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EC number: 200-927-2
CAS number: 76-03-9
The NOEL value at 21 and at 35 days wqas equal or greater than 2500
A spermhead morphology assay was performed in mice with
sodium trichloroacetate. B6C3F1 mice (24/group) were given 0, 625, 1250,
or 2500 mg/kg bw/day of test substance for five consecutive days by oral
gavage. Twelve mice per treatment group were sacrificed at 21 and 35
days after the first treatment. These sacrifice times correspond to
treatment of cells at the late spermatogonial and primary spermatocyte
periods, respectively, assuming no treatment-related delays in sperm
development. Body weights were recorded for each animal during the
dosing phase and at sacrifice, and testes and cauda epididymidal weights
were recorded at sacrifice. Ten animals from each treatment/sacrifice
group were randomly selected to be evaluated for sperm count and
morphology. The types and frequencies of spermhead abnormalities were
based on the scoring of 500 sperm per animal. Initial and sacrifice body
weights, testes and cauda epididymal weights, testes to final body
weight ratios, and sperm concentration/mg of cauda epididymis were
analyzed by one-way analysis of variance (ANOVA) at a significance level
of p < 0.05. When significant differences were found, Dunnett's test was
applied to compare the different treatment group means with the negative
control means. The numbers of morphologically abnormal sperm were
analyzed by the Kruskall-Wallis and Mann-Whitney U tests, with
differences considered significant at the p < 0.05 level. These latter
tests are nonparametric alternatives to ANOVA and Dunnett's test,
The testes-to-final-body weight ratio, the number of
sperm per milligram of cauda epididymis, and the percentage of abnormal
spermheads were unaffected in the treated animals either at 21 or 35
days following oral gavage administration.
The NOEL value at 21 and at 35 days was equal or greater
than 2500 mg/kg bw/day.
reproductive screening study was not available, however a spermhead
morphology assay was conducted with read across substances sodium
trichloroacetate in B6C3F1 mice orally dosed by gavage up to 2500 mg/kg
bw/day for five consecutive days (Meier et al., 1997). The types and
frequencies of spermhead abnormalities were based on the scoring of 500
sperm cells per animal. In addition, body weights, testes and cauda
epididymal weights, testes to final body weight ratios, and sperm
concentration/mg of cauda epididymis were analyzed. The
testes-to-final-body weight ratio, the number of sperm per milligram of
cauda epididymis, and the percentage of abnormal spermheads were
unaffected in the treated animals either at 21 or 35 days following oral
gavage administration. The NOEL value at 21 and at 35 days was equal or
greater than 2500 mg/kg bw/day.
key oral repeated dose toxicity studies in rats and dogs with sodium
trichloroacete (see Section 7.5) did not indicate reproductive toxicity
potential. When administered in rats for 4 months (Scholz and Kozlik,
1969)and for 2 years (Scholz & Shultes, 1972) there were no effects on
male and female reproductive organs up to 10000 ppm in the feed. Severe
body weight loss was observed at the highest dose levels, leading to
NOEL of 4000 ppm (approximately 365 mg/kg bw and 1600 ppm (approximately
160 mg/kg bw) for the 4-month and 2-year study, respectively. When
Sodium trichloroacetate was studied in dogs in the feed for 90 days at
500, 2000, 4000 and 8000 ppm, male animals were more affected than the
females (Scholz and Brunk, 1970). Next to mortality (in all high dosed
males and one high dosed female), body weight loss and changes were
observed in liver, heart muscles, skeletal muscles and testes
(spermatogenesis) in animals from the 2000 ppm group upwards. Based on
these results, the no-effect-level in this study was 500 ppm
(approximately 30 mg/kg bw/day). As similar effects were not seen in the
rat 90-day and lifetime studies conducted at doses of around 3x the
LOAEL for testicular toxicity derived from the dog study, the testicular
findings in dogs are considered to be secondary to body weight loss and
severe paternal toxicity, therefore no indications for reproductive
toxicity were derived from repeated dose toxicity studies in rats and
dogs. No NOAELs were determined for reproductive toxicity.
