be regarded that there is no reproductive toxicity at concentrations lower than150 mg/kg bwwhen administered orally.

Reproductive Toxcity Study 5:

In a one-generation (experiment I) and fertility (experiment II) reproductive study, pregnant female Wistar rats were given fluid orally on a regular basis at dose levels of 0.1% (w/v) or 1% (w/v) of the test chemical.Treatment with 1% (w/v) solution led to reduced body weight and fluid intake, their adrenal glands were enlarged and the level of implementation was prevented. No change in food or fluid intake was seen for rats treated with 0.1% (w/v) solution. In addition, the 0.1% (w/v) of the test chemical solution-treated rats showed a high rate of implantation.Since 0.1% (w/v) of the test chemical is regarded as a high value intake and it is concluded that the test chemical has no effect on reproductive toxicity when orally administered. Neither has it provided any further information about the possible functional significance of the test chemical endometrial concentration in female rats during early pregnancy.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

250 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The data is from a Klimisch 2 database.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity study:

Data available from different studies were reviewed to determine the reproductive toxicity of the test chemical. The studies are as mentioned below:

Reproductive Toxicity Study 2:

The above experiment was performed to study the effect of ingestion of the test chemical by parental examinations on the behavioural competence of developing animals is studied.The test chemicalwas administered in diet to male and female Sprague-Dawley rats before and during breeding, to females only during gestation and lactation, at levels of 0, about 23,45 and 90 mg/kg bw [0, 0.025, 0.05 or 0.1% (w/w)]. Dams in a positive control group were given 4 mg/kg ip of the anti-mitotic/cytotoxic drug 5-azacytidine on day 17 of gestation.The LOAEL value for the test chemical in rats is found to be about 90 mg/kg/day (0.1%). At this dose level, the test chemical did not produce any significant reduction in parental body weight or food consumption, though it significantly reduced litter size and increased offspring mortality.The LOAEL value for the test chemical is found to be about 45 mg/kg/day (0.05%) for the F1 generation based on the effect of decreased pre-weaning body weights in the offspring, delay in auditory startle and delayed olfactory orientation from the home-cage scent.Overall, the data in this experiment support the view that the test chemical at doses of up to 0.1% in the diet of growing rats produces evidence of developmental toxicity.

Reproductive Toxicity Study 3:

The effect of the test chemical on the reproductive performance of female minks was investigated.Female minks were administered with 0, 10, 100, or 1000 ppm of the test chemical, in diet for 18 days, from breeding through lactation. A total of 60 animals were used in the study. The animals were grouped in to 4 test groups 10 animals per group. The test animals were observed for , In litter observations, the kits were counted, weighed and sexed. From all the observations, it was found that, the gestation periods of the test chemical-treated mink were shorter than the controls. Kit birth weights were not significantly different from the controls. The average number of kits whelped per female mated in the control group was 5.0. Only 2.1 kits per female mated were whelped by the mink fed 100 ppm supplemental test chemical and none of the females that received the 1000 ppm supplemental test chemical diet whelped. Body weights of kits whelped and nursed by the females that received the 100 ppm supplemental test chemical diet were significantly lighter at 4 weeks of age.No detrimental effects were observed on litter size or kit survival in the group fed 10 ppm supplemental test chemical, and hence the NOAEL for reproductive toxicity in female minks is determined to be 10 ppm of the test chemical in the diet.

Reproductive Toxicity Study 4:

A study was conducted with rats to determine the effects of intake of the test chemical. A total of 27 animals were used in this study. Females were bred to normal males, wherein the test chemical was added to the diet during the latter portion of gestation and the females were permitted to litter normally. The effect of the treatment on gestation period, lactation and survival of the young was observed.It was observed that, gestation time for rats was not affected ; however, prolonged parturition was observed in rats. In fetal parameters, average mortality was slightly greater of young from those fed with the test chemical, while the weaning weight was significantly less than that of controls.In other experiment, the female rats were re-bred after removal of dietary intake of the test chemical. It was observed that the females gave birth and nursed litters normally. Thus, from all the oabove observations,LOAEL was found to be150 mg/kg bw andit is likely to be regarded that there is no reproductive toxicity at concentrations lower than150 mg/kg bwwhen administered orally.

