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EC number: 200-521-5
CAS number: 61-82-5
Two-generation reproductive toxicity in rats (OECD416, GLP, Rel.2):
NOAEL(parental toxicity) = 2 ppm (eq. to 0.12 mg/kg bw/day) ;
NOAEL(reproductive toxicity) = 15 ppm (eq. to 0.9 mg/kg bw/day)
In a two-generation reproduction toxicity study was performed in rats
according to the OECD guideline 416 and in compliance with GLP, the test
substance was given continuously to 5 groups of F0 Sprague-Dawley rats
(30/sex/dose) by admixture to the diet at the dose levels of 0.5, 2, 15
and 112.5 ppm. The F0 control animals (30 males and 30 females) received
the untreated diet only. After 72 days of treatment in males and
females, the F0 male and female rats were paired. Treatment was
continued in males until weaning of the F1 offspring and in females
during the same period. F1 pups were paired when they were 12 to 14
weeks old. The F1 females were allowed to deliver normally. Macroscopic
examination of F0 males and females, F1 males and females, F1 and F2
pups was performed. Organ weights and microscopic examination were
performed on a range of tissues.
Under the experimental conditions, the test substance was not toxic for
F0 and F1 parent animals up to 2 ppm and did not induce adverse effects
on the reproductive performance of F0 and F1 animals, nor impaired the
development of F1 and F2 off-springs up to 15 ppm. The dose of 15 ppm
was toxic for the F0 (males only) and F1 parental animals, as shown by
minimal increased thyroid activity. The 112.5 ppm dose level was
severely toxic for F0 and F1 parents, impaired their fertility and
disturbed the development of F1 and F2 litters. Nevertheless, all
findings on reproduction correlated with severe systemic parental
toxicity, so that a primary effect on reproduction is excluded.
NOAEL(parental toxicity) = 0.12 mg/kg bw/day (2 ppm)
NOAEL(reproductive toxicity) = 0.9 mg/kg bw/day (15 ppm)
- developmental toxicity in rats (OECD414, EPA rules, Rel.2):
NOAEL(maternal and developmental toxicity) = 100 mg/kg bw/day based
on effects on thyroid which are already covered by the harmonised
classification STOT-RE 2 (H373) determined from the repeated dose
- developmental toxicity in rabbits (OECD414, EPA rules, Rel.2):
NOAEL(maternal and developmental toxicity) = 4 mg/kg bw/day
and classification Cat.2 (H361d) for reproductive toxicity
- developmental toxicity in rabbits (OECD414, GLP, Rel.2):
NOAEL(maternal and developmental toxicity) = 20 mg/kg bw/day
- maternotoxicity in rabbits (No guideline, GLP, Rel.1): NOAEL(maternal
toxicity) = 3 mg/kg bw/day
In an teratogenicity study performed in 1986, test substance was daily
administered by gavage at dose levels of 0, 100, 500, or 1000 mg /kg
body weight/day in deionized water to female CD® rats on gestational
days (gd) 6 to 15.
24 out of 38 plug-positive females per group were employed for the
teratology sacrifice portion performed at gd 21 and the remaining 14
plug-positive females per group were allowed to litter and employed for
the postnatal sacrifice portion performed at postnatal day 21.
There were no treatment-related maternal deaths. Slight maternal
toxicity was indicated by reduced weight gain for gd 6 -18 at 1000 mg/kg
bw/day but not prior to or subsequent to this period, and reduced food
consumption for gd 12 -15, 15 -18 and gd 15 -21 at 500 and 1000 mg/kg
bw/day. There were no differences among groups for gestation or
lactation maternal body weights or for lactational weight gain or food
consumption. No treatment-related clinical signs were observed. At the
gd 21 sacrifice there were no effects of treatment on maternal body
weight, gravid uterine weight, or on absolute or relative liver weight.
Maternal thyroid weight was increased at 500 and 1000 mg/kg bw/day.
Reproductive parameters, including ovarian corpora lutea of pregnancy,
total, viable and nonviable implantations per litter and sex ratio were
unaffected by treatment. Fetal body weight per litter was reduced at
1000 mg/kg bw/day.