information from a 90-day oral repeated dose toxicity study in rats
dosed with trichloroacetic acid via the drinking water, only showed
increased liver and kidney organ to body weight ratios and
histopathologic changes after 5000 ppm, corresponding with 355 mg/kg bw
(Mather et al., 1990). An additional study for 90 days in rats dosed
with trichloroacetic acid via the drinking water at ca. 785 mg/kg bw ,
showed variable degrees of alterations in the lung and liver of treated
animals: in the liver, morphological changes were predominantly
localized to the portal triads, which were mildly to moderately enlarged
with random bile duct proliferation, extension of portal veins,
fibrosis, edema, and occasional foci of inflammation. In the lungs,
minimal alterations were observed as foci of perivascular inflammation
on small pulmonary veins (Bath et al., 1991).
on this comparative information between sodium trichloroacete and
trichloroacetic acid, no relevant reproductive changes were seen after
subchronic dosing for both substances. As most information was available
for sodium trichloroacetate, this substance is selected as the source
substance for read across.
to REACH 1907/2006 legislation Annex IX (amended Feb. 20, 2015 by
Commission Regulation (EU) 2015/282) an Extended One-Generation
Reproductive Toxicity Study (B.56 of the Commission Regulation on test
methods as specified in Article 13(3) or OECD 443), basic test design
(cohorts 1A and 1B without extension to include a F2 generation), one
species, most appropriate route of administration, having regard to the
likely route of human exposure, is requested if the available repeated
dose toxicity studies (e.g. 28-day or 90-day studies, OECD 421 or 422
screening studies) indicate adverse effects on reproductive organs or
tissues or reveal other concerns in relation with reproductive toxicity.
Based on the negative outcome of STCA in a spermhead morphology assay in
mice dosed up to 2500 mg/kg bw (2212 mg/kg bw TCA equivalents) and the
absence of reproductive findings in rats up to highest tested doses of
365 mg/kg and 80 mg/kg bw (322 and 70.5 mg/kg bw TCA equivalents) after
subchronic and chronic (lifetime) exposure, and the confirmatory absence
for TCA of reproductive findings up to highest tested dose of 355 mg/kg
bw in a subchronic rat study, there are no indications for adverse
effects on reproductive organs or tissues. Therefore further testing for
this endpoint is waived.
Available data indicate that TCA is a developmental toxicant in the pregnant rat at doses of> 300 mg/kg bw. Maternal and fetal toxicity were observed from 330 mg/kg bodyweight, and from 800 mg/kg also embryo-lethality. In all dose groups there was a dose-dependent increase in visceral anomalies, particularly in the cardiovascular system. In contrast, female Sprague Dawley rats dosed at 300 mg/kg showed significantly reduced fetal body weights on GD 21, but did not demonstrate cardiac malformations. Other studies have been published on the developmental toxicity of TCA in rats and in vitro. Many of these studies were conducted with excessively high TCA concentrations. The malformations seen were possibly due to too high toxic dose levels, therefore resulting in secondary findings. In fact there was no NOAEL for maternal and developmental toxicity defined for TCA. A key prenatal developmental toxicity study was conducted with read across substance Sodium trichloracetate in Sprague Dawley rats , resulting in NOAEL of 300 mg/kg bw/day for the dams and the fetuses. Test item-related embryotoxic effects were only noted at the materno-toxic dose level of 1000 mg/kg bw/day in the form of reduced fetal body weights, increased fetal and/or litter incidences of skeletal retardations (retarded ossification) and an increased fetal incidence of fetuses with a dilated cerebral ventricle, classified as a soft tissue variation. A key prenatal development study was also conducted in pregnant New Zealand white rabbits with Sodium trichloroacetate, administered orally to female rabbits at dose levels of 5, 15 and 45 mg/kg bw/day during the critical phase of organogenesis and embryo/fetal development from the 6th to 28th day of pregnancy. The NO(A)EL was 15 mg/kg bw/day for the dams as well as for the fetal organism. This NOAEL was impacted by the gastro-intestinal senstiivity of the dams.
