Tricyclo[3.3.1.13,7]decan-1-amine, N,N-dimethyl-

Toxicity to reproduction

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

Test material information

Constituent 1

Reference substance name:

Amantadine hydrochloride

EC Number:

211-560-2

EC Name:

Amantadine hydrochloride

Cas Number:

665-66-7

IUPAC Name:

adamantan-1-amine hydrochloride

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 generation)

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 index^a	95	95	85	95	90	77
(2) Gestation index^b	95	100	88	95	88	100
(3) Viability index^c	93	98	97	91	95	99
(4) Lactation index^d	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.