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EC number: 204-279-1
CAS number: 118-82-1
The substance when given at dietary levels up to 1.25% to females 7 days prior to mating and through mating and gestation, did not affect gestation length, size of pups, total number of young per litter, or stillbirths per litter compared to control animals.
The Gestation Index of Successive Generations of Rats on Diets with and
without Test Article (Table 1 )
Test article concentration in diet (ppm)
1stMating Period (%)
Average for Both Matings (%)
Initial Parents (P)
Gestation Index: Number of litters with
live pups/Number of pregnancies x 100
Groupings of Females Fed Each Diet and the Number of Litters They
Test Article Concentration in the Diet (ppm)
Number of females which produced the indicated number of litters
Number of Litters
No Test Article
Test Article Diets
Diets with and without Test Article (Viability Index) (Table
* Seventh Day for Generation F1
Viability Index: Number of Rats alive on 4thDay/
Total number Delivered x 100
Percentage Number of Animals Alive at Birth (Live birth Index) (Table 4)
Live Birth Index: Number alive at birth/ total number
delivered x 100
(Based on first observation of the litters)
Diets containing the test substance in the nominal amounts of 0, 15, 60,
100, 500, and 3000 ppm were fed to 3 successive generations of breeding
rats. Over the course of the study, animals were
affected by environmental conditions and extraneous disease that were
unrelated to test article in the diet. However, the
data warrant the following conclusions:
1. Occasional fatalities among the breeding animals
were attributable to respiratory disease, and in some cases dystocia.
2. The content of test article in the diet had no
effect on fertility of the breeding animals, or on the extent to which
they produced living offspring. Exceptional variations
in fertility index and in gestation index were attributed to the
influence of extraneous disease unrelated to test article concentration
3. The probability of survival at birth and during the
first days of life, the viability index, was generally poor among the
first generation ranging from 45.9 to 73 per cent without regard to test
article concentration in the diet fed to the parents. The
viability index improved in the second generation ranging from 89.4 to
97.4% and was normal in the third generation except for the group fed a
test article diet containing 60 ppm. At that
concentration level, viability was 84.9%. The poor
life expectancy of offspring in the various groups was attributed to
extraneous factors and not test article concentration in the diet.
4. The survival during the time the pups were nursed
(the lactation index) ranged from 47.3% to 91.9% in the second
generation, and from 66.5 to 94.6% in the third generation. The
variation was not attributed to test article concentration in the diet.
5. The content of test article in the diets of the
breeding animals exerted no remarkable effect upon the body weights of
the offspring at birth, at 4 days of age, or when weaned at 21 days of
6. No anatomical anomaly or structural abnormality was
found among 5400 rats that were offspring of animals on diets containing
A reproduction-developmental screening test according to OECD 421 did not reveal any effects on fertility or embryonic development at the highest recommended dose of 1000 mg/kg bw. The NOAEL for both parental and reproductive toxicity was 1000 mg/kg bw, the highest dose tested.
A 3 generation study in rats receiving the substance in the diet at nominal concentrations up to 3000 mg/kg diet (ppm) did not reveal any test substance related effect on fertility. The finding is corroborated by the absence of significant effects on the reproductive organs in repeated dose toxicity studies of 3 months and 2 years duration in rats and dogs at comparable dose levels. Consequently based on the available data, the substance is not classified for reproductive toxicity / fertiltiy according regulation EC 1272/2008 and amendments.
Short description of key information:A 3 generation study in rats receiving the substance in the diet at nominal concentrations up to 3000 mg/kg diet (ppm) did not reveal any test substance related effect on fertility. The finding is corroborated by the absence of signficant effects on the reproductive organs in repeated dose toxicity studies of 3 months and 2 years duration in rats and dogs at comparable dose levels.Justification for selection of Effect on fertility via oral route:A 3-generation reproduction toxicity study in rats receiving the substance in their diet is available and the key study for this endpoint.
Two developmental toxicity studies, one in rats and one in rabbits are available. Groups of pregnant rats or rabbits received either 15 or 150 mg/kg bw per day by gavage from day 6 to 15 and day of gestation respectively. Concurrent vehicle control animals were included. No test substance related effects on maternal toxicity and embyo fetal development were observed up to the highest dose tested. From the repeated dose studies it can be concluded that the administrerd dose was close to the maximum tolerated dose. The absence of developmental toxicity is also corroborated by the 3-generation study in rats. The studies in combination give sufficient confidence to conclude that the substance is unlikely to cause adverse effects to the developing embryo or fetus.
