Hydroxy(2-methylprop-2-enoato-O)zinc

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

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

Registered substance:

In a GLP-compliant Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted according to OECD Guideline 422, treatment with Hydroxy(2-methylprop-2-enoato-O)zinc at 1000 mg/kg bw/day was not tolerated by pregnant/lactating females, with 7/10 females prematurely killed between mid-gestation and Day 1 of lactation; in this 6/7 females showed evidence of abnormal parturition. All of the females were found to have several pups retained in utero, the majority of which were dead, and therefore the aetiology of the poor clinical condition of the six females was considered to be attributable to intrauterine fetal deaths.

At 1000 mg/kg bw/day, overall mean bodyweight gain of males during the course of the study was 0.80X Control, attributable to reduced weight gain during the first two weeks of treatment. In females at this dose level, mean weight gain was unaffected in Week 1, but lower than Control during Week 2 (0.40X Control) due to two females which recorded weight loss during this period. Thereafter, mean weight gain of these females was similar to Control until the final week of gestation, when the marked decline in clinical condition became apparent. Bodyweight performance of animals receiving 100 or 300 mg/kg bw/day was unaffected by treatment. Food consumption of males and females receiving 1000 mg/kg bw/day was slightly lower than Control during Week 1 of treatment. Thereafter, mean food intake of all groups of treated animals was similar to Control. Sensory reactivity, grip strength and motor activity were unaffected by treatment with test item.

A dose-dependent decrease in haematocrit and haemoglobin concentration was evident in all groups of treated males after 2 weeks of treatment. At 1000 mg/kg bw/day, decreases in erythrocytes, mean cell haemoglobin and mean cell volume and an increase in red cell distribution width were apparent in males and females, with females also showing a decrease in haematocrit, haemoglobin concentration and mean cell haemoglobin concentration. At 1000 mg/kg bw/day, an increase in all leucocyte parameters, particularly neutrophil concentrations in males and females and eosinophil concentrations in males, with an increase in total white blood cell counts; females also showed an increase in platelet counts.

At 1000 mg/kg bw/day, an increase in alkaline phosphatase and alanine amino-transferase activities and bilirubin concentrations and a reduction in total protein and albumin concentrations in males and females were observed after 2 weeks of treatment. Males also showed a decrease in bile acids and increased triglyceride concentrations, and females a decrease in aspartate amino-transferase activity and cholesterol concentrations. Chloride concentrations were high for males receiving 300 or 1000 mg/kg bw/day and for females receiving 1000 mg/kg bw/day.

Mating performance and fertility of the F0 generation animals were unaffected by treatment. Gestation length, parturition and gestation index of females receiving 1000 mg/kg bw/day was adversely affected by treatment with test item. Of the eight pregnant females in the dose group which survived to the end of gestation, only two dams completed parturition and one of these two females had a gestation length of 23.5 days, slightly longer than the expected range of 22-23 days. Abnormal parturition was apparent in the remaining six pregnant females requiring premature termination of these animals; either the onset of parturition did not occur, or a small number of pups were born with the remainder retained in utero. At 300 mg/kg bw/day, there was a suggestion of a slight shift towards a longer gestation length with 5/10 females showing a gestation length of 23 days compared to 2/10 Controls.

Among females receiving 1000 mg/kg bw/day that survived to scheduled termination on Day 7 of lactation, there was a suggestion of a slight reduction in implantation counts, with a concomitant slight reduction total litter size on Day 1 of lactation.

At scheduled termination, there were increased spleen weights in males and increased kidney weights in females at 1000 mg/kg bw/day without any association of macroscopic/microscopic abnormalities. Macroscopic examination revealed pale areas in the prostate of 2/10 males receiving 300 mg/kg bw/day and 4/10 males receiving 1000 mg/kg bw/day.

Treatment-related histopathological changes occurred in the stomach, duodenum, pancreas, eyes, and prostate. In the stomach, a dose dependent incidence/severity of inflammatory cell infiltrate composed of a variable number of eosinophils and neutrophils and globule leukocytes infiltration in the glandular stomach in males and females at 300 and 1000 mg/kg bw/day; minor inflammatory changes at 100 mg/kg bw/day; mucosal erosion/ulceration in females at 1000 mg/kg bw/day; focal intestinal metaplasia in the glandular stomach in a single male at 1000 mg/kg bw/day. At 1000 mg/kg bw/day, slight villous hypertrophy, characterised by a diffuse increase in villous height was seen in in the duodenum, moderate acinar degeneration/atrophy was observed in the pancreas and slight to moderate retinal atrophy in the eyes. In the prostate, suppurative inflammation/abscess(es) was seen with increased degree/severity at 300 and 1000 mg/kg bw/day. Minor inflammatory changes in the prostate were also seen in a single male at 100 mg/kg bw/day.

