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EC number: 293-014-3
CAS number: 91032-08-5
After subacute treatment no effects on fertility parameters were
detected in any animal.
The aim of this study was to assess the possible effects of Fatty acids, C16-18-, reaction products with diethanolamine on male and female fertility and embryofetal development after repeated dose administration in Wistar rats.
The test item was administered daily in graduated doses to 3 groups of test animals, one dose level per group for a treatment period of maximally 54 days for females and minimum of 28 days for males. Animals of control group were handled identically as the dose groups but received same dose volume of the vehicle used in this study. Each of the 4 groups comprised 10 male and 10 female Wistar rats.
During the period of administration, the animals were observed each day for signs of toxicity. At the conclusion of the test, animals were sacrificed and observed macroscopically.
Body weight and food consumption were measured weekly, except for food consumption measurements which were not taken during the mating period in female animals and the mating and post-mating period in male animals.
Haematological and clinical biochemistry evaluations were performed on blood samples collected at terminal sacrifice from five males and five randomly selected females from each group. Urinalysis was performed on samples collected at terminal sacrifice from five randomly selected males from each group.
Functional observations including sensory reactivity to different stimuli, grip strength, motor activity assessments and other behaviour observations were performed in the week before the treatment and at the end of the study on five randomly selected males and females.
After 14 days of treatment to both male and female animals were mated (1:1) for a maximum of 14 days. From the subsequent morning onwards the vaginal smears of females were checked to confirm the evidence of mating. After the confirmation of the mating, females were separated and housed individually. Each litter was examined as soon as possible after delivery of the dam to establish the number and sex of pups, stillbirths, live births, runts and the presence of gross abnormalities. Live pups were counted, sexed and litters weighed within 24 hours off parturition and on day 4 post-partum.
The males were sacrificed after completion of the mating period on days 29 and 30 and the females along with their pups were sacrificed on post natal day 4. Non-pregnant females were sacrificed on GD 26 from the day of confirmed mating.
Pups sacrificed on post natal day 4, were carefully examined for gross external abnormalities.
A full histopathological evaluation of the tissues was performed on high dose and control animals. Organs showing gross alterations were also examined histopathologically. Reproductive organs were evaluated in all study animals.
The following doses were evaluated: Control: 0 mg/kg body weight; Low Dose: 100 mg/kg body weight; Medium Dose: 300 mg/kg body weight; High Dose: 1000 mg/kg body weight.
The test item formulation was prepared freshly on each day of administration. The test item was suspended in sterile water and administered daily during 14 days of pre-mating and during mating period in both male and female animals, during the gestation period and up to post-natal day 3 in females. Males were dosed for 28 days. Non pregnant females were treated until day 25 after confirmed mating. Dose volumes were adjusted individually based on weekly body weight measurements. The administration volume was 5 mL/kg body weight.
No mortality occurred in the control or any of the dose groups during the treatment period of this study.
There were no clinical signs considered to be of toxicological relevance recorded in male and female animals of treated groups.
During the weekly detailed clinical observation, no significant changes or differences between the groups were found. There were no ophthalmoscopic findings in any of the animals of this study.
No relevant effects were observed in any of the parameters of the functional observation battery before and at the end of the treatment period. There were no biologically relevant differences in body temperature between the groups.
In both males and females, no treatment related changes were considered for body weight, body weight change and food consumption in treated groups when compared to control.
No treatment-related changes were noted for number of still births, number of runts, total number of pups born on PND 0 and number of male and female pups, sex ratio, live pups on PND 0 and PND 4.
No treatment related changes were noted for the mean litter weight, total litter weight, male and female litter weight on PND 0 and 4 in treated groups when compared to corresponding control.
No treatment related changes were noted for the precoital interval and duration of gestation in treated groups when compared to control. All pregnancies resulted in normal births.
No treatment related changes were noted for number of corpora lutea, number of implantation sites, number of live pups born on PND 0 and percentage of pre and post implantation loss in treated groups when compared to control.
There were no treatment related changes noted for copulation index (%), fertility index (%) and delivery index (%) in treated groups when compared to corresponding control group.
No treatment related changes were noted for survival of the pups from PND 0 to PND 4 in treated group when compared to control.
No treatment related changes were noted for viability index (%). No treatment-related gross external findings were observed in the treated groups.
There were no statistically significant changes considered to be of toxicological relevance noted for haematological, clinical biochemistry and coagulation parameters in male and female treated groups when compared to the corresponding control.
The urinalysis performed in male animals revealed no test item related effect in the treated groups when compared to control.
One control female, one female of LD group, one female of MD group and two females of HD group did not show any indication of recent pregnancy at terminal sacrifice. As this was not dose-related, it was not considered to be related to treatment.
At terminal sacrifice, macroscopic organ findings noted were few, and none of them was considered to be test item-related.
