N'-[3-(dimethylamino)propyl]-N,N-dimethylpropane-1,3-diamine

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1999-04-20 - 1999-06-28

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-aminopropyldimethylamine

EC Number:

203-680-9

EC Name:

3-aminopropyldimethylamine

Cas Number:

109-55-7

Molecular formula:

C5H14N2

IUPAC Name:

N,N-dimethylpropane-1,3-diamine

Specific details on test material used for the study:

- Name of test material (as cited in study report): 3-Dimethylaminopropylamin
- Analytical purity: 99.8 %
- Lot/batch No.: Mixture from January 27, 1999

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system 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 SOLUTION: 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 / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

10 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

50 mg/kg bw/day (nominal)

Doses / concentrations 4

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

Reproductive indices:

Fertility index

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

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.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

There were no substance-related mortalities in any of the male and female F0 parental animals in any of the groups.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Lowered mean body weight and impaired body weight gain were observed

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

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 lowered mean body weight and impaired body weight gain.

Food efficiency:

not examined

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

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:

effects observed, non-treatment-related

Description (incidence and severity):

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.

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive performance:

effects observed, non-treatment-related

Description (incidence and severity):

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.

Effect levels (P0)

1

Key result

Dose descriptor:

NOAEL

Remarks:

reproductive toxicity

Effect level:

200 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

reproductive performance

other: fertility

2

Key result

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

50 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male

Basis for effect level:

body weight and weight gain

food consumption and compound intake

Target system / organ toxicity (P0)

Key result

Critical effects observed:

no

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)

Based on:

act. ingr.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F1)

Key result

Critical effects observed:

no

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

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

Conclusions:

Under the conditions the oral administration of DMAPA by gavage to rats had no adverse effects on reproductive performance or fertility of the F0 parenteral animals of all substance-treated groups. Signs of general, systemic toxicity in the F0 parental animals were confined to the male rats of the 200 mg/kg bw/day group. Signs of general, systemic toxicity in the F0 parental animals were confined to the male rats of the 200 mg/kg bw/day group.
NOAEL: reproductive performance and fertility = 200 mg/kg bw/day (male/female)
NOAEL: developmental toxicity = 200 mg/kg bw/day (male/female)
NOAEL: systemic toxicity = 50 mg/kg bw/day (male)