Histopathological changes detected among the females killed prematurely at 1000 mg/kg bw/day which were considered secondary effects of treatment comprised: minimal to slight leukocytic infiltration of the endometrium of the uterus (in the presence of dead fetuses); cortical hypertrophy of the adrenal glands; involution/atrophy of the thymus.

Zinc compounds:

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).

Methacrylic acid/methyl methacrylate:

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.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

1999

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study was conducted in accordance with a recognized scientific procedure for determining the developmental toxicity of a test substance when administered repeatedly via inhalation. The study meets national and international scientific standards (OECD 414) and provides sufficient information to support the conclusions regarding the NOAEL demonstrated from the study data.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

clinical observations not followed; individual animal data not reported

Principles of method if other than guideline:

Not applicable

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: IFFA CREDO Breeding Laboratories (Saint-Germain-sur-L'Arbresle, France)
- Age at study initiation: Sexually mature females; age not specified.
- Weight at study initiation: 180-200 g
- Housing: Mated females were housed singly in clear polycarbonate cages with stainless-steel wire lids and hardwood shavings as bedding. For exposures, the females were transferred to stainless steel wire mesh exposure cages, and the cages were moved into the chambers.
- Diet: Food pellets (UAR Alimentation Villemoisson, France), ad libitum except during exposures
- Water: Filtered tap water, ad libitum except during exposures
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 21 ± 2 °C
- Humidity: 50 ± 5 %
- Photoperiod: 12 h dark / 12 h light

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

Exposures were conducted in 200 L glass/stainless-steel inhalation chambers with dynamic and adjustable laminar air Now (6-20 m^3/h). In order to prevent any leakage of the test atmospheres, the chambers were maintained at a negative pressure of no more than 3-mm water. The chamber temperature was set at 23 ± 2 °C and the relative humidity at 50 ± 5 %. Vapor generation systems consisted in delivering a constant rate of liquid chemical with an infusion pump at the top of a heated glass column filled with glass beads. Compressed air heated by a glass heater was introduced at the bottom of the glass column in a countercurrent fashion to the liquid flow.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentrations were monitored continuously with a Gas Chromatography (GC), and were determined once during each 6 h exposure by collecting the material and analyzing against a standard using GC.

Details on mating procedure:

- Impregnation procedure: Cohoused
- M/F ratio per cage: 1:2-3
- Verification of same strain and source of both sexes: Yes
- Proof of pregnancy: Sperm in vaginal smear referred to as Day 0 of gestation
- After confirmation of mating, females were returned to an individual cage.

Duration of treatment / exposure:

Days 6-20 of gestation

Frequency of treatment:

6 h/day

Duration of test:

Mated females were exposed 6 h/day on Days 6 through 20 of gestation.

Remarks:

Doses / Concentrations:
0, 50, 100, 200 and 300 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

22 pregnant females per dose for 50, 100 and 200 ppm; 23 pregnant females per dose for control and high dose (300 ppm)

Control animals:

other: exposed concurrently to filtered room air

Details on study design:

- Rationale for animal assignment: Mated females were randomly assigned to treatment groups using a randomization system stratified by body weight on GD 0.

Maternal examinations:

BODY WEIGHT: Yes
- Time schedule for examinations: GDs 0, 6, 13 and 21

FOOD CONSUMPTION
- Food consumption was measured for the intervals GDs 6-13 and 13-21.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation Day 21; the females were killed with an intrapulmonary injection of T61 (Hoechst, Frankfurt, Germany)

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes

Fetal examinations:

- Live fetuses were weighed and sexed.
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]; 50 % of the live fetuses were preserved in Bouin's solution and examined for internal soft-tissue changes.
- Skeletal examinations: Yes: [half per litter]; remaining fetuses were fixed in ethanol (70 %), eviscerated and then processed for skeletal staining with alizarin red S.