There were no changes noted for organ weight in both males and females considered to be related to treatment when compared to corresponding control.
No test item-related histopathological findings were noted in the male and female reproductive organs and other organs and tissues evaluated in males and females of the control and high dose group.
After subacute treatment no effects on fertility parameters were detecetd in male and female animals. Numbers of live pups were in the expected range and comparable to concurrent controls.
No effects on developmental parameters were detected in any animal up to
the limit dose of 1000 mg/kg bw/d.
0 mg/kg bw/d
100 mg/kg bw/d
300 mg/kg bw/d
1000 mg/kg bw/d
Initial group size
With live foetuses at gestation Day 20
OF FEMALES WITH LIVE FOETUSES ON GESTATION DAY 20 – GROUP MEAN DATA
WEIGHT GAIN PER DAY (g) OF FEMALES WITH LIVE FOETUSES ON GESTATION DAY
20 – GROUP MEAN DATA (mean daily body weight gain over the previous
period starting from gestation day 0)
= mean value of group is significantly different from control at p <
DATA AND SEX RATIOS - GROUP MEAN DATA
Implantation loss [%]
Litter weight [g]
Mean foetal weight [g]
EXAMINATION OF FOETUSES – GROUP INCIDENCE
No abnormalities detected
EXAMINATION OF FOETUSES – GROUP INCIDENCE
Metacarpal(s) no ossification 4th
Metatarsal(s) no ossification 4th
Metatarsal(s) incomplete ossification 4th
Centrum dumb-bell shaped
Asymmetrical dumb-bell shaped
Pubis incomplete ossification
Ischium incomplete ossification
Arch(es) incomplete ossification
Temporal incomplete ossification
Interparietal incomplete ossification
Supraoccipital incomplete ossification
Asymmetrical ossification 5th
No ossification 6th
Dumb-bell shaped 5th
Incomplete ossification 5th
Incomplete ossification 6th
No ossification 5th
Centrum no ossification
Centrum incomplete ossification
Centrum asymmetrical dumb-bell shaped
EXAMINATION OF FOETUSES – GROUP INCIDENCE
Innominate artery absent
Innominate artery short
Atrium enlarged / slight
Ventricle enlarged / slight
Pelvic dilatation / moderate
Pelvic dilatation /extreme
Pelvic dilatation / slight
Innominate artery longer
Lobe abnormal shape
Kinked / extreme
Pelvic dilatation / extreme
a prenatal developmental toxicity study according to OECD Guideline 414
acids, C16-18, reaction products with diethanolamine (98.81% a.i.) was
administered to 24 female Sprague-Dawley rats in 0.5% carboxymethyl
cellulose by gavage at dose levels of 0, 100, 300, or 1000 mg/kg bw/day
from days 6 through
weight, daily clinical signs and food consumption were recorded during
All females were caesarean-sectioned on Day 20 post
subjected to post
The number of corpora lutea, implantations, early and late intrauterine
deaths, live and dead foetuses, uterus weight, foetal weight and sex
were recorded. All foetuses were examined for external abnormalities.
Approximately one half of the foetuses in each litter was examined for
fixed-visceral and skeletal
animals died during the study. Four females in the low dose group and
one each in the mid- and high dose groups were found not pregnant at
necropsy. One female in control, low and mid-dose groups had unilateral
implantation. The number of females with live fetuses on gestation Day
20 was 24 in the control group, 20 in the low dose and 23 in the mid-
and high dose groups.
signs of toxicological significance were noted during the study and no
signs of reactions to treatment were observed during the dosing period.
relevant differences were noted in body weight and body weight gain of
females during the study, between control and treated groups.
relevant changes were detected in food consumption between treated and
relevant changes were seen in terminal body weight, uterus weight and
absolute weight gain, in treated animals compared to controls.
data and sex ratios were not affected by treatment.
macroscopic changes were observed at post
in treated animals, when compared to the controls.
total of 5 small foetuses (<2.7
g) were detected: 1 in each control, mid- and high dose groups and 2 in
the low dose group. No other abnormalities were detected at the external
examination of foetuses. No changes were noted at the skeletal
examination of the foetuses which were considered treatment-related. No
changes were noted at the visceral examination of the foetuses which
were considered treatment-related.
the basis of these results the dosage of 1000 mg/kg/day could be
considered the NOAEL in this study.
Neither clinical signs nor signs of reaction to treatment were noted in
treated females. No significant differences were noted in body weight,
food consumption, gravid uterus weight, litter data and macroscopic
observation of treated females when compared to controls. No
treatment-related changes were noted at the external, skeletal and
visceral examinations of the foetuses. On the basis of these results the
dose of 1000 mg/kg bw/day is considered the NOAEL in this study.
The available information does not indicate any hazard for reproduction
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