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Diss Factsheets

Toxicological information

Toxicity to reproduction

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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

Constituent 1
Chemical structure
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

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.