Statistics:

The number of CL, implantation sites, and live fetuses, maternal food consumption and various body weights were analyzed by one way ANOVA, followed by Dunnett's-test. The percentage of non-live implant, resorptions, and males and the proportion of fetuses with alterations in each litter were evaluated by Kruskal-Wallis test followed by Dixon-Massey test. Rates of pregnancy and percentage of litters with any malformations or external, visceral, or skeletal variations were analyzed using Fisher's test. Where appropriate, least squares analysis was performed. The level of significance was p < 0.05.

Indices:

None

Historical control data:

Not applicable

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
All animals survived the exposure. Exposure to 300 ppm led to significant decreases in maternal weight gain and food consumption throughout exposure. Absolute weight gain was significantly reduced at 300 ppm.

Dose descriptor:

NOAEL

Effect level:

200 ppm

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

>= 300 ppm

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- There were no significant changes in number of implantations and live fetuses, in the incidence of non-live implants and resorptions, or in fetal weights across groups. One fetus of 200 ppm and two of the 300 ppm group showed different types of malformations. There was no consistent pattern of changes to suggest any treatment-related effects. The incidences of fetuses with external, visceral, and skeletal variations did not differ between the control and the treated groups.
- No significant increase in embryo/fetal lethality or fetal malformations were observed after exposure to methacrylic acid. While maternal toxicity was observed, methacrylic acid caused no evidence of developmental toxicity up to 300 ppm.

Abnormalities:

not specified

Developmental effects observed:

not specified

See the attached document for information on tables of results

Conclusions:

Under the test conditions, the No Observed Adverse Effect Level (NOAEL) of Methacrylic acid was considered to be 200 ppm for maternal toxicity and ≥ 300 ppm for developmental toxicity in Sprague-Dawley rats.

Executive summary:

In a prenatal developmental toxicity study performed similarly to OECD Guideline 414, Methacrylic acid was administered via whole body inhalation to groups of mated female Sprague-Dawley rats (22-23/dose) at the dose levels of 0, 50, 100, 200 and 300 ppm from Days 6 to 20 of gestation. Maternal body weight and food consumption were recorded approximately once a week. On Day 21 of gestation, the dams were sacrificed and the gravid uterine weight, no. of corpora lutea, implantations, resorptions and dead and live fetus were recorded. Fetuses were sexed, weighed and examined for external, soft tissue and skeletal malformations.

All animals survived the exposure. Exposure to 300 ppm led to significant decreases in maternal weight gain and food consumption throughout exposure. Absolute weight gain was significantly reduced at 300 ppm. There were no significant changes in the number of implantations and live fetuses, in the incidence of non-live implants and resorptions, or in fetal body weights across groups. One fetus of the 200 ppm and two of the 300 ppm treated groups showed different types of malformations. There was no consistent pattern of change to suggest any treatment-related effects. The incidences of fetuses with external, visceral, and skeletal variations did not differ between the control and the treated groups.

 

Under the test conditions, the No Observed Adverse Effect Level (NOAEL) of Methacrylic acid was considered to be 200 ppm for maternal toxicity and ≥ 300 ppm for developmental toxicity in Sprague-Dawley rats.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

chronic

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

1 056 mg/m³

Study duration:

subchronic

Species:

rat

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Registered substance:

In a GLP-compliant Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted according to OECD Guideline 422, treatment with Hydroxy(2-methylprop-2-enoato-O)zinc at 1000 mg/kg bw/day was not tolerated by pregnant/lactating females, with 7/10 females prematurely killed between mid-gestation and Day 1 of lactation; in this 6/7 females showed evidence of abnormal parturition. All of the females were found to have several pups retained in utero, the majority of which were dead, and therefore the aetiology of the poor clinical condition of the six females was considered to be attributable to intrauterine fetal deaths.

At 1000 mg/kg bw/day, overall mean bodyweight gain of males during the course of the study was 0.80X Control, attributable to reduced weight gain during the first two weeks of treatment. In females at this dose level, mean weight gain was unaffected in Week 1, but lower than Control during Week 2 (0.40X Control) due to two females which recorded weight loss during this period. Thereafter, mean weight gain of these females was similar to Control until the final week of gestation, when the marked decline in clinical condition became apparent. Bodyweight performance of animals receiving 100 or 300 mg/kg bw/day was unaffected by treatment. Food consumption of males and females receiving 1000 mg/kg bw/day was slightly lower than Control during Week 1 of treatment. Thereafter, mean food intake of all groups of treated animals was similar to Control. Sensory reactivity, grip strength and motor activity were unaffected by treatment with test item.