Reproductive Toxcity Study 5:

In a one-generation (experiment I) and fertility (experiment II) reproductive study, pregnant female Wistar rats were given fluid orally on a regular basis at dose levels of 0.1% (w/v) or 1% (w/v) of the test chemical.Treatment with 1% (w/v) solution led to reduced body weight and fluid intake, their adrenal glands were enlarged and the level of implementation was prevented. No change in food or fluid intake was seen for rats treated with 0.1% (w/v) solution. In addition, the 0.1% (w/v) of the test chemical solution-treated rats showed a high rate of implantation.Since 0.1% (w/v) of the test chemical is regarded as a high value intake and it is concluded that the test chemical has no effect on reproductive toxicity when orally administered. Neither has it provided any further information about the possible functional significance of the test chemical endometrial concentration in female rats during early pregnancy.

Effects on developmental toxicity

Description of key information

Developmental toxicity study:

Based on the data available from different studies, LOAEL for the test chemicalwas considered to be 250 mg/kg bw/day, when male and female rats were treated with the test chemical orally. Thus, comparing this value with the criteria of CLP regulation, the test chemical is likely to classify as developmental toxicant.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

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

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 a publication

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

The above experiments were performed for the assessment and evaluation of the effects of the test chemical on the developmental parameters of the test animals.

GLP compliance:

not specified

Specific details on test material used for the study:

- Molecular formula (if other than submission substance): I-O3.K
- Molecular weight (if other than submission substance): 213.995 g/mol
- Substance type: Inorganic
- Physical state: No Data Available
- Impurities (identity and concentrations): No Data Available

Species:

other: Study 2: rat; Study 3: rat; Study 4: hamster, Syrian

Strain:

other: Study 2: Sprague-Dawley; Study 3: Long-Evans; Study 4: Syrian

Details on test animals or test system and environmental conditions:

Study 2: TEST ANIMALS
- Source: Laboratory Supply Co., Inidanapolis, IN
- Weight at study initiation: 200-240 g
- Diet (e.g. ad libitum): Purina rat chow
- Acclimation period: 5 days
- Sex: Male/ Female

Study 3: Details on test animal
TEST ANIMALS
- Housing:Animals were housed individually in wire cages. Prior to littering, rats were transferred to 3 X 3 mesh wire cages.
- Diet (e.g. ad libitum):Purina Laboratory Chow were provided ad libitum
- Water (e.g. ad libitum):Tap water was supplied ad libitum

Study 4: TEST ANIMALS
- Housing: Animals were housed in individual wire cages. Prior to littering, the hamsters were provided sterilized bedding in cages with solid metal floors.
- Diet (e.g. ad libitum): Purina laboratory chow for hamsters, ad libitum
- Water (e.g. ad libitum): Tap water was supplied ad libitum
- Sex: Male/Female

Route of administration:

other: Study 2, 3 and 4: oral: feed;

Vehicle:

other: Study 2: Purina rat chow meal; Study 3: Diet as Purina Laboratory Chow; Study 4: Purina laboratory chow for hamsters

Details on exposure:

Study 2: The newborn offspring were exposed through lactating females until weaning
Study 3: No Data Available
Study 4: No Data Available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No Data Available

Details on mating procedure:

Study 2:- Proof of pregnancy: The day on which sperm were found was considered to be day 0 of gestation.
- M/F ratio per cage: No data available
- Length of cohabitation: 1-4 days
- Proof of pregnancy: The day on which sperm were found was considered to be day 0 of gestation.
- Any other deviations from standard protocol: No data available

Study 3:- The sexually mature females were bred to normal males of the breed or strain.

- Monogamous pairs of rats were mated. When breeding occurred, the time of first copulation was recorded and gestation subsequently calculated from this time to birth of the first young of the litter. Fourteen female rats which had been fed with the test chemical and had produced but lost all young in one or more litters were subsequently re-bred after removal of the test chemical

- After successful mating each pregnant female was caged (how): Individually

Study 4: Sexually mature females were bred to normal males of the breed or strain. After successful mating each pregnant female was caged individually.

Duration of treatment / exposure:

Study 2: Male: 2 week(s) pre-mating
Female: 2 week(s) pre-mating to 13 day(s) post-birth
Offspring: After weaning upto 90 days of age

Study 3: 12 days

Study 4: 12 days

Frequency of treatment:

Study 2, 3 and 3: Daily

Duration of test:

Study 2: Males: 14 days before mating and during 1-4 days of breeding
Females: 14 days before mating, 1-4 days of breeding, 22 days of gestation and 21 days of lactation
Offspring: After weaning, up to 90 days of age

Study 3: From breeding to day 21 of suckling

Study 4: From breeding to day 21 of suckling

Remarks:

Study 2: (I) Doses / Concentrations:
0, About 23,45 and 90 mg/kg bw
Basis:
nominal in diet
for parents
(II) Doses / Concentrations:
0,About 42,81 and 160 mg/kg bw
Basis:
nominal in diet
for offspring
Study 3: Doses / Concentrations:
0,150 mg/kg bw (2500 ppm)
Basis:
Study 4: Doses / Concentrations:
160 mg/kg bw (2500 ppm)
Basis:
nominal in diet

No. of animals per sex per dose:

Study 2: Negative control: 22 pregnant females
Positive control: 27 pregnant females
0.025% (w/w) test chemical: 30 pregnant females
0.05% (w/w) test chemical: 26 pregnant females
0.1% (w/w) test chemical: 19 pregnant females
Study 3: 27 females
Study 4: No Data Available

Control animals:

yes

Details on study design:

Study 2: - Positive-control: Dams were given two ip injections of 2 mg/kg of 5-azacytidine on day 17 of gestation.

- Other: Litters with fewer than eight live offspring were not kept beyond 1 day after birth. Litters of more than 12 were reduced to 12 by a random selection procedure that balanced the sex distribution as much as possible

Maternal examinations:

Study 2: Parental body weights were measured at weekly intervals except during breeding, and food consumption was measured on selected rats during all phases of the experiment.
Study 3:
Study 4:

Ovaries and uterine content:

No Data Available

Fetal examinations:

Study 2: - Incisor eruption was observed daily from day 8 until all incisors were visible.
- Eye opening was observed daily from day 10 until both eyes were fully open in all rats.
- Testicular development was checked each day from day 10 until both testes could first be seen as two small nodules in the scrotum.
- Vaginal patency was noted daily on females
Study 3: All surviving young from each female in the control and experimental groups were permitted to nurse through the normal suckling period.
Study 4: All surviving young from each female in the control and experimental groups were permitted to nurse through the normal suckling period

Statistics:

Study 2: 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. Adjustments of Duncan's test for unequal group sizes were made. On all tests litter was used as the unit of analysis. Frequency data were analysed using Fisher's test for uncorrelated proportions.
Study 3 and 4: The statistical data was analyzed by using Analysis of Variance (ANOVA).

Indices:

Study 3 and 4: Pups Viability Index.

Historical control data:

No Data Available

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

Study 4: The mortality among nursing hamsters from females fed with the test chemical was high.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Study 2: No changes in the maternal body weights were observed at any given dose levels.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Study 2: Maternal food consumption was reduced during lactation in the 0.025% (w/w) of the test chemical.
Study 3: Voluntary feed intake of rats fed with the test chemical was about 6 to 7% less than that of control rats and this reduced feed intake
Study 4: Voluntary feed intake of the diets containing added test chemical by the pregnant and lactating hamsters was approximately 10% less than that of the controls.

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:

not specified

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:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

effects observed, treatment-related

Description (incidence and severity):

Study 2:The test chemical produced significant increased mortality in offspring in the 0.1% (w/w) group at birth and up to day 24 after birth. The 0.025% (w/w) of the test chemical group, by contrast, showed reduced mortality up to day 24.
Study 3: An increased incidence of death in the neonates, with <10% of the young surviving for 3 days.
Study 4: Mortality of the young was high but approximately equal in both the experimental and control groups.

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

Study 2: Gestation time for rats was not affected by the test chemical.
Study 3: Gestation time for rats was not affected by the test chemical.
Study 4: No Data Available
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): Study 2: Gestation time for rats was not affected by the test chemical.
Study 3: Gestation time for rats was not affected by the test chemical.
Study 4: No Data Available

Changes in number of pregnant:

not specified

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Study 2: Gestation time for rats was not affected by the test chemical; however, prolonged parturition was observed in rats.No signs of the beginning of lactation were observed.
Study 3 and 4: No Data Available

Dose descriptor:

LOAEL

Effect level:

0.025 other: % (w/w) per day

Based on:

test mat.

Basis for effect level:

other: Maternal Toxicity

Abnormalities:

not specified

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Study 2: The test chemical decreased body weights in both the 0.1 and 0.05% (w/w) groups. These effects were virtually identical for both males and females and were significant on days 14 and 21 in the test chemical groups, but not earlier. There were no significant weight reductions found in the 0.025% (w/w) group.

Study 3: Weaning weight was significantly less than that of controls.

