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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Jan-June 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
N-[3-(dimethylamino)propyl]-N,N',N'-trimethylpropane-1,3-diamine
EC Number:
223-362-3
EC Name:
N-[3-(dimethylamino)propyl]-N,N',N'-trimethylpropane-1,3-diamine
Cas Number:
3855-32-1
Molecular formula:
C11H27N3
IUPAC Name:
N-[3-(dimethylamino)propyl]-N,N',N'-trimethylpropane-1,3-diamine
Test material form:
gas under pressure: refrigerated liquefied gas

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Animals were selected and/or grouped based on stratified randomization by using body weights taken before treatment. Computerized statistical programme was used for randomization.

Initially (acclimatization and randomization period), all animals were housed in groups of two/ three in polycarbonate cages (approximate internal dimensions of 365 mm x 202 mm x 180 mm height) with corn cob bedding. After randomization, males and females were housed individually. During the mating phase, animals were housed on one male: one female basis within each dose group.

After successful mating, the females were returned to their original cages and housed individually during gestation and lactation.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Daily dose levels
Group 1 : 0 mg/kg body weight
Group 2 : 50 mg/kg body weight
Group 3 : 100 mg/kg body weight
Group 4 : 200 mg/kg body weight
Group 1S : 0 mg/kg body weight
Group 4S : 200 mg/kg body weight
Details on mating procedure:
Animals were paired on a one male: one female basis within each dose group, for a maximum period of fourteen Days. Each female was examined for the presence of a copulation plug in the vagina. The presence of sperm in the vaginal smear was taken as positive evidence of mating (Day 0 of gestation).
Each pregnant female was observed twice a Day around the period of expected parturition (Gestation Day 19 – Day 23).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of the dose formulations were taken immediately after dilution of the concentrates with the diluent (vehicle) on treatment start date (Day 1 – Premating i.e., 19/02/2013) and towards treatment end date (After first dam sacrifice i.e., 03/04/2013) for homogeneity (mean of homogeneity were given as dose concentration) analysis. On week 5, samples of all dose formulations was analysed for dose concentrations by analysing triplicate samples.
Duration of treatment / exposure:
Up to 42 days for males, up to two weeks premating phase, two weeks pairing, three weeks gestation and early lactation for females, at dose levels of 50, 100 and 200 mg/kg/day.
Frequency of treatment:
Allocation A (Males were administered with test item daily up to 42 Days; Females were administered with test item daily during premating, mating, gestation periods and up to Day 4 post partum)

Allocation B (Satellite groups was dosed continuously without mating and dosing was stopped on first schedule sacrifice of dam)
Doses / concentrations
Remarks:
Doses / Concentrations:

Basis:
nominal in water
No. of animals per sex per dose:
Group1-Control : 10 males, 10 females
Group 2-Low dose : 10 males, 10 females
Group 3-Intermediate dose : 10 males, 10 females
Group 4 - High dose : 10 males, 10 females
Control animals:
yes
Positive control:
None.

Examinations

Parental animals: Observations and examinations:
Recorded Observations:

Twice daily - Viability / Mortality
Clinical Signs : Daily cage-side clinical observations

Clinical Signs:
- during Acclimatization Period (daily)
- during Treatment Period: Twice daily on initial 3 Days after treatment; once daily thereafter
- during Recovery Period: Once daily


Feed Consumption during Treatment Period:
Feed weights were recorded weekly for males until termination (Day 8, Day 15, Day 22, Day 29, Day 36 and Day 42)
Females: feed weights recorded weekly at the following Days
Premating- Day 8 and Day 15
Gestation - Day 7, Day 14, Day 20
Lactation - Day 4

Body weights
- Males once weekly
- Females:
during Premating - Day 1, Day 8 and Day 15
during Gestation - Day 0, Day 7, Day 14 and Day 20
during Lactat0ion Day 1, Day 4



During Recovery Period, all observations recorded once Weekly.


