Orthoperiodic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The NOAEL for reproductive toxicity in the rat was determined to be ca. 90 mg/kg bw/day (administered in the diet) (potassium iodide)

Link to relevant study records

Reference

Reference 1

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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 reproductive toxicity of the test material to parental animals 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.

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 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.

Details on mating procedure:

- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of gestation

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

No. of animals per sex per dose:

Up to 30 females (19-30)

Control animals:

yes, plain diet

Positive control:

Positive-control dams were given two ip injections of 2 mg/kg of 5-azacytidine on day 17 of gestation

Parental animals: Observations and examinations:

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.

Litter observations:

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.

Postmortem examinations (parental animals):

GROSS PATHOLOGY (parental animals): No data
HISTOPATHOLOGY (parental animals): No data

Postmortem examinations (offspring):

On day 90 after birth, rats from each litter that had not been tested behaviourally were killed with an overdose of ether and the cerebellum, medulla-pons, prosencephalon and eyes were weighed.

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

Mortality:

no mortality observed

Description (incidence):

There were no significant effects on parental mortality.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

A marginal decease in body weight (p < 0.09) was seen in male rats dosed at 0.1 % w/w test material prior to breeding. No effects were found on maternal body weight during gestation.
A reduction was found (P < 0.05) for maternal body weight during lactation in the group dosed at 0.025 % w/w test material.

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

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

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

Potassium iodide significantly increased the proportion of litters born with less than eight live offspring at the highest dose (0.1 %). This group also showed a significant reduction in mean litter size, as did the 0.25 % group although this effect fell short of statistical significance. None of the other criteria used to assess reproductive performance showed any effects.

Key result

Dose descriptor:

NOAEL

Remarks:

reproductive toxicity

Effect level:

0.1 other: % w/w in diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects

Key result

Dose descriptor:

NOAEL

Remarks:

reproductive toxicity

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

Key result

Critical effects observed:

no

Clinical signs:

no effects observed

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

Potassium iodide produced significant increases in offspring mortality in the 0.1 % group at birth and up to day 24 after birth. By contrast, the 0.025 % group showed reduced mortality up to day 24.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Potassium iodide decreased pre-weaning body weights in both the 0.1 and 0.05 % groups (P < 0.001). These effects were virtually identical for males and females and were significant on days 14 and 21, but not earlier. The reduction in weight in the 0.1 % group (P < 0.05) was 7.7 % on day 14 and 7.3 % on day 21, for males and females combined. The reduction in weight in the 0.05 % group (P < 0.05) was 12.5 % on day 14 and 6.8 % on day 21 for males and females combined. There were no significant weight reductions in the 0.025 % group.

Food consumption and compound intake (if feeding study):

not examined

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

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

No effects were found on cerebellar or total brain weights. The medulla-pons showed a significantly reduced weight (P < 0.05) in the 0.1 % group only. Prosencephalon weight was not significantly reduced. Both absolute and relative thyroid weights showed no significant group effects, although thyroid weights relative to body weight were significantly higher in females than in males (P <0.01).

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Key result

Dose descriptor:

NOAEL

Remarks:

embryotoxicity

Generation:

F1

Effect level:

0.05 other: % w/w in diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

Key result

Dose descriptor:

NOAEL

Remarks:

embryotoxicity

Generation:

F1

Effect level:

ca. 81 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

Key result

Critical effects observed:

no

Key result

Reproductive 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:

The results indicate that potassium iodide at dietary levels of up to 0.1 % of the diet, or about 90 mg/kg/day, produced only minor effects on parental weight gain and food consumption, and no significant effects on parental mortality, fertility, pregnancy maintenance, or gestation length. There was evidence suggesting that potassium iodide was embryotoxic. Litter size was significantly reduced, but birth weight and external morphology among those born alive were not significantly altered.

Executive summary:

The reproductive 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 reproductive toxicity of the test material to parental animals 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. The results indicate that potassium iodide at dietary levels of up to 0.1 % of the diet, or about 90 mg/kg/day, produced only minor effects on parental weight gain and food consumption, and no significant effects on parental mortality, fertility, pregnancy maintenance, or gestation length. There was evidence suggesting that potassium iodide was embryotoxic. Litter size was significantly reduced, but birth weight and external morphology among those born alive were not significantly altered.

Reference 2

Endpoint:

one-generation reproductive toxicity

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

Key result

Dose descriptor:

NOAEL

Remarks:

reproductive toxicity

Effect level:

0.1 other: % w/w in diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects

Key result

Dose descriptor:

NOAEL

Remarks:

reproductive toxicity

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

Key result

Critical effects observed:

no

Key result

Dose descriptor:

NOAEL

Remarks:

embryotoxicity

Generation:

F1

Effect level:

0.05 other: % w/w in diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

Key result

Dose descriptor:

NOAEL

Remarks:

embryotoxicity

Generation:

F1

Effect level:

ca. 81 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

90 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The study was performed to sound scientific principles with a sufficient level of detail to assess the quality of the relevant results. As the study was conducted on the read-across substance, potassium iodide, it has been assigned a reliability score of 2.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

The reproductive 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 reproductive toxicity of the test material to parental animals 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. The results indicate that potassium iodide at dietary levels of up to 0.1 % of the diet, or about 90 mg/kg/day, produced only minor effects on parental weight gain and food consumption, and no significant effects on parental mortality, fertility, pregnancy maintenance, or gestation length. There was evidence suggesting that potassium iodide was embryotoxic. Litter size was significantly reduced, but birth weight and external morphology among those born alive were not significantly altered.

Effects on developmental toxicity

Description of key information

The NOAEL for developmental toxicity in the rat was  determined to be  ca.160 mg/kg bw/day (administered in the diet) (potassium iodide)

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

160 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The study was performed to sound scientific principles with a sufficient level of detail to assess the quality of the relevant results. As the study was conducted on the read-across substance, potassium iodide, it has been assigned a reliability score of 2.

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

Potassium iodide 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) of the diet. 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. 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. Pre-weaning tests included: observation of incisor eruption, testicular development, surface righting reflex development, auditoy startle, negative geotaxis development, swimming development, olfactory orientation and open-field activity. Post-weaning observations included: open-field activity, running wheel activity and vaginal patency; rats were also subjected to a brightness discrimination modified-T swimming maze test, a rotating rod test, an avoidance test and a passive avoidance test.

Under the conditions of the test there was no evidence suggesting that potassium iodide was embryotoxic. Litter size was significantly reduced, but birth weights and external morphology among those born alive were not significantly altered.

No change in thyroid weight was observed indicating that these doses were not overtly thyrotoxic. Thyroid hormones were not assessed, however, and it is possible that thyroid function could have been altered in these animals. Nevertheless, the data are consistent with a picture of impaired thyroid function.
Several tests of post-weaning behaviour showed effects at the lowest dose, 0.025 % potassium iodide. M-maze errors were increased at this dose and rotorod performance decreased. However, because these effects were not found at the higher doses it appears unlikely that they were related to potassium iodide. At present, these effects can only described as 'false positives'.
The only effect on post-weaning behaviour that appeared to be consistently related to potassium iodide exposure was the reduction in nocturnal running-wheel activity found among the tested females. It may be that female cyclicity makes them more sensitive to the influence of chronic moderate iodide exposure than males and this could explain the contrast with the results of an acute test of activity and exploration, the open-field test, on which no consistent iodide-related effects were found.

The NOAEL for developmental toxicity was therefore determined to be 0.1 % w/w, equivalent to 160 mg/kg bw/day.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation 1272/2008, the test material does not require classification for reproductive or developmental toxicity.