There was no significant increase in the incidence of malformations in
any treated group relative to controls and no differences among groups
for pooled external, visceral, skeletal or total variations. At 1000
mg/kg bw/day there were seven variations with incidences different from
that of controls, including dark fetal thyroids and indications of
reduced ossification. Enlarged and/or dark fetal thyroids also exhibited
an increased incidence at 500 and 1000 mg/kg bw/day relative to that in
Postnatal observations indicated no differences among groups for any pup
parameters at any time points evaluated, including litter sizes, sex
ratio, pup weights per litter or survival indices. Maternal thyroid
weights were still increased at 500 and 1000 mg/kg bw/day at postnatal
Under the test condition, administration of test material by gavage to
CD® rats during organogenesis resulted in evidence of maternal and
fetotoxicity toxicity at 500 and 1000 mg/kg bw/day. Postnatal
evaluations indicated all observed maternal and perinatal effects were
transient except for enlarged maternal thyroids. No teratogenicity was
observed at any dose level.
NOAEL (maternal and developmental toxicity) = 100 mg/kg bw/day
STOT-RE 2 (H373) based on effects on thyroid
(see section 7.5 Repeated dose toxicity)
Test substance was also tested in rabbits in the same period the same
lab as for Study N°1. Test substance was daily administered by gavage at
dose levels of 0, 4, 40, or 400 mg /kg bw/day in deionized water to
female New Zealand White rabbits on gestational days (GD) 6 to 18.
Twenty two mated females per group were employed.
There were no treatment-related maternal deaths. Maternal toxicity at 40
and 400 mg/kg bw/day was indicated by an increase in the incidence of
spontaneous abortions at both dosage levels, and by a reduction in body
weight and weight gain during and after the dosing period. Gravid
uterine weight and absolute liver weight were unaffected by treatment,
but liver weight relative to body weight was increased at 400 mg/kg
bw/day. The number of ovarian corpora lutea per doe, of total
implantations per litter was increased and the percent live fetuses per
litter was significantly decreased at 400 mg/kg bw/day. Fetal body
weight per litter was significantly reduced at 400 mg/kg bw/day.
At 40 and 400 mg/kg bw/day there were significant increases in the
incidence of individual malformations, of malformations by category
(external, visceral includng craniofacial, and skeletal) and of total
malformations. The malformations involved the head, limbs, vertebral
column and tail. There were no treatment-related effects on the
incidence of individual fetal external variations. The incidence of a
number of individual visceral (including craniofacial) and skeletal
variations was increased at 40 and 400 mg/kg bw/day. The incidence of
variations by category and of total variations was increased at 40 and
400 mg/kg bw/day.
Under the test condition, administration of test material by gavage to
New Zealand White rabbits during organogenesis resulted in evidence of
maternal and embryo/fetotoxicity including teratogenicity at 40 and 400
NOAEL (maternal and developmental toxicity) = 4 mg/kg bw/day
Cat. 2 (H361d) for Reproductive toxicity
An oral teratogenic study was
conducted according to OECD Guideline No. 414 (Teratogenicity), EPA OPP
83.3 (Prenatal developmental) and EC guideline (Comission Directive
88/302/EEC) in compliance with GLP to evaluate the potential toxic
effects of the test substance on the pregnant female and fetuses
Sixteen female Russian
rabbits were daily treated orally by gavage with Amitrole from day 6
to18 p.c. in doses of 0, 5, 20, and 80 mg/kg bw, respectively. On the
29th day of gestation the fetuses were delivered by cesarian section.
Investigations were performed on general tolerance of the test compound
by the dams as well as on its effect on intrauterine development.
Appearance, behavior, and
mortality were not affected by the treatment up to and including the
dose of 80 mg/kg bw/day. Macroscopic signs of compound related organ
damage at necropsy were not evident up to and including 80mg/kg bw/day.
Body weight gain and feed consumption in the 80 mg/kg group were reduced
mainly during the first week of treatment. The water in take was
decreased and excretory products (smallscybala) were affected at 80
With respect to intrauterine
development, the gestation rate, the resorption rate, the number of
fetuses and fetal sex as well as the weight and appearance of the
placentas were unaffected by the treatment up to and including 80 mg/kg
The male fetal weight was
marginally reduced at the dose of 80 mg/kg bw/day.
