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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:
key study
Study period:
2012
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012

Materials and methods

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

Test material

Constituent 1
Chemical structure
Reference substance name:
N-[3-(dimethylamino)propyl]stearamide
EC Number:
231-609-1
EC Name:
N-[3-(dimethylamino)propyl]stearamide
Cas Number:
7651-02-7
Molecular formula:
C23H48N2O
IUPAC Name:
N-[3-(dimethylamino)propyl]octadecanamide
Test material form:
other: white pellets

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Rat: Crl:WI(Han) (outbred, SPF-Quality). Nulliparous and non-pregnant
females and untreated animals were used at initiation of the study.
Rationale This species and strain of rat has been recognized as appropriate for
general and reproduction toxicity studies. WIL Research Europe B.V. has
general and reproduction/developmental historical data in this species
from the same strain and source. This animal model has been proven to
be susceptible to the effects of reproductive toxicants.
Source F0 Charles River Deutschland, Sulzfeld, Germany.
Age at start F0-treatment Approximately 11 weeks.
Number of F0-animals 40 females and 40 males.
Acclimatization F0 At least 5 days prior to start of treatment.
Health inspection F0 Upon receipt of the animals.
Randomization F0 Prior to commencement of treatment, by computer-generated random
algorithm according to body weight, with all animals within ± 20% of the
sex mean.
Identification F0 Earmark and tattoo.
Mating procedures Following a minimum of 14 days of exposure for the males and females,
one female was cohabitated with one male of the same treatment group,
avoiding sibling mating. Detection of mating was confirmed by evidence
of sperm in the vaginal lavage or by the appearance of an intravaginal
copulatory plug. This day was designated Day 0 post-coitum. Once
mating occurred, the males and females were separated. Female no. 77
was mated with a proven male of the same dose group since the male
that she was intended to be mated with was sacrificed before mating.
A maximum of 14 days was allowed for mating, after which females who
had not shown evidence of mating were separated from their males.
Parturition The females were allowed to litter normally. Day 1 of lactation was
defined as the day when a litter was found completed (i.e. membranes
and placentas cleaned up, nest build up and/or feeding of pups started).
Females that were littering were left undisturbed.
Number of pups 423 pups.
Identification of pups On Day 1 of lactation, all pups were individually identified by means of
subcutaneous injection of Indian ink.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on exposure:
Parental animals
Method Oral gavage, using a plastic feeding tube. Formulations were placed on a
magnetic stirrer during dosing.
Dose volume 5 mL/kg body weight. Actual dose volumes were calculated according to
the latest body weight.
Frequency Once daily for 7 days per week, approximately the same time each day
with a maximum of 6 hours difference between the earliest and latest
dose. Animals were dosed up to the day prior to scheduled necropsy.
Exposure period Males were exposed for 28 days, i.e. 2 weeks prior to mating, during
mating, and up to the day prior to scheduled necropsy. Females were
exposed for 41 - 54 days, i.e. during 2 weeks prior to mating, during
mating, during post-coitum, and during at least 4 days of lactation (up to
the day prior to scheduled necropsy). Female no. 47 (Group 1) was not
dosed during littering.
Details on mating procedure:
Accommodation
Pre-mating Animals were housed in groups of 5 animals/sex/cage in Macrolon plastic
cages (MIV type, height 18 cm).
Mating Females were caged together with males on a one-to-one-basis in
Macrolon plastic cages (MIII type, height 18 cm).
Post-mating Males were housed in their home cage (Macrolon plastic cages, MIV type,
height 18 cm) with a maximum of 5 animals/cage. Females were
individually housed in Macrolon plastic cages (MIII type, height 18 cm).
Lactation Pups were kept with the dam until termination in Macrolon plastic cages
(MIII type, height 18 cm).
Duration of treatment / exposure:
Males were exposed for 28 days, i.e. 2 weeks prior to mating, during
mating, and up to the day prior to scheduled necropsy. Females were
exposed for 41 - 54 days, i.e. during 2 weeks prior to mating, during
mating, during post-coitum, and during at least 4 days of lactation (up to
the day prior to scheduled necropsy). Female no. 47 (Group 1) was not
dosed during littering
Frequency of treatment:
Once daily for 7 days per week, approximately the same time each day
with a maximum of 6 hours difference between the earliest and latest
dose. Animals were dosed up to the day prior to scheduled necropsy.
Doses / concentrations
Dose / conc.:
5 mg/kg bw/day
No. of animals per sex per dose:
10 female 10 male

Examinations

Parental animals: Observations and examinations:
Mortality / Viability At least twice daily. Animals showing pain, distress or discomfort, which
was considered not transient in nature or was likely to become more
severe, were sacrificed for humane reasons based on OECD guidance
document on humane endpoints (ENV/JM/MONO/ 2000/7). The
circumstance of any death was recorded in detail.
Clinical signs At least once daily from start of treatment onwards, detailed clinical
observations were made in all animals.
The time of onset, grade and duration of any observed sign was
recorded. Signs were graded for severity and the maximum grade was
predefined at 3 or 4. Grades were coded as slight (grade 1), moderate
(grade 2), severe (grade 3) and very severe (grade 4). For certain signs,
only its presence (grade 1) or absence (grade 0) was scored. In the data
tables, the scored grades were reported, as well as the percentage of
animals affected in summary tables.
Body weights Males and females were weighed on the first day of exposure and weekly
thereafter. Mated females were weighed on Days 0, 4, 7, 11, 14, 17 and
20 post-coitum and during lactation on Days 1 and 4. On Day 11 of the
premating period, Group 4 animals were additionally weighed to monitor
their health status (results are retained in the raw data but have not been
reported). Group 4 males were weighed daily from Days 12-14 of the
premating period in order to correct the actual dose volume for lower
body weights recorded for these animals on a daily basis. Body weights
determined daily between the regular body weight determinations (i.e. on
Days 1, 8, 15, 22 and 28) are not reported since these were intended for
calculation of the actual dose volumes only.
Food consumption Weekly, except for males and females which were housed together for
mating and for females without evidence of mating. Food consumption of
mated females was measured on Days 0, 4, 7, 11, 14, 17 and 20 postcoitum
and on Days 1 and 4 of lactation.
Water consumption Subjective appraisal was maintained during the study, but no quantitative
investigation was introduced as no treatment related effect was
suspected.
General reproduction data Male number paired with, mating date, confirmation of pregnancy, and
delivery day were recorded. Pregnant females were examined to detect
signs of difficult or prolonged parturition, and cage debris of pregnant
females was examined to detect signs of abortion or premature birth. Any
deficiencies in maternal care (such as inadequate construction or
cleaning of the nest, pups left scattered and cold, physical abuse of pups
or apparently inadequate lactation or feeding) were examined

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
Clinical signs at 200 mg/kg (including hunched posture, rales,
piloerection and lean appearance) were essentially reversible
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Reversible changes in body weight and food intake for males at 200 mg/kg were considered not
adverse in nature
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
slightly lower lower food intake and body weight in females at this dose
during post-coitum/lactation.
Clinical biochemistry findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
> 200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance
Key result
Dose descriptor:
NOAEL
Effect level:
> 200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Developmental neurotoxicity (F1)

Behaviour (functional findings):
no effects observed

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
sexual maturation
clinical signs
mortality
ophthalmological examination

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion