Ammonium iodide

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

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 from peer reviewed journal

Data source

Reference

Reference Type:

publication

Title:

Developmental toxicity and psychotoxicity of test material in rats

Author:

Vorhees et.al

Year:

1984

Bibliographic source:

Food and Chemical Toxicology.

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

The reproductive and developmental toxicity study of test material was performed on male and female rats.

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Test material

Test material information

Constituent 1

Reference substance name:

Potassium iodide

EC Number:

231-659-4

EC Name:

Potassium iodide

Cas Number:

7681-11-0

Molecular formula:

IK

IUPAC Name:

potassium iodide

Details on test material:

- Name of test material (as cited in study report): Potassium iodide
- Molecular formula : KI
- Molecular weight : 166.0 g/mol
- Substance type: Inorganic
- Physical state: Solid

Specific details on test material used for the study:

No data available

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

No data available

Sex:

male/female

Details on test animals or test system and environmental conditions:

Details on test animals and env. conditions
TEST ANIMALS
- Source: Laboratory Supply Co., Indianapolis, IN
- Weight at study initiation: 200-240g
- Diet (e.g. ad libitum): Purina rat chow meal
- Acclimation period:5 days

Administration / exposure

Route of administration:

oral: feed

Vehicle:

not specified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Test material mixed with feed

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): Purina rat chow meal
- Storage temperature of food:No data

Details on mating procedure:

- M/F ratio per cage: No data
- Length of cohabitation: No data
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy:day sperm were found was considered to
be day 0 of gestation

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days ( Dietary treatments were given continuously
to both males and females for 14 days
before mating and for l-14 days during breeding, and
to females only during gestation (22 days) and lactation
(21 days).)

Frequency of treatment:

Daily

Details on study schedule:

- F1 parental animals not mated until [...] weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were [...] days of age.:90 days of age
- Age at mating of the mated animals in the study: [...] weeks

Doses / concentrations

Remarks:

F0: 0, 25,50,100mg/kg/day
F1: 0, 25,50,100mg/kg/day

No. of animals per sex per dose:

No data available

Control animals:

yes

Details on study design:

No data available

Positive control:

yes (5-azacytidine 2mg/kg )

Examinations

Parental animals: Observations and examinations:

Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes
DETAILED CLINICAL OBSERVATIONS: Yes
Time schedule: daily
BODY WEIGHT: Yes
Time schedule for examinations: Parental body weights were measured at weekly intervals except during breeding
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes food consumption
was measured on selected rats during all
phases of the experiment.
Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

STANDARDISATION OF LITTERS
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. At this time, two males and two females from each litter were designated for preweaning testing. In addition to these four, two other males and two other females from each litter were later designated for post-weaning testing

PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring:
[all litters were examined and data collected on litter size, sex distribution, weight, and number of dead and/or malformed offspring.]

GROSS EXAMINATION OF DEAD PUPS:
[no / yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead.]

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY:

ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY:

Postmortem examinations (parental animals):

No data available

Postmortem examinations (offspring):

All pups not selected for mating were taken for necropsy at day 21 post partum or shortly thereafter; organ weights were recorded for brain, spleen and thymus.

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. Adjustments of Duncan's test for unequal group sizes were made sing the procedure of Kramer (1956). 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).

Reproductive indices:

No data available

Offspring viability indices:

No data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

A reduction in male (P < 0.01), but not female, food consumption was found in the 0. 1% dose group prior to breeding, but this reduction resulted in only a marginal decrease 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 0.025% dose group but not dose related

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

no effects observed

Description (incidence and severity):

eye opening was unaffected by treatment.

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:

no effects observed

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Description (incidence and severity):

no significant effects on parental mortality, fertility, pregnancy maintenance, or gestation length.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

100 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

ophthalmological examination

organ weights and organ / body weight ratios

reproductive performance

Remarks on result:

other: overall no effects on reproductive performance was observed

Target system / organ toxicity (P0)

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Description (incidence and severity):

Test material produced significant increases in offspring mortality in the 0. I% group at birth and up to day 24 after birth. The 0.025% dose group, by contrast, showed reduced mortality up to day 24

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Test material produced a consistent decrease in offspring body weight throughout postnatal life which was generally dose-dependent

Food consumption and compound intake (if feeding study):

not specified

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:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No change in thyroid weight was observed indicating that these doses were not overtly thyrotoxic

Gross pathological findings:

no effects observed

Description (incidence and severity):

external morphology among those born alive were not significantly altered.

