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Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental 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:
developmental 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:
maternal toxicity
Effect level:
0.1 other: % w/w
Based on:
test mat.
Basis for effect level:
other: no effects
Key result
Dose descriptor:
NOAEL
Remarks:
maternal toxicity
Effect level:
90 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no effects
Key result
Abnormalities:
no effects observed
Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
0.1 other: % w/w
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects
Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
160 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
The test material delayed auditory startle at the two highest doses tested throughout the first 90 days after birth. The test material also delayed olfactory orientation to the home-cage scent at the middle dose and decreased female running-wheel activity at all dose levels. In rats sacrificed 90 days after birth, the test material was found to have reduced brain weight at 0.1 % and reduced body but not brain weight at 0.05 %. No significant effect was found on absolute or relative thyroid weight at 90 days of age. Several additional behavioral effects were observed in the low dose, however these were not considered significant as there was no dose-response relationship. The test material produced evidence of developmental toxicity consistent with a picture of impaired thyroid function.
Executive summary:

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.

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. 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.
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
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
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of gestation
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)
Duration of test:
Up to 90 days of age of the second generation.
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

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Maternal 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:
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.
Fetal examinations:
PRE-WEANING TESTING
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. Surface righting-reflex development was measured daily beginning at day 3 after birth in two trials/day (30 set max/trial). The day on which rats met a criterion of turning from the supine to the prone position in ≤ 2 seconds was recorded. The time spent pivoting during a 60-set period was measured on days 7, 9, and 11.
Auditory startle was elicited by a 0.2 second stimulus produced by a horn. The rat was placed on an enclosed platform 16 cm from the horn inside a sound-insulated chamber. At the position where the rat was confined the sound pressure level was 120 dB. The presence or absence of a startle response was determined by the experimenter through an observation window. Rats were given two trials/day beginning on day 10 and ending when all test animals showed the response.
Negative geotaxis development was assessed in one trial/day (60 set max) on days 6, 8, 10 and 12 of age. Rats were placed facing downward on a 25° inclined plane and the time they took to rotate through 180° to a head-up orientation was noted.
Swimming development was assessed once every other day on days 6-24. Rats were placed in a tank of water (26.2 °C) for 5-15 set and swimming direction, angle in the water and limb movements (paddling) were rated on each rat.

Direction scores consisted of sinking (0 points), floating (1), circling (2) or swimming straight, in an arc, or changing direction (3).

Angle in the water was scored as head submerged (0), nose at surface (I), nose and tip of head above surface (2), ears half-way above surface (3), or ears completely above surface (4).

Limb movements were scored as no paddling (0), paddling with front and hind limbs (1), paddling primarily with hind limbs (2), or paddling with hind limbs only (3).
In addition, the olfactory orientation and open-field activity were also measured in preweaning testing.

POST-WEANING OBSERVATIONS
Open-field activity was observed as in the pre-weaning open-field test, but a field with twice the diameter was used and defaecation frequency was also measured. Testing took place on three consecutive days (3 min each day) between days 40 and 45 after birth.
Running-wheel activity was measured in Wahmann steel activity-wheel chambers. The number of wheel revolutions made by each rat was recorded twice a day at 9:00 - 10:00 and 16:0 - 17:00 on days 26-50.

Vaginal patency was noted daily on females from day 30 until all females in each litter were patent.

On days 25, 26 and 27 of age rats were tested in a brightness discrimination modified-T swimming maze (M-maze).

Between days 60 and 65, rats were given two trials/day on two successive days on a rotating-rod test. The horizontal rod was 11.4 cm in diameter and had a granular surface. Each rat was placed on the slowly turning rod and the rod was then rotated at a gradually accelerating pace. The speed of the rod was adjusted to maintain the rat on the centre of the rod. If the rat's performance improved, the rod was accelerated up to a maximum of 30 rpm. Each trial lasted 3 minutes. The successful performance criterion was staying on the rod for 2 minutes at 30 rpm.

Active avoidance testing began on days 70-80 and was carried out in an aluminium chamber (20.3 x 21 x 17.8 cm) in which a wheel served as the manipulandum (Kinney & Vorhees, 1979). A 9-second white-noise warning stimulus preceded a 0.75-mA scrambled foot shock on each trial; rats could avoid the shock by turning the wheel during the 9-second stimulus. Rats were given 20 trials/day for up to 10 days to learn the response. Those rats that success- fully learned the response (18 avoidances/20 trials) were then given extinction training (9-second warning stimulus not followed by a shock). During extinction training rats had to learn not to respond on 18 trials out of 20. Those rats that successfully met the extinction criterion were then given the original response conditions as a test of re-learning (reacquisition).

Passive avoidance testing began at approximately day 110 and was carried out in a two-chamber apparatus with one dark (30.5 x 20.3 x 19 cm) and one light side (40.6 x same). On each trial a rat was placed in the light side and the time taken to enter the dark side was measured. Each rat was given one trial/day until it remained in the light side for 3 min.

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: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Description (incidence):
The results indicate that potassium iodide at dietary doses of up to 0.1 % produced no significant effects on parental mortality.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The results indicate that potassium iodide at dietary doses of up to 0.1 % produced only minor effects on parental weight gain.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The results indicate that potassium iodide at dietary doses of up to 0.1 % produced only minor effects on parental food consumption.
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

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
The results indicate that potassium iodide at dietary doses of up to 0.1 % produced no significant effects on pregnancy maintenance.
Description (incidence and severity):
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): The results indicate that potassium iodide at dietary doses of up to 0.1 % produced no significant effects on gestation length.
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
The results indicate that potassium iodide at dietary doses of up to 0.1 % produced no significant effects on parental fertility.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
maternal toxicity
Effect level:
0.1 other: % w/w
Based on:
test mat.
Basis for effect level:
other: no effects
Key result
Dose descriptor:
NOAEL
Remarks:
maternal toxicity
Effect level:
90 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no effects

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Birth weights among those born alive were not significantly altered.
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): Potassium iodide produced a consistent decrease in offspring body weight throughout postnatal life which was not generally dose-dependent.
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
Litter size was significantly reduced.
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
Litter size was significantly reduced.
External malformations:
no effects observed
Description (incidence and severity):
External morphology among those born alive were not significantly altered.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
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.
Behaviourally, the doses of potassium iodide used produced delayed early development of several indices of reflex ontogeny. These included delayed auditory startle response development, delayed olfactory orientation towards their home-cage scent, and delayed maturation of several aspects of swimming co-ordination. Physical milestones of development were not affected, nor were early measures of locomotor activity.
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.
Details on embryotoxic / teratogenic effects:
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.

Effect levels (fetuses)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
0.1 other: % w/w
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects
Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
160 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental 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.

When the offspring were 27 - 42 days old the dosages were 42 mg/kg/day for the 0.025 % group, 81 mg/kg/day for the 0.05 % group and 160 mg/kg/day for the 0.1 % group.

Applicant's summary and conclusion

Conclusions:
The test material delayed auditory startle at the two highest doses tested throughout the first 90 days after birth. The test material also delayed olfactory orientation to the home-cage scent at the middle dose and decreased female running-wheel activity at all dose levels. In rats sacrificed 90 days after birth, the test material was found to have reduced brain weight at 0.1 % and reduced body but not brain weight at 0.05 %. No significant effect was found on absolute or relative thyroid weight at 90 days of age. Several additional behavioral effects were observed in the low dose, however these were not considered significant as there was no dose-response relationship. The test material produced evidence of developmental toxicity consistent with a picture of impaired thyroid function.
Executive summary:

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.

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