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Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
400 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Concerning zinc effects on reproduction, zinc deficiency but also zinc excess are known to result in impairment of fertility and of foetal development.

When male rats were dosed with about 200 mg Zn2+/kg bw via the food for 30-32 days before mating, a statistically significant reduction in male reproductive performance was observed. This effect was attributed to a reduction in sperm motility. It is not known whether the reduced sperm motility in males are a direct effect of zinc on the sperm cells or if they are the result of disturbances in other physiological functions. A study on rats exposed to zinc oxide, adverse effects on fertility and foetal development occured at dose levels of 200 mg Zn2+/kg bw/day, in conjunction with perturbation of parental and foetal copper homeostasis. In a repeated dose toxicity study with zinc monoglycerolate hypoplasia of prostate and seminal vesicles was observed at doses of 300 mg Zn2+/kg bw/day, but not at 13 or 60 mg Zn2+/kg bw/day. As these effects were only seen at dose levels which produced very severe general toxicity, it is impossible to conclude that these adverse effects are directly related to zinc.

In contrast, in repeated dose toxicity studies with zinc sulphate, no effects on the reproductive organs were seen at dose levels up to 1100 mg and 565 mg Zn2+/kg bw/day for mice and rats, respectively. Also, in the combined repeated dose toxicity study with reproduction / developmental toxicity screening test according to OECD guideline 422 on the registered substance, mating performance and fertility were not impacted up to 1000 mg/kg bw/day and no histopathological findings were detected in sexual organs in both sexes (except prostate in males).

In a 90-day inhalation study with up to 300 ppm methacrylic acid, no changes in the reproductive organs of male and female rats and mice were

detected histopathologically. Also, in a recent study performed according to OECD guideline 416 in compliance with GLP, all data recorded during gestation and lactation in terms of embryo-/fetal and pup development gave no indications for any developmental toxicity in the F1 and F2 offspring up to a dose level of 400 mg/kg bw/day. Up to this dose level, the test substance did not adversely influence pup viability and pup body weights. Sex ratio and sexual maturation was not directly affected at any dose level therefore the NOAEL for reproduction/fertility and developmental toxicity was 400 mg/kg bw/day, ie. the highest dose tested.


Justification for selection of Effect on fertility via oral route:
More than one study was considered to assess the potential of the registered substance towards reproductive toxicity, therefore no study was selected.

Effects on developmental toxicity

Description of key information
In developmental toxicity studies performed similarly to OECD guideline 414 with mice, rats, hamsters and rabbits, neither reproductive nor developmental or maternal effects were observed up to the highest dose tested. In other studies, high dose levels of zinc (up to 200 Zn2+/kg bw/day) have been reported to result in resorptions and retarded foetal growth, but not in external malformations. In a study performed similarly to OECD guideline 414, inhalation exposure to methacrylic acid up to 300 ppm induced decreases in bodyweight gain and food consumption in dams but no treatment-related effects on fetuses development.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Additional information

In developmental toxicity studies performed similarly to OECD guideline 414 with mice, rats, hamsters and rabbits, neither reproductive nor developmental or maternal effects were observed up to the highest dose tested. In other (non-guideline) studies, high dose levels of zinc (up to 200 Zn2+/kg bw/day) have been reported to result in resorptions and retarded foetal growth, but not in external malformations. No resorptions and growth retardation were seen at 100 mg Zn2+/kg bw/day. At both 100 and 200 mg Zn2+/kg bw/day changes in maternal and fetal copper status were observed. These results are in line with the observations found in the combined repeated dose toxicity study with the reproduction / developmental toxicity screening test (according to OECD Guideline 422) on the registered substance where parturition was adversely affected at 1000 mg/kg bw/day with many grossly normal but dead pups. This similarity in results between the registered substance and zinc compounds strenghtens the possibility to deduce the potential of the registered substance towards reproduction and developmental toxicity with zinc compounds.

Evidence of zinc toxicity during human pregnancy has not been reported, probably because high exposures to zinc during pregnancy are not frequent. In contrast, zinc is necessary for normal growth and development therefore zinc deficiency can cause multiple adverse effects to the foetus or may result in reduced fertility and delayed sexual maturation in animals as well as in humans.

In a study performed similarly to OECD guideline 414, inhalation exposure to methacrylic acid up to 300 ppm induced decreases in bodyweight gain and food consumption in dams but no treatment-related effects on fetuses development.


Justification for selection of Effect on developmental toxicity: via oral route:
More than one study was considered to assess the potential of the registered substance towards reproductive toxicity, therefore no study was selected.

Justification for selection of Effect on developmental toxicity: via inhalation route:
More than one study was considered to assess the potential of the registered substance towards reproductive toxicity, therefore no study was selected.

Justification for classification or non-classification

In a combined repeated dose toxicity with reproduction/developmental toxicity screening test with the registered substance, parturition was adversely affected at 1000 mg/kg bw/day with many grossly normal but dead pups. Similar results were found in a

vailable data with animals exposed to zinc excess: adverse effects on fertility and foetal development may occur at dose levels of 200 mg Zn2+/kg bw/day, in conjunction with other effects such as perturbation of parental and foetal copper homeostasis. In multi generation studies, developmental effects such as decrease in body or organ weights were observed in F1 and/or F2 generations but always in the presence of maternal toxicity.

Evidence of zinc toxicity during human pregnancy has not been reported, probably because high exposures to zinc during pregnancy are not frequent. In contrast, zinc is necessary for normal growth and development therefore zinc deficiency can cause multiple adverse effects to the foetus or may result in reduced fertility and delayed sexual maturation in animals as well as in humans (WHO, 2001). As the difference is high between the zinc dose at which clinical signs in humans are effective (higher than 0.8 mg/kg bw/day) and the dose at which reproductive effects have been reported in animals (200 mg/kg bw/day), it is considered unlikely that reproductive effects will occur in humans at zinc exposure levels at which clinical signs can be observed.

Concerning the potential of the methacrylate part of the substance towards reproduction and developmental toxicity, all data show no effect of methacrylic acid or the related substance methyl methacrylate on reproduction, fertility and developmental toxicity (up to maternal toxic doses).

In conclusion, there is no experimental evidence that would justify a classification of zinc compound, methyl methacrylate or methacrylic acid and, as a consequence, zinc methacrylate for hazardous effects for reproductive or developmental toxicity under the Dangerous Substance Directive 67/548/EEC or Regulation (EC) 1272-2008.

WHO (2001). Environmental Health Criteria 221 Zinc. http://www.inchem.org/documents/ehc/ehc/ehc221.htm#1.0