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

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Study period:

1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.

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 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

ophthalmological and neurobehavioral examination not performed

Principles of method if other than guideline:

Not applicable

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Shizuoka Agriculture Cooperative Association for Laboratory Animals
- Age at arrival: 4 weeks
- Weight at study initiation: 120-150 g (male); 90-110 g (female)
- Fasting period before study: No data
- Housing: Animals were housed at 4/sex/cage in stainless cages with a wire-meshed bottom
- Diet: Pulverized chows M (Oriental Yeast Co.), ad libitum, mixed with test material
- Water: Ad libitum
- Acclimation period: One week

ENVIRONMENTAL CONDITIONS
- Temperature: 24±1 °C
- Humidity: 55 ± 5 %
- Air changes (per hr): No data
- Photoperiod: 10 h dark/14 h light cycle

Route of administration:

oral: feed

Vehicle:

other: Mixed with basic feed

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): Pulverized chows M
- Storage temperature of food: No data

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

Not applicable

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
0, 300, 3000, 30000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

12

Control animals:

yes, plain diet

Details on study design:

The animals were divided into four groups, each of which included 12 animals of each sex and fed on diet containing Zinc sulfate heptahydrate at four different concentration levels 0, 300, 3000 and 30000 ppm, for 13 weeks.

Positive control:

None

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily


BODY WEIGHT: Yes
- Time schedule for examinations: Weekly


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Time schedule for examinations: Twice weekly
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes


WATER CONSUMPTION: Yes
- Time schedule for examinations: Twice weekly

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY AND CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: Yes (under light ether anaesthesia)
- Animals fasted: No data
- How many animals: Male: 12, 12, 12 and 12 animals in control, low, mid and high dose groups, respectively; Female: 11, 12, 11 and 12 animals in control, low, mid and high dose groups, respectively
- Parameters checked:
Haematology: Erythrocyte count, hemoglobin, leukocyte count and differential count of leukocyte (%)
Clinical chemistry: Total plasma protein, alkaline phosphatase, glucose, urea nitrogen, SGOT, SGPT, cholesterol and calcium.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
After necropsy at the termination of the study the following organs were weighed: Brain, pituitary, thyroid, heart, thymus, liver, kidney, spleen, adrenals, gonads (testes or ovaries), and muscles (triceps surae).

HISTOPATHOLOGY: Yes
- For histopathology following organs and tissues were collected: Brain, pituitary, thyroid, heart, thymus, liver, kidney, spleen, adrenals, gonads (testes or ovaries), and muscles (triceps surae), submaxillary glands, lungs, mesenteric lymph nodes, pancreas, stomach, small and large intestine, accessory genital organs, bone and bone marrow (sternum and femur), and lesions of gross abnormalities
- 3 or 4 µm paraffin sections from the specimens were stained with hematoxylin-eosin, periodic acid Schiff's reaction and azan for microscopic observations.

Other examinations:

None

Statistics:

Student's t-test was used to estimate the statistical differences between controls and treated groups.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

effects observed, treatment-related

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY:
- At 30000 ppm: Animals 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.
- At ≤ 3000 ppm: No remarkable signs in either sex. Two females, one of the control and one of the 3000 ppm group, were killed in extremis due to suppurative pyelitis during the study.

BODY WEIGHT AND WEIGHT GAIN:
- At 30000 ppm: Depressed weight gain and dwarfism was observed 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 ≤ 3000 ppm: No statistically significant differences were observed when compared to control.

FOOD & WATER CONSUMPTION AND COMPOUND INTAKE (if feeding 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 ≤ 3000 ppm: No statistically significant differences were observed when compared to control.

FOOD EFFICIENCY:
There were some fluctuations in food efficiency in each group.
- At 30000 ppm: Slight reduction in overall average value was shown only in males.
- At ≤ 3000 ppm: No statistically significant differences were observed when compared to control.


HAEMATOLOGY:
-At 30000 ppm: A moderate reduction in leukocyte count was shown in both sexes. Males showed a slight decrease in hematocrit and hemoglobin concentration.
- At 3000 ppm: No remarkable changes in animals but there was a slight increment of hemoglobin concentration in females.

CLINICAL CHEMISTRY:
- 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.


ORGAN WEIGHTS:
-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 chemically treated groups of both species, no clear relationship with the treatment could be shown.
- At ≤ 3000 ppm: Statistically significant changes were not observed when compared to control.

