Zinc methacrylate

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

53.5 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral (subacute)

 In a GLP-compliant Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted according to OECD Guideline 422, the read across substance zinc monomethacrylate was administered to three groups of Crl:CD(SD) rats at 0, 100, 300 and 1000 mg/kg bw/day by oral (gavage). The F0 males were treated for two weeks before pairing up to necropsy after a minimum of five weeks. The F0 females were treated daily for two weeks before pairing, throughout pairing, during gestation and lactation until the day prior to termination on Day 7 of lactation. During the study, data was recorded on mortality, clinical signs, behavioural assessments, body weight change, food and water consumption, haematology, blood chemistry, mating performance, fertility and gestation length. All animals were subjected to a gross necropsy examination, selected organs were weighed and histopathological evaluation of selected tissues was performed. 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. Under the test condition, the read across substance zinc monomethacrylate NOAEL for systemic toxicity was considered to be 100 mg/kg bw/day in male and female rats (Stanndard, 2013). Similar results can be expected for zinc dimethacrylate.  

In a non-GLP repeated dose oral toxicity study, the read across substance zinc monomethacrylate was administered by oral gavage to groups of Crl:CD(SD) rats (3/sex/dose) at the dose-levels of 100, 300, 600 and 1000 mg/kg bw/day for 14 consecutive days. Examinations during the study included: mortality, clinical signs, body weight, food and water consumption, blood chemistry, organ weights and macroscopic examination. No mortality and no treatment-related clinical signs were observed. Reduced weight gain was apparent in groups receiving 300 mg/kg bw/day and higher doses during the first 3 days of treatment, with a concomitant reduction in food consumption at 600 and 1000 mg/kg bw/day over the same period; thereafter mean weight gain and food intake were unaffected in all dose groups. Following 2 weeks of treatment, some minor biochemical changes in the plasma were evident at 1000 mg/kg bw/day, manifest as slight increases in alkaline phosphatase and alanine amino transferase activity in males and females, and a suggestion of a slight increase in urea concentrations in males only. Terminal necropsy revealed slightly low absolute and bodyweight-relative liver weights and slightly high spleen and testes weights in males receiving 1000 mg/kg bw/day. There were no macroscopic abnormalities detected that were clearly related to treatment. One male and one female receiving 1000 mg/kg bw/day and one female receiving 600 mg/kg bw/day showed macroscopic abnormalities in the glandular stomach (dark areas and/or multiple punctate foci); the toxicological significance of these macroscopic abnormalities is uncertain. Under these test conditions, the read across substance zinc monomethacrylate NOAEL was considered to be 100 mg/kg bw/day in Sprague-Dawley rats (Stanndard, 2013).Similar results can be expected for zinc dimethacrylate.  

Oral (subchronic)

In a repeated dose toxicity study conducted similarly to the OECD Guideline 408, Zinc sulphate heptahydrate was administered by oral (feed) to groups of ICR mice (12/sex/dose) at the dose-levels of 0, 300, 3000 and 30000 ppm for 13 weeks. Examinations during the study included: mortality, clinical signs, body weight, food and water consumption, haematology, blood chemistry, gross pathology, organ weights and macroscopic examination. At 30000 ppm, depressed spontaneous motility before death or sacrifice. Four males and one female in this group were found dead or killed in extremis during the study. Histological findings of these animals revealed impairment of the urinary tract and regressive changes in the exocrine gland of the pancreas. Mortality was 33.3 % in males and 8.3 % in females. At ≤ 3,000 ppm, no treatment related toxic signs were noticed. At 30000 ppm, a more prominently retarded growth resulting in smaller body size than those of other groups. At 300 ppm, a significant but very slight depression of weight gain was seen in females for a week after commencement, followed by a rapid recovery to the control level. The food intake of male and female mice was depressed during the first week of the study in comparison to that of the controls but showed a tendency to recover afterwards at 30000 ppm. Average food intake of these animals then remained at only a slightly lower level than that of the control group. The overall average food efficiency was much lower than the control group at 30000 ppm. Water consumption was decreased in both sexes during the first week at 30000 ppm; though males soon recovered, females showed persistent lower intake during the study. Male and female mice in the 30000 ppm group showed moderately lower values in hematocrit and hemoglobin concentration than control group; the leukocyte count in males also decreased moderately. Morphological changes of erythrocyte anisocytosis, polychromatophilia and poikilocytosis, were seen in six males and four females which were reported by necropsy or microscopic observation to have fore-stomach ulcers. Though some significant fluctuations were seen in hematocrit, no dose dependent abnormalities were found in hemoglobin concentration and erythrocyte count in males or females at less than 3000 ppm group. A slight to moderate decrease in total protein, glucose and cholesterol and a moderate to marked increase in alkaline phosphatase and urea nitrogen were observed at 30000 ppm. Additional significant changes occurring in these animals were depression of SGPT level and increase in calcium level in females, and an increase of SGOT level in males. At 3000 ppm, some fluctuations with significant differences from controls were seen in several parameters but these were all within the acceptable historical limits of mice of this strain and age. Coincidental increase in absolute and relative weight was found in the thyroids of males and the kidneys of females at 30000 ppm. At 30000 ppm, marked emaciation, ischemic discoloration of the kidney and thyroid, atrophy of the pancreas, edematous thickening of the upper small intestine and slight splenomegaly were recorded in addition to several cases of fore stomach ulcer. Histopathological lesions included catarrh at the upper intestine, ulcers at the boundary of fore- and glandular stomach, proliferation of erythropoietic immature cells in the splenic red pulp as well as pancreatic lesions were observed at 30000 ppm. Under the test conditions, the NOEL of read across substance Zinc sulfate heptahydrate was determined to be 3000 ppm (approximately equivalent to 458 mg/kg bw/day in males or 479 mg/kg bw/day in females) in mice (Maita, 1981). Similar result can be expected for the test substance.  