Histopathological findings:

not specified

Other effects:

not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

the doses of test material used here 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

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not specified

Effect levels (F1)

Dose descriptor:

LOAEL

Generation:

F1

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

viability

mortality

body weight and weight gain

organ weights and organ / body weight ratios

Remarks on result:

other: Overall developmental effects observed

Target system / organ toxicity (F1)

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Overall reproductive toxicity

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

Any other information on results incl. tables

Table : Reproductive performance of rats fed 0-0.1% test material in the diet

Values of reproductive performance parameters
				test groups
Parameter		Negative control	Positive control	0.025%	0.05%	0.1%
No. of females with sperm		22	27	30	26	19
Females (with sperm) delivering (%)		86.4	81.5	63.2	69.2	73.3
No. of liters with<8 live offspring		0	10˟	1	1	9˟
Gestation length (mean ± SEM)		22.1 ± 0.1	22.1 ± 0.1	22.4 ± 0.2	22.1 ± 0.1	22.1 ± 0.1
No. born/litter (mean days ± SEM)		11.5 ± 0.5	9.3 ± 0.9˟	9.8 ± 0.6	11.6 ± 0.5	9.1 ± 0.6˟
Total no. of offspring delivered		218	195	108	185	199
Mean male/female ratio		0.95	1.05	1.02	1.13	1.02
No. of litters tested after birth	19		12	11	17	13

 

positive-control dams received two ip injections of 5-azacytidine on day 17 of gestation (day 0 of gestation was day sperm were found).

Values marked with asterisks differ significantly from the corresponding negative-control value: *P < 0.05 (see text for details of statistical analysis).

 

 

  

Table : Mortality of offspring from rats fed 0-0.1% test material in the diet

 

 

Mortality(%)
			test groups
Age(days)#	Negative control	Positive control	0.025%	0.05%	0.1%
0-1	0.0	12.3˟˟	0.9	0.5	6.0˟˟
2-24	13.1	28.6˟˟	5.1˟	14.8	21.9˟
25-90	1.0	0.0	1.4	4.0	5.2

 

T After weaning (day 21) offspring were fed test material in their diet at the same level fed to their parents.

# Birth date considered to be day 0.

§Positive-control dams received two ip injections of 5-azacytidine on day 17 of gestation.

Values marked with asterisks differ significantly from the corresponding negative-control value:

*P < 0.05; **P < 0.01 (see text for details of statistical analyses).

 

 

 

 

 

Table: Preweaning reflex development in offspring of rats fed 0.010% test material in the diet

 

Values in preweaning tests of behavior
Treatment group	No. of litters tested	Auditory startles	Pivoting time on days 7,9,11 combined(sec)	Olfactory orientation scores on days 9,11,13,15 combined
Negative control	19	12.5 ± 0.2	5.5 ± 0.7	15.7 ± 2.8
Positive control	12	13.7 ± 0.6˟	10.0 ± 1.9˟	14.3 ± 3.5
0.025% KI	11	13.3 ± 0.2	5.2 ± 1.1	16.3 ± 3.9
0.05% KI	17	13.7 ± 0.2˟	5.4 ± 0.9	10.7 ± 3.1˟
0.1%KI	13	13.8 ± 0.2˟	7.0 ± 1.8	12.5 ± 4.0

 

T Birth date was considered to be day 0.

#Maximum number tested; on some tests 1-2 fewer litters in a group were used because of incomplete data on these litters.

§Values represent mean day (+SEM) on which all members of all litters showed the startle response.

¶Positive-control dams were given two ip injections of 5-azacytadine on day 17 of gestation.

Test values are means +SEM of scores on two males and two females from each litter. Values marked with asterisks differ significantly from the corresponding negative-control value:

*P < 0.05 (see text for details of statistical analyses

 

 

 

Post-weaning running-wheel activity in females during the dark cycle of testing on the last four blocks (days 34-49; 4 days/block) of testing in rats fed 0-0.1% test material in the diet

 

Treatment group	No. of rats tested	Mean no. of wheel revolutions during the dark cycle summed across 4 days block (% of negative control activity)
			3	4	5	6
Negative control	7		3275.4	5296.6	8246.6	8213.1
Positive control	7		3206.6(97.9)	4635.8 (87.5)	5847.4 (70.9)**	4149.0(50.5)**
0.025% KI	7		2179.7 (66.5)	2657.6 (50.2)**	3138.3 (38.0)**	3248.4(39.6)**
0.05% KI	10		2418.9(73.8)	3724.9(70.3)*	3987.6(48.4)**	3790.9(46.2)**
0.1% KI	8		1233.6(37.7)**	1880.5(35.5)**	1983.4(24.0)**	1037.1(12.6)**
Range of SEM Values			440.7-1011.0	715.0-1175.5	978.5-1564.4	374.6-1698.4

Values marked with asterisks differ significantly from the corresponding negative-control value: *P < of statistical analyses).