GROSS PATHOLOGY
No remarkable gross lesions were attributable to the treatment.

HISTOPATHOLOGY: NON-NEOPLASTIC
- At 30000 ppm: Pancreatic lesions as well as degeneration and necrosis of the acinar cells, clarification of centroacinar cells and interstitial fibrosis. 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.

Dose descriptor:

NOEL

Effect level:

3 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: - No remarkable clinical signs in either sex at ≤ 3000 ppm diet admix, approximately equivalent to 234 zinc sulphate mg/kg bw/day (male) and 243 zinc sulphate mg/kg bw/day (female) (equivalent to approximately 53.5 mg Zn/kg bw/day)

Critical effects observed:

not specified

None

Conclusions:

Under the test conditions, the NOEL of 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.

Executive summary:

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 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.

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

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

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

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: The study was performed according to the Annex VB.29, 67/548/EEC with some minor restrictions (the list of serum chemistry parameters was limited, i.e. there were no parameters of protein metabolism. Adrenals were not weighed)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Sprague-Dawley rats, Fischer-344 rats and B6C3F1-mice

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

6 hours/day and 5 days/week

Remarks:

Doses / Concentrations:
20, 100, and 300 ppm (equivalent to 0.0714, 0.357, and 1.071 mg/L)
Basis:
nominal conc.

No. of animals per sex per dose:

10

Control animals:

yes, sham-exposed

Details on study design:

Each dose and control group consisted of 10 males and 10 females. Additionally, 10 animals per sex/group were exposed for 4 days and killed on day 5

Positive control:

None

Details on results:

No exposure-related death was recorded. After 90 days of exposure high-dose animals had reduced body weight gains (-10%) and food consumption (-9%) (male F-344 rats) or reduced body weight gains (both sexes of B6C3F1-mice -11% in males, (-12% in females). Reduced leukocyte counts and an increased activity of alkaline phosphatase were observed in female high-dose mice. An increased level of BUN was seen in high-dose males of F-344 rats. In both rat strains reduced absolute liver weights were found in high-dose males, as well as in both sexes of high-dose B6C3F1-mice. The liver/body weight ratio was comparable to that of the controls, only after adjustment to the brain weight a significant decrease of relative liver weight
was obvious. In mice, the liver/body weight ratio was lower in high-dose mice of both sexes (significant only in males), the liver/brain weight ratio was significantly higher in high-dose males and significantly lower in high-dose female mice.
Microscopically, all treatment groups of both rat strains and mice of the high-dose group showed a rhinitis of the anterior regions of the turbinates. The incidences in rats showed no clear dose relationship. The high-dose rats had a more severe inflammation than the other groups. A low-grade rhinitis almost without additional lesions was also evident in some of the control rats (not seen in mice). At high-dose level the incidence of rhinitis was increased compared to control rats; in some of the treated rats rhinitis was accompanied by ulceration, epithelial hyperplasia and vesiculation, goblet cell hyperplasia, and exudation of the respiratory epithelium. Ulceration of the anterior part of the nose was also observed in some high-dose male and female mice. A degeneration of olfactory epithelium of the mid part of the nasal cavity was observed in mice at mid- and high-dose level, but not in the rat nose. The lesion consisted of intracellular accumulation of an orange-pink material in the cytoplasm of ciliated cells (eosinophilic globules) which appeared to be the sustencular cells lining the middle portions of the septum and dorso-medioal aspects of the dorsal scroll of the nasal turbinates in histological sections at level B and C. In severe cases this material filled the cell, displaced the nucleus or in most severely affected areas epithelial cells dropped out. In all treated Sprague-Dawley groups increased lymphocytic infiltrations in the larynx were found in both sexes, in males a higher incidence of focal aggregates of lymphocytes in the lung periphery was seen (both findings showed no clear dose relation). Outside the upper respiratory tract, lymphocytic hyperplasia of mandibular lymph nodes were more frequent in high-dose animals of both rat strains compared to controls. The kidneys of male high-dose mice showed cytomegaly of tubular epithelium. Other findings showed no relationship
to treatment. After interim sacrifice on day 5 satellite animals of each strain showed acute inflammation and, in mice, necrosis of the anterior respiratory epithelium of the turbinates similar to the findings reported after 90 days. Food consumption (-16% in males, - 14% in females), body weight gain (-30% in males, -38% in females) and lower final mean body weights (-5% in males and -6% in females, non significant) were reduced in high-dose F344 rats. At this time, high-dose mice also presented lower final mean body weights (-8% in males, -7% in females) and high-dose males of
the SD strain showed a reduction of food consumption of 13%.