Study 4: No Data Available
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Study 2: The test chemical decreased body weights in both the 0.1 and 0.05% (w/w) groups. These effects were virtually identical for both males and females and were significant on days 14 and 21 in the test chemical groups, but not earlier. There were no significant weight reductions found in the 0.025% (w/w) group.
Study 3: Survival of the young and body weights at weaning were equal to those of controls.
Study 4: No Data Available

Reduction in number of live offspring:

not specified

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

effects observed, treatment-related

Description (incidence and severity):

Study 2: The test chemical produced significant increased mortality in offspring in the 0.1% (w/w) group at birth and up to day 24 after birth. The 0.025% (w/w) of the test chemical group, by contrast, showed reduced mortality up to day 24.
Study 3: No Data Available
Study 4: Mortality of the young was high but approximately equal in both the experimental and control groups. The cause of high mortality is not known.

External malformations:

no effects observed

Description (incidence and severity):

Study 2: Upper and lower incisor eruption and eye opening were unaffected by treatment. No significant group effects were found on vaginal patency or on testicular development.
Study 3:

Skeletal malformations:

not specified

Visceral malformations:

no effects observed

Description (incidence and severity):

Study 2: No significant effect was found on absolute or relative thyroid weight at 90 days of age. No effects were found on cerebellar or total brain weights. The medulla pons showed a significantly reduced weight in the 0.1% (w/w) of the test chemical group only.

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Study 2: - Test chemical delayed auditory startle at the two highest doses by 1 day but did not significantly affect surface-righting or negative geotaxis behaviour and the behavioral tests of active or passive avoidance learning.
- The 0.025% (w/w) and 0.05% (w/w) of the test chemical groups showed delayed olfactory orientation towards their home-cage scent, but only in the 0.025% (w/w) group the delay was significant
- Open field activity: All groups except 0.1% (w/w) showed shorter starting latencies.
- Running wheel activity: females in all groups were significantly less active during dark cycle. There was no significant difference among males.
- M-maze: The 0.025% (w/w) of the test chemical group made significantly more errors on the swimming M-maze
- Rotorod: the 0.025% (w/w) of the test chemicalgroup required significantly more trials to reach criterion.

Study 3 and 4: No Data Available

Dose descriptor:

LOAEL

Effect level:

0.025 other: % (w/w) per day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

changes in postnatal survival

visceral malformations

other: Please see 'remarks'

Abnormalities:

not specified

Developmental effects observed:

yes

Lowest effective dose / conc.:

0.025 other: % (w/w) per day

Treatment related:

not specified

Relation to maternal toxicity:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

From all the above observations, it was concluded that the LOAEL for the test chemical was found to be 45 mg/kg bw.

Executive summary:

Developmental toxicity study:

Data available from different studies were reviewed to determine the developmental toxicityof the test chemical. The studies are as mentioned below:

Developmental toxicity study 2:

The above experiment was performed to study the effect of ingestion of the test chemical by parental examinations on the behavioural competence of developing animals is studied.The test chemicalwas administered in diet to male and female Sprague-Dawley rats before and during breeding, to females only during gestation and lactation, at levels of 0, about 23,45 and 90 mg/kg bw [0, 0.025, 0.05 or 0.1% (w/w)]. Dams in a positive control group were given 4 mg/kg ip of the anti-mitotic/cytotoxic drug 5-azacytidine on day 17 of gestation.The LOAEL value for the test chemical in rats is found to be about 90 mg/kg/day (0.1%). At this dose level, the test chemical did not produce any significant reduction in parental body weight or food consumption, though it significantly reduced litter size and increased offspring mortality.The LOAEL value for the test chemical is found to be about 45 mg/kg/day (0.05%) for the F1 generation based on the effect of decreased pre-weaning body weights in the offspring, delay in auditory startle and delayed olfactory orientation from the home-cage scent.Overall, the data in this experiment support the view that the test chemical at doses of up to 0.1% in the diet of growing rats produces evidence of developmental toxicity.

Developmental Toxicity Study 3:

A study was conducted with rats to determine the effects of intake of the test chemical. A total of 27 animals were used in this study. Females were bred to normal males, wherein the test chemical was added to the diet during the latter portion of gestation and the females were permitted to litter normally. The effect of the treatment on gestation period, lactation and survival of the young was observed.It was observed that, gestation time for rats was not affected ; however, prolonged parturition was observed in rats. In fetal parameters, average mortality was slightly greater of young from those fed with the test chemical, while the weaning weight was significantly less than that of controls.In other experiment, the female rats were re-bred after removal of dietary intake of the test chemical. It was observed that the females gave birth and nursed litters normally. Thus, from all the above observations,LOAEL was found to be150 mg/kg bw andit is likely to be regarded that there is no reproductive and developmental toxicity at concentrations lower than150 mg/kg bwwhen administered orally.

