Registration Dossier

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
fertility, other
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles.

Data source

Reference
Reference Type:
publication
Title:
The toxicologic and pharmacologic properties of amantadine hydrochloride.
Author:
Vernier VG, Harmon JB, Stump JM, Lynes TE, Marvel JP, Smith DH
Year:
1969
Bibliographic source:
Toxicol Appl Pharmacol. 1969, 15(3):642-65.

Materials and methods

Principles of method if other than guideline:
In a rat 3 litter reproduction study weanling rats were treated for 9 weeks preceding the first mating with a diet providing 10 mg/kg bw of amantadine hydrochloride. 3 weeks before the third mating (week 30 of test) the dosage of the drug-treated group was raised to 32 mg/kg bw daily. Fertility, gestation, viability, and lactation indices were determined.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1-adamantanamine hydrochloride
- Physical state: white crystalline substance
- Analytical purity: no data


Test animals

Species:
rat
Strain:
other: Wistar-derived Food and Drug Research Laboratories' rats
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): no data
- Mixing appropriate amounts with (Type of food): Purina Laboratory Chow
- Storage temperature of food: no data

Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: At approximately 100 days of age, pairs of rats were housed together. The dams were returned to their original cages when they became obviously pregnant (by observation, palpation, or significant weight gain) and were permitted to remain there through parturition and lactation. After resting a month the females were remated with different males.

Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
9 weeks preceding the first mating, rats remained on this drug dosage continuously through the experiment.
Frequency of treatment:
continuously
Details on study schedule:
- F1 parental animals not mated until 4 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were weaned of.
- Age at mating of the mated animals in the study: 100 days
Doses / concentrations
Remarks:
Doses / Concentrations:
10 mg/kg bw up to week 27 and 32 mg/kg bw thereafter
Basis:
nominal in diet
No. of animals per sex per dose:
20
Control animals:
not specified

Examinations

Parental animals: Observations and examinations:
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): yes
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring:
number of pups, stillbirths, live births, postnatal mortality, presence of gross congenital anomalies, weight gain, number of surviving offspring at 4 and 21 days.

Reproductive indices:
fertility, and gestation indices
Offspring viability indices:
viability, and lactation indices

Results and discussion

Results: P0 (first parental animals)

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
- no abnormalities of physical characteristics for the parent generation was observed.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- no apparent adverse effects at 10 mg/kg bw.
- when the dose was raised to 32 mg/kg bw prior to and during the third litter, the fertility and lactation indexes were somewhat depressed. These effects appeared to be related to the excitatory pharmacologic properties of the test substance at this dose


Results: F1 generation

Details on results (F1)

VIABILITY / CLINICAL SIGNS / BODY WEIGHT / SEXUAL MATURATION / GROSS PATHOLOGY
- no observed abnormalities of development or physical characteristics of the offspring of rats which received the drug from weaning to maturity and were then carried through 3 reproduction cycles.
- No fetal abnormalities were noted.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Table 1: Summary of rat reproduction and lactation performance with Amantadine HCl administered daily orally

Drug

Control

Amantadine HCl

Dose

[mg/kg]

0

0

0

10

10

32

Mating cycle

1

2

3

1

2

3

(1) Fertility indexa

95

95

85

95

90

77

(2) Gestation indexb

95

100

88

95

88

100

(3) Viability indexc

93

98

97

91

95

99

(4) Lactation indexd

65

91

84

63

97

65

(5) Number of matings

20

20

20

20

19

17

(6) Number of pregnancies

19

19

17

19

17

13

Number of litter

 

 

 

 

 

 

(7)   Alive at day 4

18

19

15

18

15

13

Number of pups

 

 

 

 

 

 

(8)   Cast alive

181

198

138

157

130

122

(9)   Cast dead

5

3

25

8

15

8

(10) Alive at day 4

169

193

134

143

124

121

(11) Alive at day 21

109

176

112

90

121

79

Number of pups/litter

 

 

 

 

 

 

(12) Cast

9.6

10.4

9.2

8.3

8.7

11.1

(13) Alive

5.7

9.3

7.5

4.7

8.0

7.2

Mean body weight of pups

 

 

 

 

 

 

(14) Cast

6.1

6.4

6.2

6.0

6.6

5.9

(15) Alive at day 21

34.4

39.8

43.0

36.4

41.9

37.3

aPercent matings resulting in pregnancies (line 6/line 5).

bPercent of pregnancies resulting in litters cast alive (line 7/line 6).

cPercent of pups cast alive that survived at 4 days (line I0/line 8).

dPercent of pups alive at 4 days survived to weaning at 21 days (line 11/line 10).

Applicant's summary and conclusion

Conclusions:
Under the conditions of the study there is a possible risk of impaired fertility in rats.