Litter observations:
For each litter the following were recorded:
- Number of offspring born
- Number of offspring alive were recorded daily and reported on Days 1 and 4 postpartum
- Sex of offspring on Days 1 post partum
- Clinical condition of offspring from birth to Day 4 post partum
- Individual offspring body weights on Days 1 and 4 post partum
Postmortem examinations (parental animals):
All the animals were subjected to gross examination.
Statistics:
Statistical methods were used to analyze the Body weight, feed consumption, hematological, biochemical parameters and organ weight data, Pre-coital interval, gestation length, litter size and litter weights, sex ratio, corpora lutea and implantation sites, Implantation losses, viability indices, offspring body weight and body weight change.
Reproductive indices:
The folllwoing were observed
-Mating performance and fertility (Pre-coital interval, mating index and pregnancy index)
-Gestation and parturition Data (Gestation length and parturition index)
- Litter Responses (Pre implantation loss, Live/birth index, Sex ratio)
Offspring viability indices:
Number of offspring alive on Day 4/ Number of offspring alive on Day 1 x 100

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Treatment had no effect on urinary parameters in both the sexes with an exception of decreased epithelial cells in low dose group when compared with control.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight and body weight gain (%) showed a treatment-related decrease.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Body weight and body weight gain (%) showed a treatment-related decrease.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Mild to moderate treatment-related effects: centrilobular and/or arterial vacuolation in liver, vacuolation of glomerular tuft in kidneys; vacuolation in urinary bladder, thymus, arteries, skeletal muscle, choroid plexus, ovaries.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Test substance intake: Feed consumption was significantly decreased in the high dose group when compared with control group animals, and is consodered treatment-related.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No treatment-related effects were detected on mating performance. Mating index for all the groups is 100% (as confirmed by presence of sperm in the vaginal smear).
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
Description (incidence and severity):
The pre and post implantation loss in all treated groups was comparable with control group.

Effect levels (P0)

Key result
Dose descriptor:
NOEL
Effect level:
ca. 100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance
Remarks on result:
other: No treatment-related effects were observed on reproduction/ development indices of animals in the 50 and 100 mg/kg/day dose groups. Mating index, fertility index, gestation length, pre-implantation loss, post-implantation loss, sex ratio and offspring gro

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
no mortality observed
Description (incidence and severity):
All animals survived the scheduled treatment or recovery periods.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was significant decrease in the male offspring body weights at Day 1 and Day 4 in the intermediate and high dose group when compared with control and low dose group.
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
Reddened testes was observed in one male pup each from two dams of low dose.
Histopathological findings:
not examined

Effect levels (F1)

Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
ca. 100 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Remarks on result:
other: Test item related microscopic changes were observed in the testes and epididymides of male and ovaries of female animals in the high dose group (200 mg/kg/day). No treatment-related effects were observed on reproduction/ development indices of animals in

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
This study was performed according to OECD Guidelines (No. 422/GLP) and is considered of good quality. Recorded results show a consistent treatment-related effect

Oral administration of the test substance to Wistar rats by gavage (50, 100 and 200 mg/kg/day) resulted in treatment-related clinical signs, changes in the body weights, feed consumption and microscopic effects in male and female animals dosed at 100 and 200 mg/kg/day. No toxicologically significant effects were detected in both sex treated with 50 mg/kg/day.

The vacuolation detected in the various organs of high dose and intermediate dose group were considered to be treatment related and no recovery of microscopic changes were noted in the satellite group. Hence, the 'No Observed Effect Level' (NOEL) for systemic toxicity is considered to be 50 mg/kg/day.

Treatment-related reproduction / developmental toxicity effect of influencing the sex ratio (decrease in the % male offspring) were observed in the high dose group (200 mg/kg/day).

Test item related microscopic changes were observed in the testes and epididymides of male and ovaries of female animals in the high dose group (200 mg/kg/day).

No treatment-related effects were observed on reproduction/ development indices of animals in the 50 and 100 mg/kg/day dose groups. Mating index, fertility index, gestation length, pre-implantation loss, post-implantation loss, sex ratio and offspring growth and development were unaffected.

Some of the observed effects appear consistent with the animals being administered a corrosive/irritating substance. However, a No Observed Effect Level (NOEL) for systemic toxicity was derived at 50 mg/kg/day, whilst teh No Observed Effect Level (NOEL) for reproductive effects was determined as 100 mg/kg/day.