External, visceral and
skeletal examination of the fetuses revealed no effects of Amitrole on
intrauterine development up to and including the dose of 20 mg/kg
bw/day. At the dose of 80 mg/kg a slight increase in skeletal variations
was observed (fusions of sternebrae). A teratogenic potential of
Amitrole was not evident.
Under the test conditions:
- the maternal NOAEL is 20
mg/kg bw/day, based on reduced body weight gain and
food/water consumption observed at the high dose (80 mg/kg bw/day).
- the fetal NOAEL is 20 mg/kg
bw/day, based on the skeletal variations (fusions of sternebrae)
observed at the high dose (80 mg/kg bw/day).
An oral prenatal developmental toxicity study was conducted in
compliance with GLP to evaluate the potential toxic effects (mainly on
thyroid function) of the test substance on the pregnant female rabbit.
Three groups of mated female rabbits (10/dose) of the KBL New Zealand
White strain, received the test substance in aqueous solution, by oral
gavage, at 0 (purified water), 3, 15 or 75 mg/kg bw/day, daily from Day
6 to Day 18 post-coitum, inclusive and were sacrified on day 29
post-coitum. Foetuses were only submitted to an external examination.
No treatment-related clinical signs were observed at any dose-level.
There were no deaths ascribed to treatment with the test substance.
There was no abortion in any group. The body weight gain, the food and
water consumption were similar in the control and the 3 and 15 mg/kg
bw/day groups. In the 75 mg/kg bw/day group, the body weight gain, food
consumption and water consumption were lower than that of the control
group (body weight gain: -66%, p < 0.01; food consumption: -37%, p <
0.001; water consumption: -24%). In blood chemistry, there were no
notable changes at 3 and 15 mg/kg bw/ day. At 75 mg/kg bw/day, there was
a higher cholesterol level and a lower level of the total thyroid
hormones T3 and T4 (cholesterol: +225%, p < 0.01; T3: -51%, p < 0.01;
T4: -29%, p < 0.01). All the hysterectomy parameters were similar in the
control and the treated groups: pre- and post-implantation loss, number
of foetuses and foetal weight. There were no treatment-related external
malformations or variations in the foetuses of the 3 and 15 mg/kg bw/day
groups. In the 75 mg/kg bw/day group, 3/66 foetuses displayed a
domed-head, probably related to dilatation of cerebral
ventricles/hydrocephaly. A relationship to treatment with the test
substance cannot be ruled out. In dams, there were no notable
differences in thyroid weights between the control and treated females,
and there were no macroscopic changes (including in the thyroids) that
were attributed to treatment with the test substance. The severity of
the morphological changes indicative of thyroidal hyperactivity was
similar between the dams given 3 mg/kg bw/day and the control dams.
However, slightly higher severity was seen in the treated dams given 15
or 75 mg/kg bw/day. There were no signs of hyperactivity in the thyroids
of the foetuses of any control or treated groups.
Under the test conditions, the test substance when administered to
pregnant female rabbits, daily from Day 6 to Day 18 post-coitum, at 3,
15 or 75 mg/kg bw/day was clearly maternotoxic at 75 mg/kg bw/day. There
were signs of slight thyroidal hyperactivity at 15 and 75 mg/kg bw/day,
among the dams.
NOAEL (maternal toxicity) = 3 mg/kg bw/day
In the developmental toxicity
study in rabbits (test N°2), malformations of the head and limbs were
observed. In a recent study focussing on maternotoxicity in rabbits
(test N°4), in which only external examination of the foetuses was
performed, malformations of the head were observed.
According to a weight of
evidence approach for developmental toxicity and the conclusion on
the peer review of the pesticide risk assessment of the active substance
amitrole (EFSA, Journal 2014; 12(7):3742), the NOAEL of 3 mg/kg
bw/day for maternal and developmental toxicity in rabbits and the
harmonised classification as Cat.2 (H361d) is confirmed for AMITROLE.
The substance has an harmonized
classification in Cat.2 (H361d: Suspected of damaging the unborn child)
for reproductive toxicity according to the Regulation (EC) No 1272/2008.
Developmental toxicity was reported in
reliable studies. As the substance already has an harmonized
classification, no addition self-classification is proposed.
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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