In a repeated dose toxicity study conducted similarly to the OECD Guideline 408, Zinc sulphate heptahydrate was administered by oral (feed) to groups of Wistar rats (12/sex/dose) at the dose-levels of 0, 300, 3000 and 30000 ppm for 13 weeks. Examinations during the study included: mortality, clinical signs, body weight, food and water consumption, haematology, blood chemistry, gross pathology, organ weights and macroscopic examination. At 30000 ppm, rats showed symptom of discarding the diet from the food jar by picking it out with their fore-limbs. This symptom began a week after commencement of the experiment and persisted throughout the study. No moribund animals of either sex were found. Depressed weight gain and dwarfism was observed at 30000 ppm in males; weight gain of females in this group was slightly depressed during the study with significant differences to control animals in the 1st to 5th week of the study. At 30000 ppm, food intake of males decreased after the third week of the study. A similar reduction was seen in females of this group during the 1st to 6th week but then disappeared. A slightly lower value of average food and water intake was reported only in males. At 30000 ppm, a moderate reduction in leukocyte count was shown in both sexes and males showed a slight decrease in hematocrit and hemoglobin concentration. Significant reductions or reductive tendencies were seen in rats in the following parameters: SGOT and SGPT in all male groups, total protein, cholesterol and calcium levels in males in the 30000 ppm group and calcium level in females in both the 3000 and 30000 ppm groups. At 30000 ppm, a slight or moderate decrease in absolute and relative weights was seen in the liver and kidney among males. Significant fluctuations of absolute or relative organ weights were seen in various organs from treated groups of both species, no clear relationship with the treatment could be shown. No remarkable gross lesions were attributable to the treatment. At 30000 ppm, pancreatic lesions as well as degeneration and necrosis of the acinar cells, clarification of centroacinar cells and interstitial fibrosis were observed. No other lesions attributable to the treatment. No histopathological abnormalities were observed in the bone or male genital organs which had elsewhere been reported to have sustained toxic changes due to an overdose of Zinc. There were no significant differences of any effects were observed at ≤ 3000 ppm when compared to control. Under the test conditions, the NOEL of read across substance Zinc sulphate heptahydrate was determined to be 3000 ppm (approximately equivalent to 234 mg/kg bw/day in males or 243 mg/kg bw/day in females) in rats (Maita, 1981). Similar result can be expected for the test substance. 

Oral (chronic)

A two years toxicity study was performend in 1964 to study the tolerance of animals to chronic ingestion of the methyl methacrylate. Twenty-five male and female Wistar rats were administered three doses of methyl methacrylate in the drinking water for two years. Initial doses of 6, 60 or 2000 ppm were partially raised to 7, 70 and 2000 ppm after 5 months. A special design was employed to reduce the volatilization and measurements which showed that the methyl methacrylate concentrations remained within 15% of the nominal concentration for 72 hours. Body weight depression was also observed at 2000 ppm but it did not persist beyond the first few weeks of the study. Significant depression of fluid consumption was observed at 2000 ppm, although this tended to regress at the end of the study. Individual observations of depressed food consumption tended to parallel periods of depressed growth. There were significantly increased kidney ratios for female rats at 2000 ppm. These effects were believed to be a consequence of reduced food intake and reduced body weights, and in the absence of any histopathology, were considered as not biologically relevant. Therefore the NOAEL is considered to be >= 2000 ppm, corresponding to 90.3 mg/kg bw/day and 193.8 mg/kg bw/day, for males and females, respectively, on the basis of treatment specific fluid consumption rates and body weights. No relevant effects were observed after exposure of rats in drinking water up to the highest dose tested (2000 ppm, limited by palatability). Under the study conditions, the NOAEL was determined to be 124.1 mg/kg bw/day (Borzelleca, 1964).

Conclusion

The zinc NOAEL derived from the feeding studies with zinc sulphate was determined to be approximately 104 mg Zn/kg bw/day in mice and approximately 53.5 mg/kg bw/day in rats. At higher doses absolute kidney weights were decreased in high dose males and histopathology showed pancreatic damage (degeneration, necrosis of acinar cells, clarification of centroacinar cells and interstitial fibrosis) in rats. In mice, at the highest dose level 4 males and 1 female were found dead or killed in extremis. Histological findings of these animals revealed impairment of the urinary tract and regressive changes in the exocrine gland of the pancreas. Only the high dose animals showed moderately lower haematocrit and haemoglobin concentrations. The leucocyte counts of high dose males were moderately decreased. Total protein, glucose and cholesterol were reduced and alkaline phosphatase and urea nitrogen were increased in high dose animals. High dose females showed reduced ALAT and increased calcium levels, ASAT was increased in high dose males. Absolute and relative thyroid weights of males were increased in the highest dose group. Kidney weights of females were also increased at the highest dose. Gross pathology and histopathology showed changes in kidneys, thyroids, pancreas (degeneration/necrosis of acinar cells, clarification of nucleoli), gastrointestinal tract, and spleen.

Justification for classification or non-classification

The basic assumption to deduce the toxicological properties of the registered substance (based on its behaviour in water) is that after intake of the substance, it is mainly transformed into the ionic species, zinc cation and the methacrylate. These ionic species are the determining factors of the biological activities of the registered substance.  

Based on the results of the sub-acute, sub-chronic and chronic repeated dose toxicity studies with zinc monomethacrylate, zinc sulphate and methyl methacrylate, the registered substance does not warrant any classification under the EU CLP Regulation (EC) 1272/2008.