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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
Study period:
20. Apr 1999 - 28. Jun 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report Date:
1999

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Specific details on test material used for the study:

- Lot/batch No.: Mixture from January 27, 1999

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Boehringer Ingelheim, Pharma KG, Biberach/Riss
- Age at study initiation: 89-90 days
- Weight at study initiation: Males: 399.7 (365.8 - 430.9) g; Females: 262.5 (235.6 - 291.5) g
- Housing: individually in type DK 111 stainless steel wire mesh cages.
- Diet: Kliba Iaboratory diet rat/mouse/hamster ad libitum
- Water: tap water ad libitum
- Acclimation period: 13 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 30 - 70 %
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): The preparations were prepared twice a week, every 96 hours latest.


Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: maximum 2 weeks
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test substance solutions were analyzed by gas chromatography.
Duration of treatment / exposure:
males: 28 days
females: 46-56 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
10 mg/kg body weight/day: as the expected no observed adverse effect level.
50 mg/kg body weight/day: as the intermediate dose level.
200 mg/kg body weight/day: as the dose level with possible toxic effects.

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily. The nesting, littering, and lactation behavior of the dams was generally evaluated in the mornings in connection with the daily clinical inspection of the dams.


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

Sperm parameters (parental animals):
Parameters examined in P male parental generations:
testis weight, epididymis weight

Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain.

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals after themating period.
- Maternal animals: All surviving animals after the last litter of each generation was weaned.


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

Postmortem examinations (offspring):
All surviving pups, all stillborn pups andthose pups that died before schedule, were examined externally, eviscerated and their organs were assessed macroscopically.
Statistics:
DUNNETT-test, FISHER'S EXACT test, WILCOXON-test

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
see " Details on results"
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
see " Details on results"
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
see " Details on results"
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
see " Details on results"
Food efficiency:
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:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
see " Details on results"

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
There were no substance-related mortalities in any of the male and female F0 parental animals in any of the groups. One high dose male animal showed piloerection on study day 2. Another male animal of this test group had respiratory sounds between days 11-23.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
The food consumption of the high dose F0 male animals was statistically significantly reduced during study weeks 0 - 1 and remained slightly reduced for the whole study period without attaining statistical significance. This was in-line with Iowered mean body weight and impaired body weight gain.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
With the exception of two F0 parental females all mated females of test groups 0 - 3 (0, 10, 50, 200 mg/kg body weight/day) became pregnant. Therefore, the fertility index varied between 90 and 100 %. This difference concerning the female fertility index was regarded to be spontaneous in nature and not associated with the treatment of the animals.

ORGAN WEIGHTS (PARENTAL ANIMALS)
The mean absolute and relative weight parameters did not show significant differences when compared with the control group.

GROSS PATHOLOGY (PARENTAL ANIMALS)
A few gross lesions were noted in the forestomach (erosion/ulcer and thickening of wall) in a high dose male; liver (small yellow focus: in a control male, two males of the mid and one of the high dose group; a mid sized necrosis in a mid dose female rat; lungs (atelectasis, diffuse red discoloration or large hematoma in three different males of the high dose group); kidneys (clay colored discoloration or focal unilateral contraction in the cortex of two different high dose males), and spleen (focal grey white deposition in a low dose group male).

Two animals were not pregnant. In one control animal a dilation of the uterine horns may have contributed to this situation.

HISTOPATHOLOGY (PARENTAL ANIMALS)
With the exception of the clay colored discoloration of the kidneys of one animal (male, high dose group), all gross lesions could be correlated with a meaningful microscopic finding. Histopathology of testes, epididymides and ovaries did not reveal any treatment related microscopic finding.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Remarks:
reproductive performance and fertility
Effect level:
200 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
reproductive performance
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
50 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: body weight; food consumption

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
no effects observed
Description (incidence and severity):
see " Details on results"
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
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:
no effects observed
Description (incidence and severity):
see " Details on results"
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined

Results: F1 generation

Details on results (F1)

VIABILITY (OFFSPRING)
There were no substance-related differences concerning pup viability and mortality.

CLINICAL SIGNS (OFFSPRING)
The F1 pups did not show any clinical signs which could be attributed to the treatment. An unilateral microphthalmia was the only clinical observations which occurred in one high dose pup. However, this finding was considered to be spontaneous in nature in respect to the known historical background data of the rat strain investigated in the present study.

BODY WEIGHT (OFFSPRING)
Mean body weights/body weight gains were not influenced by the test substance administration.

GROSS PATHOLOGY (OFFSPRING)
The macroscopic examination of all pups did not reveal any differences between the test groups neither in the type nor in the number of pup necropsy observations.
OnIy spontaneous findings were seen at necropsy (e.g. post mortem autolysis, dilated renal pelvis and microphthalmia) in a few of the large number of examined F1 pups of all groups including the controls generally without a dose-response relationship.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Generation:
F1
Effect level:
200 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
viability
mortality

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Under the conditions of this reproduction/developmental toxicity screening test, the oral administration by gavage of 3-Dimethylaminopropyl- amin had no adverse effects on reproductive performance or fertility of the F0 parental animals of all substance-treated groups. There were no signs of developmental toxicity in the progeny of the F0 parents up to and including the high dose group (200 mg/kg body weight/day).

Signs of general, systemic toxicity in the F0 parental animals were confined to the male rats of the 200 mg/kg body weight/day group. Toxicity was characterized by decreased food consumption.

Applicant's summary and conclusion