this prenatal developmental toxicity study, the test item Sodium
trichloracetate was administered to female rats at dose levels of 100,
300 or 1000 mg/kg bw/day (administration volume: 5 mL/kg bw/day), orally
by gavage from the 6th to 19th day of pregnancy.
the present test conditions, the no-observed-adverse-effect level
(NOAEL) was 300 mg Sodium trichloracetate/kg bw/day for the dams.
1000 mg Sodium trichloracetate/kg b.w./day, a marked reduction in food
consumption and a slight reduction in body weight and body weight gain
were noted for a few days after the start of treatment. Six of 20 dams
revealed an enlarged spleen during macroscopic examination at laparotomy.
no-observed-adverse-effect level (NOAEL) for the fetal organism was also
300 mg Sodium trichloracetate/kg b.w./day.
item-related embryotoxic effects were only noted at the materno-toxic
dose level of 1000 mg Sodium trichloracetate/kg bw/day in the form of
reduced fetal body weights, increased fetal and/or litter incidences of
skeletal retardations (retarded ossification) and an increased fetal
incidence of fetuses with a dilated cerebral ventricle, classified as a
soft tissue variation.
malformation was noted at any of the test item treated groups.
test item did not possess any teratogenic effect. The no-observed
adverse-effect level (NOAEL) for teratogenicity was 1000 mg Sodium
A prenatal developmental toxicity study conducted
in female Long-Evans rats from 6th to the 15th day of gestation dosed at
oral doses of 330, 800, 1200 and 1800 mg/kg bw (Smith et al., 1989).
Maternal and fetal toxicity (decreased fetal weight and length ) were
observed from 330 mg/kg bodyweight, and from 800 mg/kg also
embryo-lethality. In all dose groups there was a dose-dependent increase
in visceral anomalies, particularly in the cardiovascular system.
Maternal spleen and kidney weights increased in a dose related manner.
The mean frequency of soft tissue malformations especially in the
cardiovascular system, ranged from 9% at the low dose (330 mg/kg/day) to
97% at the high dose (1800 mg/kg/day).
In contrast, Fisher et al. (2001) dosed female
Sprague Dawley rats from 6thto the 15thday of
gestation, and observed significantly reduced fetal body weights on GD
21, but did not observe treatment-related effects on the incidence of
cardiac malformations. The reason for the inconsistent findings is
unknown. Smith et al. (1989) considered the cardiac malformation
(levocardia) to be an ill-defined malformation and possibly of trivial
appearance as found in Bouin’s fixed slices, therefore they are of
uncertain biological relevance. In addition, the available data also did
not permit identification of NOAEL values for the developmental or
maternal toxicity of TCA, since in each study, adverse effects were
observed at the lowest or only dose tested.
Other studies have been published on the
developmental toxicity of TCA in rats exposed via the oral route. Some
of these studies were conducted with excessively high TCA concentrations
(e.g. Singh, 2006) or with a single dose of TCA (e.g.Johnson et al.,
1998), and therefore provide limited information useful for informing
the dose-response relationship for TCA in the low-dose region (EPA,
In vitro studies with mouse and rat whole embryo
cultures were used to assess the potential for developmental toxicity of
TCA (Hunter et al., 1996: Saillenfait et al., 1995). TCA induced a
variety of morphologic changes in mouse and rat whole embryo cultures,
supporting the appearance of soft-tissue malformations observed in vivo
at maternally toxic doses. However, because of the high concentrations
used in these assays, in vitro test systems are limited in their utility
to predict adverse developmental effects and associated toxic potencies
in intact organisms.
