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Toxicity to reproduction

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Administrative data

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.
Cross-reference
Reason / purpose for cross-reference:
other: read across: target
Reference
Endpoint:
one-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
The source material is potassium iodide and the target is sodium periodate. The analogue approach has been used due to the predicted common breakdown products specifically ionised iodine whilst the potassium ion in the source material and the sodium ion in the target material are historically established to have similar properties. Once injested, the materials are anticipated to form highly similar breakdown products with historically recognised similarities.
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
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.

Data source

Reference
Reference Type:
publication
Title:
Developmental Toxicity And Psychotoxicity Of Potassium Iodide In Rats: A Case For The Inclusion Of Behaviour In Toxicological Assessment
Author:
Vorhees, C.V., Butcher, R.E., and Brunner, R.L.
Year:
1984
Bibliographic source:
Food and Chemical Toxicology, Vol. 22, No. 12, pp 963-970

Materials and methods

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

Test material

Constituent 1
Reference substance name:
Potassium iodide
EC Number:
231-659-4
EC Name:
Potassium iodide
Cas Number:
7681-11-0
IUPAC Name:
potassium iodide
Details on test material:
- Name of test material (as cited in study report): Potassium iodide (food grade potassium iodide (Mallinckrodt Inc.) was purchased from the Tab Chemical Company, Chicago, IL)

Test animals

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

Administration / exposure

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)
Doses / concentrationsopen allclose all
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

Examinations

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).

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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 / performance (P0)

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.

Effect levels (P0)

open allclose all
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

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

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

Effect levels (F1)

open allclose all
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

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.