| 4.1.Adverse effects after single exposure
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Toxicity via the oral, inhalation and dermal routes is low.
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Toxicity via the oral, inhalation and dermal routes is low.
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Toxicity via the oral, inhalation and dermal routes is low.
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Toxicity via the oral, inhalation and dermal routes is low.
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| 4.2.Adverse effects from local contact (skin, eyes and respiratory tract)
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Not irritating to the eyes and the skin and not skin sensitizer. Inhalation of relatively low concentrations in the air produced histopathological changes in the lining of the upper respiratory tract after 4 weeks.
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Slightly irritating to the skin and the eyes and no skin
sensitizer.
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Not irritating to the eyes, the respiratory tract and the skin. and not a skin sensitizer.
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Not irritating to the eyes, the respiratory tract and the skin and not a skin or respiratory sensitizer.
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| 4.3. Adverse effects on genetic material (mutagenicity)
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Not mutagenic.
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Not mutagenic.
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Not mutagenic.
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Not mutagenic.
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| 4.4. Adverse effects after repeated exposure
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Oral administration to rats revealed effects on the liver and the kidneys. No effects on the nervous system and the testes were seen in this study up to the highest dose level. However, testes effects were observed in another rat study. Exposure by inhalation didn’t reveal any systemic
toxicity.
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Oral administration to rats showed that the liver, the kidneys and the testes are the main target organs. The liver lesions consisted of weight increase, swelling of liver cells and increase of peroxisomes in liver cells. The kidney lesions included chronic progressive nephropathy. The testes were small with aspermia at the highest dose levels.
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Oral administration to rats showed that the liver is the main target organ. The liver effects consisted of an increase in organ weight, changes in blood biochemistry (increase of transaminases) and an increase in peroxisomes in liver cells. No increase in peroxisomes in liver cells was noted in non-rodent species including man. In male rats an increase of kidney pathology was observed (nephropathy) which is based on a mechanism that is not relevant to man.
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Oral administration to rats and dogs for 3 months
showed that the liver is the main target organ. The liver effects in rats
consisted of an increase in organ weight and of peroxisomes in liver cells. Kidney effects were only observed in male rats.Inhalation did not cause any systemic effects, only local inflammatory changes were noted in the lungs.
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| 4.5. Carcinogenicity
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No adequate long term carcinogenicity studies are available. An increase of peroxisomes in liver cells of rats was reported. Liver tumors produced in rodents by other phthalates were shown to be based on peroxisome proliferation and cell proliferation, a mechanism of action that is recognized to be of very limited relevance to man.
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Long term carcinogenicity studies in mice and rats revealed liver tumors, Leydig cell (testes) tumors and leukemia. The mechanism of action of the liver tumors is based on the increase of peroxisomes in liver cells which is recognized to have very limited relevance to man. The evidence for relevance to man of the two other
tumor types remains inconclusive.
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An increase in liver tumors was observed in mice and rats after oral administration in cancer studies. The mechanism of action of these tumors is based on the increase of peroxisomes in livers cells which is recognized to have very limited relevance to man. Other tumors were kidney tumors and mononuclear cell leukemia which both of them are considered to be specific to the rodent species tested and without relevance to man.
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No long term carcinogenicity tests have been
performed. - An increase of peroxisomes in liver cells was reported. This is indicative of the possibility to develop liver tumors in rodents. The mechanism of action of these tumors is recognized to have very limited relevance to man.
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4.6. Adverse effects on fertility
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A 2-generation toxicology study in rats did reveal effects on fertility at high dose only
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A 3-generation reproduction toxicology study
demonstrated testicular toxicity (small testes and aspermia at the highest
dose level). Developing and pre-pubertal rats were shown to be more sensitive
than adult rats in this study.
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No adverse effects on fertility were noted
in the rat. At very high dose levels in mice a decrease in testicular weight,
abnormal sperm and atrophy of the uterus and the ovaries was seen after 3
months of treatment.Testicular effects were not observed in
other non-rodent species (marmosets and monkeys). No changes in reproductive
parameters were noted in a 2-generation reproduction toxicity study.
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A 2-generation toxicology study in rats did not
reveal any significant effects on fertility.
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| 4.7. Adverse effects on the development of the embryo and the fetus
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Toxicity to the embryo and malformations of the
fetus were observed in mice and embryotoxicity in rats in the absence of
maternal toxicity.
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Exposure of the dams of rats to very high doses,
close to maternal toxicity, led to embryotoxicity, malformations and fetal
development effects. Embryotoxicity and malformation were also observed in
mice at dose levels which were below those of maternal toxicity. Testicular
toxicity and developmental toxicity, observed in different animal species and
at relatively low dose levels are considered relevant to humans.
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Exposure of the dams of rats to very high doses led
to soft tissue malformations and fetal development effects.
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Exposure of the dams of rats to very high doses did
not produce any malformations but revealed fetal development effects in the
presence of slight maternal toxicity.
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| 4.8. Adverse effects on pre- and post-natal development
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Delayed preputial separation and malformations of
the reproductive tract of male rats were seen after oral exposure. Delayed
preputial separation was reported in the male offspring at a lower dose.The weak estrogenic effects detected in vitro could not be confirmed in vivo. However, there are indications of an anti-androgenic effect.
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Effects on testicular development in pre-pubertal rats were seen in a 3-generation reproduction toxicology study.
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In 1- and 2-generation reproduction toxicology studies in the rat a reduction in pup weight was observed. In vitro and in vivo assays did not demonstrate estrogenic activity. However, a peri-natal reproduction toxicology study in the rat revealed a very slight increase of the incidence of effects in male offspring (areolas/ nipples, malformation of the reproductive organs).
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In reproduction toxicology studies in the rat a reduction in pup body weight and survival were observed. Oral administration to pubertal rats didn’t reveal any adverse effects on the development of the reproductive system. In vitro and in vivo assays did not demonstrate estrogenic or anti-androgenic activity.
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| 4.9. Potential hormone-like effects
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No effect observed, but there are some indications that the potential for an endocrine related effect cannot be ruled out.
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Many studies have demonstrated an endocrine disruption effect and an effect on sexual development in animal studies.
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No effects observed.
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No effects observed.
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