A key prenatal developmental toxicity study was
conducted with read across substance Sodium trichloracetate in Sprague
Dawley rats dosed at 100, 300 or 1000 mg/kg bw/day by oral gavage from
the 6th to 19th day of pregnancy (Hansen, 2014). The NOAEL was 300 mg/kg
bw/day for the dams. At 1000 mg /kg bw/day, a marked reduction in food
consumption and a slight reduction in body weight and body weight gain
were noted for a few days after the start of treatment. Six of 20 dams
revealed an enlarged spleen during macroscopic examination at
laparotomy. The NOAEL for the fetal organism was also 300 mg/kg bw/day.
Test item-related embryotoxic effects were only noted at the
materno-toxic dose level of 1000 mg/kg bw/day in the form of reduced
fetal body weights, increased fetal and/or litter incidences of skeletal
retardations (retarded ossification) and an increased fetal incidence of
fetuses with a dilated cerebral ventricle, classified as a soft tissue
variation. No malformations were noted at any of the test item treated
groups; the test item did not possess any teratogenic effect. The NOAEL
for teratogenicity was 1000 mg/kg bw/day.
to REACH 1907/2006 legislation Annex IX and X, pre-natal developmental toxicity
testing in a second species is based on the outcome of the first test
and all other relevant available data.According
to OECD TG 414, the preferred non-rodent species is the rabbit. Data were
also available from read-across substance Sodium trichloroacetate.
supporting/dose-range-finding study was conducted in the rabbit by oral
administration to select the dose levels for the main prenatal
developmental toxicity study. Sodium trichloroacetate was administered
orally to female rabbits at dose levels of 60, 100, 300 and 1000 mg/kg
bw/day, during the ‘critical’ phase of organogenesis and embryo/fetal
development from the 6th to 28th day of pregnancy (Hansen, 2015a).
Treatment with 300 mg and 1000 mg/kg bw/day caused pronounced clinical
signs of toxicity in the dams. Effects on the reproductive performance
were noted in the dams and dosing in groups 3 and 4 was discontinued on
gestation day 10 and a fifth group was added to the study. Group 5 was
treated with 60 mg/kg bw/day. At 60 mg Sodium trichloroacetate/kg
bw/day, one dam died on gestation day 29 immediately before laparotomy.
One further dam aborted on gestation day 22 and was sacrificed on the
following morning. At 100 mg Sodium trichloroacetate/kg bw/ day, one dam
aborted on gestation day 26 and was sacrificed on the following morning.
At 300 mg Sodium trichloroacetate/kg bw/ day, one dam was found dead on
gestation day 10. Clinical and macroscopic observations in the dams were
observed from 60/kg bw/day onwards, including lesions of the stomach,
which are considered to be test item-related. Also in the foetuses,
effects were observed from 60 mg/kg bw/day, such as increases late and
total resorptions and slightly decreased fetal and placental weights.
Based on the data obtained in this study, dose levels are suggested for
the prenatal developmental toxicity study in rabbits with Sodium
trichloroacetate by oral administration were 5, 15 and 45 mg/kg bw/day.
The dosing in rabbits was technically limited by
the gastro-intestinal tolerance to the substance, therefore a low NOAEL
was derived compared to the rat study. The rabbit is known as a
difficult species as maternal gastro-intestinal disturbance may prevent
testing higher dose levels, or gastro-intestinal disturbance may have
impact on physiology and gestation. Therefore, although the rabbit study
is also entered as a key study, the NOAEL is not considered to be fully
equally representative as the rat NOAEL.
Based on the read across
between trichloroacetate and sodium trichloroacetate, and the
absence of malformations in the prenatal developmental toxicity
study in rats with sodium trichloroacetate there is no need to
classify the substance for reproductive toxicity in accordance to
criteria listed in the CLP Regulation (EC 1272/2008).
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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