T Positive-control dams were given two ip injections of 5-azacytadine on day 17 of gestation

 

Post-weaning body and organ weight of rats fed 0-0.1% test material in the diet

Treatment group	Body weight (g) at		Organ weight at day 90t
	Day 42t	Day 90t	Meduna-pons (mg)	Prosencephalon(mg)	Eyes(mg)	Thyroid(mg)
Male
Negative control	145.6 ±  3.9 (56)	371.5 ± 12.5 (14)	223±  6	1420 ±  30	268 ±  3	6.7±  1.2(9)
Positive control #	116.1 ±  3.8 (26)**	315.0 ± 22.6*(7)**	223±  7	1357±  27**	255±  5*	-
0.025% KI	143.0 ± 3.5 (52)**	371.1 ± 8.0(10)	206 ±  4	1446±  25	264±  4	6.6 ± 0.9(8)
0.05% KI	134.6 ± 3.5(52)**	339.3± 15.6(15)*	217 ± 5	1425±  18	226±  3	8.8 ± 4.4(15)
0.1% KI	122.9 ± 4.1(37)**	321.6 ± 11.8(10)**	205 ± 5*	1430 ± 20	261 ± 3	9.0 ± 1.3 (9)
Female
Negative control	127.5 ± 2.4(57)	242.6 ± 5.4(14)	207± 7	1394±  18	257 ±	9.4 ±  1.8(8)
Positive control #	101.7 ± 2.6(31)**	203.4 ± 4.1(9)**	201 ±  7	1267 ± 28**	243±  3	-
0.025% KI	121.3 3.0(33)	225.0±  9.2 (8)	206 ± 4	1365±  14	256 ± 2	11.2 ± 4.1 (7)
0.05% KI	113.6±  2.4 (53)**	221.3 ± 6.1(13)*	205±  6	1379 ± 23	251±  4	14.4 ± 11.6(13)
0.1% KI	105.7 ± 3.2(37)**	206 ± 6.4(10)**	191 ± 5*	1328 ± 21	245 ± 5	13.8 ± 3.6(7)

tBirth date was considered to be day 0.

#Positive-control dams were given two ip injections of 5-azacytadine on day 17 of gestation,

Values are means + SEM for the number of animals given in parentheses. Brain and eye weights are for the numbers of animals used for day-90 body weights; thyroid groups are smaller since some were missed when body and brain weights were taken. Values marked with asterisks differ significantly from the corresponding negative-control values: *P < 0.05; **P < 0.01 (see text for details of statistical analyses).

Applicant's summary and conclusion

Conclusions:

The NOAEL for reproductive toxicity was considered to be 100 mg/kg bw/day as No effects on reproductive parameters were observed and LOAEL for developmental toxicity was considered to be 100mg/kg bw. When male and female Sprague-Dawley rats were treated with test material orally.

Executive summary:

The reproductive and developmental toxicity study of test material was performed inmale and female Sprague-Dawleyrats. The test material mixed with Purina rat chow meal in dose concentration0, 25,50,100mg/kg/day. Dietary treatments were given continuously to both males and females for 14 days before mating and for l-14 days during breeding and to females only during gestation (22 days) and lactation (21 days). After weaning, the offspring were given dietary test material, at the level their parents had received, throughout the remainder of the experiment (up to 90 days of age for most animals). Negative control dams received no treatment. Positive-control dams were given two ip injections of 2 mg/kg of 5-azacytidine. On day 17 of gestation (day sperm were found was considered to be day 0 of gestation). 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. 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.Pre weaning observations and post weaning observations were made.

The results indicate that test material at dietary doses of up to 100 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 test material was embryotoxic. Litter size was significantly reduced, but birth weights and external morphology among those born alive were not significantly altered.

Test material produced a consistent decrease in offspring body weight throughout postnatal life which was generally dose-dependent. No change in thyroid weight was observed indicating that these doses were not overtly thyrotoxic. Behaviorally, the doses of test material used here 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. Hence The NOAEL for reproductive toxicity was considered to be 100 mg/kg bw/day as No effects on reproductive parameters were observed and LOAEL for developmental toxicity was considered to be 100mg/kg bw. When male and female Sprague-Dawley rats were treated with test material orally.