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EC number: 237-159-2
CAS number: 13674-87-8
NOAEL of 200 mg/kg/day can be derived for reproductive toxicity based on
the statistically signif
A negative result was obtained in a fertility study carried out in male
rabbits in which animals were dosed daily with concentrations of TDCP up
to 200 mg/kg/day for twelve weeks and then mated with two females during
the last week of treatment. Mating, fertility, pregnancy parameters,
sperm analysis and the male reproductive tract were unaffected by
In a 2-year carcinogenicity study in rats, an
evaluation was made of the male reproductive system. Only control and
high dose animals were evaluated at 12 months, and no significant
differences were noted at this time point. Effects were noted in the
testes, epididymis and seminal vesicles in all animals at 24 months,
with a trend for higher incidence in the treated groups.
An increase in interstitial cell tumours of the
testes in the mid and high dose males at the 12 and 24 months was
observed in this study. Therefore, it is possible that the effects
observed on the testes may be secondary to an effect of the Leydig cell
tumours. It should also be considered that the effects noted in the male
reproductive system are only observed in animals at 24 months and,
therefore, may be secondary to the natural ageing process of rats rather
than a specific effect on the male reproductive system.
In addition to these points, as indicated above, no
effect on the male reproductive system and no effects on fertility were
observed in the fertility study in male rabbits. Therefore, based on a
weight of evidence, it is considered that there is no concern for male
No evaluation of the female reproductive system was included in the
2-year carcinogenicity study with TDCP. However, the authors reported
that all organs and tissues were examined microscopically in the high
dose and control animals in this study. As no effects on the female
reporductive organs were reported, it can rasonably be assumed that no
effects were observed on the female reproductive organs in this study.
Although there may be an apparent data gap for female fertility the EU
risk assessment report concluded that there was no need to conduct a
further study on reproductive endpoints based on the following rational
“In considering this data gap, and the possible requirement for a female
fertility study to address this endpoint, the available data for TDCP
was reviewed. In the chronic toxicity study with TDCP, a LOAEL of 5
mg/kg was derived for repeated dose toxicity and carcinogenicity and
brought forward to risk characterisation for both of these endpoints.
Given the low LOAEL derived from this study, it is considered possible
that any risk to female fertility will already be covered by the LOAEL
for repeated dose toxicity and carcinogenicity, and the subsequent
conclusions drawn for both of these endpoints.
This consideration is further supported by a study by Janer et al.,
(2007), where a retrospective analysis of the relationship between
NOAEL’s for effects on fertility, obtained from two-generation
reproductive toxicity studies, and those for repeated dose toxicity,
obtained from subchronic studies, was conducted. The results showed that
on average there was no, or only a small difference (less than
two-fold), in the NOAEL’s between the two types of studies. This
supports the view that the endpoint for female fertility is likely to be
already covered by the LOAEL derived from the chronic study and any risk
for female fertility will be addressed within the risk characterisation
for repeated dose toxicity and carcinogenicity.” Taking this view into
consideration and for animal welfare reasons the applicant is not
proposing any further studies on toxicity to reproduction at this point
Short description of key information:
A negative result was obtained in a fertility study carried out in
male rabbits in which animals were dosed daily with concentrations of
TDCP up to 200 mg/kg/day for twelve weeks and then mated with two
females during the last week of treatment. Mating, fertility, pregnancy
parameters, sperm analysis and the male reproductive tract were
unaffected by treatment.
An overall NOAEL of 100 mg/kg/day can be derived for developmental toxicity based on the statistically significant increased resorptions and the decreased foetal viability index at 400 mg/kg/day seen in the Stauffer Chemical Company developmental study reported (1978).
In relation to developmental effects, there are no data available
in humans. In a developmental study in rats, a dose of 400 mg/kg/day
significantly increased the rate of resorptions compared to controls. At
this high dose there was also evidence of retarded skeletal development.
All of this was accompanied by significant maternal toxicity at this
high dose. There was no evidence of embryotoxicity in the absence of
maternal effects. The NOAEL for developmental toxicity was 100
mg/kg/day, based on the statistically significant increased resorptions
and the decreased foetal viability index at 400 mg/kg/day.
In a second developmental study on rats, the highest dose of 400
mg/kg/day resulted in the deaths of 11 out of 15 of the dams with a
reduction in live foetuses and a significantly high incidence of foetal
deaths. No observations were noted at 200 mg/kg/day.
An overall NOAEL of 100 mg/kg/day can be derived for developmental
toxicity based on the statistically significant increased resorptions
and the decreased foetal viability index at 400 mg/kg/day seen in the
first developmental study reported. This NOAEL is taken forward to risk
characterisation in preference to the NOAEL of 200 mg/kg identified in
the second study described, as only the abstract from the second study
is available in English and therefore, full details of the study are not
available to the Rapporteur.
In vitro studies with TDCP point to potential impairement of
neurodevelopment through different pathways,
which might point to a long-term impact on behaviour, locomotion and
cognitive capacity of the offspring.
Neurodifferentation (Dishaw): Studies with neuronal PC12 cells indicated
that TDCP can influence neurodevelopment by decreasing cell number and
altering the neurodifferentation pathway. These observations were
substantiated in early life stage zebrafish studies, were exposure at
concentrations below the overt toxicity significantly altered larval
swimming activity was observed (Dishaw).
HPT-axis (Wang): Altered T3/T4 balance, which can lead to distrubances
However the neurodevelopmental rat study ( Moser) conducted to confirm
these observations, was not convincing. The results of the set of
different assessments of the offsprings were variable and not conclusive
and are not supportive for the observations made in the in vitro studies.
The ECHA Committee for Risk Assessment in its opinion of Sept. 3 2010
proposed a harmonized classification of the substance as carcinogen
category 2 (CLP) H351 or category 3 according to Dir. 67/548/EEC with
R40 and S (2)-36/37. The committee reviewed carcinogenicity and
reproductive toxicity data and came to the conclusion that no
classification for reproductive toxicity was proposed as there is
insufficient evidence for classification of TDCP as a male reproductive
toxicant. Based on two developmental toxicity studies in rats the
committee came to the conclusion that no classification for
developmental toxicity is proposed as there was no evidence of
embryotoxicity in the absence of maternal toxicity.
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