Dose descriptor:

NOAEC

Remarks:

for rats

Effect level:

300 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Dose descriptor:

NOAEC

Remarks:

for mice

Effect level:

100 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: lower body weight gains at the high dose (300 ppm) were not associated to a reduction of food consumption

Critical effects observed:

not specified

Conclusions:

Conclusively, the high dose of 300 ppm (1.071 mg/l) represented the NOAEC for systemic effects in rats. In mice, lower body weight gains at the high dose (300 ppm) were not associated to a reduction of food consumption, so that 100 ppm (0.357 mg/l) was the NOAEC for systemic effects. The decrease of absolute liver weights was not considered to represent a clear adverse effect because of the lack of corresponding findings (clinical pathology and histopathology). For explanation, reduction of the absolute weights may be related to lower final body weight as liver/body weight ratio was normal in rats and not conclusive in mice. Similarly, the higher incidence of lymphocytic hyperplasia in the mandibular lymph nodes of male rats was not considered to be a clear adverse effect. More likely this effect can be interpreted to be related to the inflammatory changes of the upper and lower respiratory tract and to the assumption that minimum traces of methacrylic acid were swallowed.

Executive summary:

In a valid 90-day inhalation study, Sprague-Dawley rats, Fischer-344 rats and B6C3F1-mice were exposed (whole body exposure) to 20, 100, and 300 ppm (equivalent to 0.0714, 0.357, and 1.071 mg/l) of methacrylic acid (purity > 99%) on 6 hours/day and 5 days/week. Each dose and control group consisted of 10 males and 10 females. Additionally, 10 animals per sex/group were exposed for 4 days and killed on day 5.

Conclusively, the high dose of 300 ppm (1.071 mg/l) represented the NOAEC for systemic effects in rats. In mice, lower body weight gains at the high dose (300 ppm) were not associated to a reduction of food consumption, so that 100 ppm (0.357 mg/l) was the NOAEC for systemic effects. The decrease of absolute liver weights was not considered to represent a clear adverse effect because of the lack of corresponding findings (clinical pathology and histopathology). For explanation, reduction of the absolute weights may be related to lower final body weight as liver/body weight ratio was normal in rats and not conclusive in mice. Similarly, the higher incidence of lymphocytic hyperplasia in the mandibular lymph nodes of male rats was not considered to be a clear adverse effect. More likely this effect can be interpreted to be related to the inflammatory changes of the upper and lower respiratory tract and to the assumption that minimum traces of methacrylic acid were swallowed.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

357 mg/m³

Study duration:

subchronic

Species:

rat

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

Registered substance:

In a study performed according to OECD guideline 422, 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. 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. 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. 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:

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.

Methacrylic acid/methyl methacrylate:

In subacute, subchronic and chronic inhalation studies on rats and mice, the predominant target organ was the respiratory tract. In rats, the primary target tissue was the olfactory epithelium of the nasal passages showing degeneration/necrosis. These local effects are considered as not relevant for the registered substance because it is not a skin irritant and it has no such strong corrosive properties as methacrylic acid and methyl methacrylate. No convincing evidence for any systemic toxicity arising from repeated inhalation and oral exposures has arisen in these studies except a general reduction in bodyweight gain and food consumption. Also, it may be assumed that lower bodyweight gains may be related to the nasal irritation via lower consumption of food. In carcinogenicity studies on methyl methacrylate, the lowest NOAEC identified was 400 ppm which is equivalent to 1640 mg/m3.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Well conducted and well described study in accordance with GLP and OECD Guideline 422 without any deviation

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
One study recorded for this endpoint

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 and zinc cation and the methacrylic part of the substance are the determining factors of the biological activities of the registered substance. This assumption is confirmed by the similarity of toxicological effects observed between the OECD guideline 422 study performed on the registered substance and effects found in repeated toxicity studies on zinc compounds (mainly the decrease in several haematological parameters and the dead pups found in gestating females at high dose).

As neither zinc compounds (such as zinc chloride or zinc sulphate) nor methacrylic acid/methyl methacrylate are classified for repeated dose toxicity, there is no reason to classify the registered substance under the Directive 67/548/EEC and the CLP Regulation (EC) No 1272/2008.