Developmental Toxicity Study 4:

A one-generation study was conducted on Syrian hamsters to determine the effects of excess of the test chemical intake.Females were bred with normal males while the test chemical (2500 ppm per day or 160 mg/kg bw) was added to their diet during the latter portion of gestation and the females were permitted to litter normally. The effect of the treatment on gestation period, lactation and survival of the young was observed. After all the observations were performed, it was found that, in maternal animals, the mortality among nursing hamsters from females fed with the test chemical was high. Also, voluntary feed intake of the diets containing added test chemical by the pregnant and lactating hamsters was approximately 10% less than that of the controls. However, these cases were considered as sporadic. In fetal parameters, mortality of the young was high but approximately equal in both the experimental and control groups, however, the cause of high mortality is not known. In some cases, some cases of “wet tail” and evidence of dehydration were observed in both control and treated animals.Since there was an absence of specific effects upon reproduction and lactation in pregnant female hamsters, or no increased levels of mortality of the young compared to control, NOAEL of both the parental generation and the F1 generation was considered to be 2500 ppm per day of the test chemical.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

250 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The data is from a Klimisch 2 database.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Developmental toxicity study:

Data available from different studies were reviewed to determine the developmentaltoxicityof the test chemical. The studies are as mentioned below:

Developmental toxicity study 2:

The above experiment was performed to study the effect of ingestion of the test chemical by parental examinations on the behavioural competence of developing animals is studied.The test chemicalwas administered in diet to male and female Sprague-Dawley rats before and during breeding, to females only during gestation and lactation, at levels of 0, about 23,45 and 90 mg/kg bw [0, 0.025, 0.05 or 0.1% (w/w)]. Dams in a positive control group were given 4 mg/kg ip of the anti-mitotic/cytotoxic drug 5-azacytidine on day 17 of gestation.The LOAEL value for the test chemical in rats is found to be about 90 mg/kg/day (0.1%). At this dose level, the test chemical did not produce any significant reduction in parental body weight or food consumption, though it significantly reduced litter size and increased offspring mortality.The LOAEL value for the test chemical is found to be about 45 mg/kg/day (0.05%) for the F1 generation based on the effect of decreased pre-weaning body weights in the offspring, delay in auditory startle and delayed olfactory orientation from the home-cage scent.Overall, the data in this experiment support the view that the test chemical at doses of up to 0.1% in the diet of growing rats produces evidence of developmental toxicity.

Developmental Toxicity Study 3:

A study was conducted with rats to determine the effects of intake of the test chemical. A total of 27 animals were used in this study. Females were bred to normal males, wherein the test chemical was added to the diet during the latter portion of gestation and the females were permitted to litter normally. The effect of the treatment on gestation period, lactation and survival of the young was observed.It was observed that, gestation time for rats was not affected ; however, prolonged parturition was observed in rats. In fetal parameters, average mortality was slightly greater of young from those fed with the test chemical, while the weaning weight was significantly less than that of controls.In other experiment, the female rats were re-bred after removal of dietary intake of the test chemical. It was observed that the females gave birth and nursed litters normally. Thus, from all the above observations,LOAEL was found to be150 mg/kg bw andit is likely to be regarded that there is no reproductive and developmental toxicity at concentrations lower than150 mg/kg bwwhen administered orally.

Developmental Toxicity Study 4:

A one-generation study was conducted on Syrian hamsters to determine the effects of excess of the test chemical intake.Females were bred with normal males while the test chemical (2500 ppm per day or 160 mg/kg bw) was added to their diet during the latter portion of gestation and the females were permitted to litter normally. The effect of the treatment on gestation period, lactation and survival of the young was observed. After all the observations were performed, it was found that, in maternal animals, the mortality among nursing hamsters from females fed with the test chemical was high. Also, voluntary feed intake of the diets containing added test chemical by the pregnant and lactating hamsters was approximately 10% less than that of the controls. However, these cases were considered as sporadic. In fetal parameters, mortality of the young was high but approximately equal in both the experimental and control groups, however, the cause of high mortality is not known. In some cases, some cases of “wet tail” and evidence of dehydration were observed in both control and treated animals.Since there was an absence of specific effects upon reproduction and lactation in pregnant female hamsters, or no increased levels of mortality of the young compared to control, NOAEL of both the parental generation and the F1 generation was considered to be 2500 ppm per day of the test chemical.

Justification for classification or non-classification

From the NOAEL and LOAEL values obtained for the test chemical for toxicity to reproduction as well as developmental toxicity, it is considered that the chemical may qualify for classification as a reproductive or developmental toxicant.