A dose-dependent decrease in haematocrit and haemoglobin concentration was evident in all groups of treated males after 2 weeks of treatment. At 1000 mg/kg bw/day, decreases in erythrocytes, mean cell haemoglobin and mean cell volume and an increase in red cell distribution width were apparent in males and females, with females also showing a decrease in haematocrit, haemoglobin concentration and mean cell haemoglobin concentration. At 1000 mg/kg bw/day, an increase in all leucocyte parameters, particularly neutrophil concentrations in males and females and eosinophil concentrations in males, with an increase in total white blood cell counts; females also showed an increase in platelet counts.

At 1000 mg/kg bw/day, an increase in alkaline phosphatase and alanine amino-transferase activities and bilirubin concentrations and a reduction in total protein and albumin concentrations in males and females were observed after 2 weeks of treatment. Males also showed a decrease in bile acids and increased triglyceride concentrations, and females a decrease in aspartate amino-transferase activity and cholesterol concentrations. Chloride concentrations were high for males receiving 300 or 1000 mg/kg bw/day and for females receiving 1000 mg/kg bw/day.

Mating performance and fertility of the F0 generation animals were unaffected by treatment. Gestation length, parturition and gestation index of females receiving 1000 mg/kg bw/day was adversely affected by treatment with test item. Of the eight pregnant females in the dose group which survived to the end of gestation, only two dams completed parturition and one of these two females had a gestation length of 23.5 days, slightly longer than the expected range of 22-23 days. Abnormal parturition was apparent in the remaining six pregnant females requiring premature termination of these animals; either the onset of parturition did not occur, or a small number of pups were born with the remainder retained in utero. At 300 mg/kg bw/day, there was a suggestion of a slight shift towards a longer gestation length with 5/10 females showing a gestation length of 23 days compared to 2/10 Controls.

Among females receiving 1000 mg/kg bw/day that survived to scheduled termination on Day 7 of lactation, there was a suggestion of a slight reduction in implantation counts, with a concomitant slight reduction total litter size on Day 1 of lactation.

At scheduled termination, there were increased spleen weights in males and increased kidney weights in females at 1000 mg/kg bw/day without any association of macroscopic/microscopic abnormalities. Macroscopic examination revealed pale areas in the prostate of 2/10 males receiving 300 mg/kg bw/day and 4/10 males receiving 1000 mg/kg bw/day.

Treatment-related histopathological changes occurred in the stomach, duodenum, pancreas, eyes, and prostate. In the stomach, a dose dependent incidence/severity of inflammatory cell infiltrate composed of a variable number of eosinophils and neutrophils and globule leukocytes infiltration in the glandular stomach in males and females at 300 and 1000 mg/kg bw/day; minor inflammatory changes at 100 mg/kg bw/day; mucosal erosion/ulceration in females at 1000 mg/kg bw/day; focal intestinal metaplasia in the glandular stomach in a single male at 1000 mg/kg bw/day. At 1000 mg/kg bw/day, slight villous hypertrophy, characterised by a diffuse increase in villous height was seen in in the duodenum, moderate acinar degeneration/atrophy was observed in the pancreas and slight to moderate retinal atrophy in the eyes. In the prostate, suppurative inflammation/abscess(es) was seen with increased degree/severity at 300 and 1000 mg/kg bw/day. Minor inflammatory changes in the prostate were also seen in a single male at 100 mg/kg bw/day.

Histopathological changes detected among the females killed prematurely at 1000 mg/kg bw/day which were considered secondary effects of treatment comprised: minimal to slight leukocytic infiltration of the endometrium of the uterus (in the presence of dead fetuses); cortical hypertrophy of the adrenal glands; involution/atrophy of the thymus.

Zinc compounds:

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.

Methacrylic acid:

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:
Only one study available by this route of exposure

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 available 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, Hydroxy(2-Methylprop-2-enoato-O)Zinc for hazardous effects for reproductive or developmental toxicity under the Dangerous Substance Directive 67/548/EEC or Regulation (EC) No 1272-2008.

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