Uterine and Litter Data
Implant sites (mean)
Resorption sites (mean)
Dead Fetuses (mean)
Live Fetuses (mean) grams/cm
Length Dead fetuses
Incubation Survival (Percent)
Skeletal Examination Data
15 mg/kg group
150 mg/kg group
Closure Grade 0
Nonossified Parts, Parietal Bone
Vertebrae - caudal
Nonossified Dorsal Arches
Sternum Ossification Centers
Pelvis Ossification Centers Absent
Forepaws Ossification Centers
Total Number Absent
Hindpaws Ossification Centers
Forty-five female albino rabbits were bred by artificial insemination
after stimulation of ovulation by administration of Pituitary
Luteinizing Hormone. Fifteen animals were assigned to
each test or control group. Test article was administered orally by
capsule to female rabbits from day 6 to day 18 of pregnancy. Test
article doses were either 15 or 150 mg/kg body weight, and control
animals received empty gelatin capsules. Pregnancy was
observed in 36 of the 45 animals bred (14 control, 13 low dose group, 9
high dose group). One control and one low dose female
died during the study before pregnancy could be determined. Abortion
was noted in 3 control animals. One control animal
delivered naturally; all other control and test litters were delivered
by Caesarian section. Appearance,
behavior, body weight gain, and food consumption were comparable among
control and test animals. All
uterine, litter, and Caesarian data were also comparable. There
was no indication of a treatment related effect in fetal external
appearance, visceral anatomy, development and skeletal structure of the
test offspring compared to control.
The number and placement of uterine implantation and resorption sites was comparable in dosed and control group animals.
The number, weight and length of life foetusses in the test substance groups was comparable to controls.
One dead fetus was found in the control group, but none in the dose groups. One control group female had three, on other one late resorption sites. Two low group females had one resorption site each.
The number of litters with resorption sites was 11/18 in controls, 7/17 in the low dose and 8/18 in the high dose group.
A few fetusses in controls and test groups appeared small in size, with similar incidence.
Visceral structures were examined by Wilson's sectioning technique in 58 control, 61 low dose and 68 high dose fetuses.
Observations in all groups included clotted blood in thoracical, abdominal and intestinal, or cranial regions, dilated renal pelvis dilated lateral brain ventricel in one control and ligh colores area of the liver in one control fetus.
No clearly test substance related differences in incidence of findings from controls were observed.
Skeletal examinations: skull, ribs, sternum, vertebrae, pelvic gridle, long bones, forepaws, hind paws evaluated. Changes observed occured with comparable incidence in dose and control groups.
The substance was investigated for enbryotoxic and/or teratogenic
effects in goups of 17 to 18 pregnant female albino rats . The test
material was mixed with corn oil and administered by oral gavage at
dosage levels of 15 and 150 mg/kg/day from Day 6 through Day 15 of
gestation . Control animals received corn oil only.
No maternal deaths occurred. All control and test litters were delivered
by Caesarean section . Appearance, behavior , body weight gain , and
food consumption were comparable among control and test animals. All
uterine, litter, and Caesarean data were comparable among control and
test groups. There was also no compound-related effect noted with
respect to external appearance, visceral anatomy, development , or
skeletal structure of the fetuses. Under the conditions of this study no
indications of a possible developmental effect were observed.
screening study and two developmental toxicity studies, one in
rats and one in rabbits are available. In the latter groups of pregnant
rats or rabbits received either 15 or 150 mg/kg bw per day by gavage
from day 6 to 15 and day 6 to 18 of gestation respectively. Concurrent
vehicle control animals were included. No test substance related effects
on maternal toxicity and embyo fetal development were observed up to the
highest dose tested. From the repeated dose studies it can be concluded
that the administrerd dose was close to the maximum tolerated dose. The
absence of developmental toxicity is also corroborated by the
3-generation study in rats. The studies in combination give sufficient
confidence to conclude that the substance is unlikely to cause adverse
effects to the developing embryo or fetus.
Consequently, based on the available data the substance is not
classidfied for toxicity to reproduction/ developmental toxicity
according to regulation 1272/2008 and amendments.
When pregnant rats were given diets containing the substance at
concentrations of 0.125 to 1.25% of the dry weight of the food, there
were no effects on length of gestation, size of pups, or total number of
young per litter. There was not an increase compared
to control in numbers of stillborn pups in the litters. This study
corroborates the findings of the 2 available teratogenicity studies in
rats and rabbits.
Based on the weight of evidence from all
available studies, a 3 -generation dietary study in rats, repeated dose
dietary studies of 90 -day and 2 year duration in rats and dogs,
developmental toxicity studies by gavage in rats and rabbits, and a
dietary study in rats covering the prenatal and complete gestation and
parturition period in rats, that consistently showed no substance
related effects on fertility and/or embryo-fetal development up to the
highest dose tested, no classification for reproductive endpoints,
neither fertility no developmental toxicity is warranted according to
regulation EC 1972/2008 and amendments.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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