Registration Dossier

Administrative data

Description of key information

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:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity 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:
mouse
Strain:
ICR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Shizuoka Agriculture Cooperative Association for Laboratory Animals
- Age at arrival: 4 weeks
- 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 MF (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 MF
- 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: 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, 10, 11 and 8 animals in control, low, mid and high dose groups, respectively; Female: 12, 12, 12 and 11 animals in control, low, mid and high dose groups, respectively
- Parameters checked: Erythrocyte count, hemoglobin, leukocyte count and differential count of leukocyte (%)


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: Male: 12, 10, 10 and 8 animals in control, low, mid and high dose groups, respectively; Female: 11, 12, 12 and 10 animals in control, low, mid and high dose groups, respectively
- Parameters checked: 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, mesentery 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: 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 ≤ 3000 ppm: No treatment related toxic signs

BODY WEIGHT AND WEIGHT GAIN:
- 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.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- At 30000 ppm: 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. Average food intake of these animals then remained at only a slightly lower level than that of the control group.

FOOD EFFICIENCY:
- Food efficiencies were markedly lower than those of the control group during the first week of the study, corresponding to the decrease in food intake.
- At 30000 ppm: The overall average food efficiency was much lower than the control group.

WATER CONSUMPTION:
-At 30000 ppm: Decreased in both sexes during the first week. Though males soon recovered, females showed persistent lower intake during the study.


HAEMATOLOGY:
- Male and female mice in the 30000 ppm group showed moderately lower values in hematocrit and hemoglobin concentration than those of the 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.

CLINICAL CHEMISTRY:
-At 30000 ppm: A slight to moderate decrease in total protein, glucose and cholesterol and a moderate to marked increase in alkaline phosphatase and urea nitrogen. 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.


ORGAN WEIGHTS:
-At 30000 ppm: Coincidental increase in absolute and relative weight was found in the thyroids of males and the kidneys of females
- At ≤ 3000 ppm: Statistically not significant values when compared to control.


GROSS PATHOLOGY
-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.


HISTOPATHOLOGY: NON-NEOPLASTIC
-At 30000 ppm: There were lesions attributable to the treatment in the pancreas, upper intestine, stomach, spleen and kidney. The pancreatic acinar cells had swollen nuclei with an increased number of clarified nucleoli and whirl-like profiles in their cytoplasm which were more basophilically stained than the controls. Single cell necrosis of the acinar cells was also a common feature in these animals. Moreover, a decrease in the number of acinus and ductule like metaplasia of acinar cells was demonstrated. There was mucosal catarrh in the upper intestine with proliferation of epithelial cells and edema at lamina propria, slight to moderate ulcerative lesions in the boundary of the fore-stomach and proliferation of erythropoietic immature cells in the splenic red pulp of these animals. Regressive changes of the renal cortex were observed in the females.
- At ≤ 3,000 ppm: Statistically not significant values when compared to control.
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 458 zinc sulphate mg/kg bw/day (male) and 479 zinc sulphate mg/kg bw/day (female) (equivalent to approximately 104 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 458 mg/kg bw/day in males or 479 mg/kg bw/day in females) in mice.
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 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 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.
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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP and guideline compliant study from a read accross substance
Qualifier:
according to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Age when supplied; sex: about 7 weeks, male and female
Supplier: Charles River Laboratories, Research Models and Services, Germany GmbH; Sandhofer Weg 7, 97633 Sulzfeld
During the period when the rats were not exposed they were housed singly in wire cages (type DK III, Becker & Co., Castrop-Rauxel, FRG (floor area about 800 cm²)). Underneath the cages, waste trays were fixed containing bedding material (Type Lignocel FS14 fibres,
dustfree bedding supplied by SSNIFF, Soest, Germany)
The motor activity measurements were conducted in Polycarbonate cages with wire covers from Ehret, Emmendingen, FRG (floor area about 800 cm²) and bedding.
The animals were kept in fully air-conditioned rooms in which a temperature in the range of 20 - 24°C and relative humidity in the range of 30 - 70% were ensured by means of a central air-conditioning system.
A light/dark rhythm of 12 hours was maintained.
The room was completely disinfected using a disinfector ("AUTEX", fully automatic, formalinammonia-based terminal disinfector) before the start of the study. Usually, each week the floor and the walls were cleaned with water containing about 1 % Mikroquat®.
The animals were maintained on milled mouse/rat laboratory diet “GLP”, (Provimi Kliba SA, Kaiseraugst, Basel Switzerland) and tap water ad libitum.
Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
For each concentration, the test substance was supplied to the two-component atomizer of a thermostated vaporizer at a constant rate by means of the piston metering pump. The vapor was generated by spraying the substance with compressed air into a counter current of conditioned supply air (about 50% ± 20% relative humidity, 22°C ± 2°C). Thereafter it was further mixed with conditioned supply air and passed into the inhalation system.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentrations of the inhalation atmospheres in test groups 1 - 4 were analyzed by HPLC.
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 hours/day, 5 days/week
Remarks:
Doses / Concentrations:
0, 70 mg/m³ (20 ppm), 141 mg/m³ (40 ppm), 352 mg/m³ (100 ppm ), 1232 mg/m³ (350 ppm )
Basis:

No. of animals per sex per dose:
10/sex/dose
Control animals:
yes, sham-exposed
Details on study design:
Ten male and ten female Sprague Dawley rats per test group were whole body exposed to a vapor of the test substance on 6 hours per working day for 90 days (65 exposures). The target concentrations were 20, 40, 100 and 350 ppm (corresponding to 70, 141, 352 and 1232 mg/m3). A concurrent control group was exposed to conditioned air.
Observations and examinations performed and frequency:
The animals were examined for evident signs of toxicity or mortality twice a day (in the morning and in the late afternoon) from Mondays to Fridays and once a day (in the morning) on Saturdays, Sundays and public holidays. The clinical condition of the test animals was recorded once during the preflow period and on post-exposure observation days and at least 3 times (before, during and after exposure) on exposure days.
During exposure only a group wise examination was possible.The body weight of the animals was determined at the start of the preflow, at the start of the exposure period and then, as a rule, once a week as well as one day prior to gross necropsy. As a rule, the animals were weighed at the same time of the day.
Body weight change was calculated as the difference between body weight on the respective exposure day and body weight on the day of the first exposure. Group means were derived from the individual differences.
Food consumption was determined weekly and calculated as mean food consumption in grams per animal and day.Food efficiency (group means) was calculated based upon individual values for body weight and food consumption.
Before the start of the exposure period (day -6) the eyes of all animals, and at the end of the study (day 82) the eyes of the animals of test group 0 (control group) and test group 4 (high concentration) were examined with an ophthalmoscope (HEINE Optotechnik, Herrsching, FRG)) for any changes in the refracting media.
Functional observation battery (FOB) was carried out on the assigned animals once before the exposure period and once against the end of the exposure period.Motor activity was measured on the same day and with the same animals as FOB was performed.
Sacrifice and pathology:
In the morning, blood was taken from the retro-orbital venous plexus from fasted animals. The animals were anaesthetized using isoflurane (Isoba®, Essex GmbH Munich, Germany). The blood sampling procedure and the subsequent analysis of the blood and serum samples were carried out in a randomized sequence. For urinalysis the individual animals were transferred to metabolism cages (withdrawal of food and water) and urine was collected overnight. The urine samples were evaluated in a randomized sequence. At necropsy specimen were sampled from fasted anesthetized male animals in a randomized sequence for sperm analyses.
Hematological parameters were determined in blood with EDTA-K3 as anticoagulant using a particle counter (Advia 120 model; Bayer, Fernwald, Germany): Furthermore differential blood smears were prepared and stained according to Wright without being evaluated.
An automatic analyzer (Hitachi 917; Roche, Mannheim, Germany) was used to examine the clinicochemical parameters.
With the exception of volume, color, turbidity, sediment examination and the specific gravity, all the urine constituents were determined semi-quantitatively using test strips (Combur-9-test M, Roche, Mannheim, Germany) and a reflection photometer (Miditron M; Roche, Mannheim, Germany).
Immediately after necropsy and organ weight determination the right testis and cauda epididymis were taken from all male animals.
Sperm motility examinations were carried out in a randomized sequence. Sperm morphology and sperm head count (cauda epididymis and testis) were evaluated for the control and highest dose group, only.
The animals were killed under Narcoren anesthesia by exsanguination from the abdominal aorta and vena cava. The animals were then be necropsied and subjected to a grosspathological assessment. Animals that died intercurrently or were killed in a moribund state were necropsied and assessed by gross-pathology as quickly as possible.
Statistics:
DUNNETT, C.W. (1955): A multiple comparison procedure for comparing several treatments with a control. JASA, Vol. 50, 1096– 1121
DUNNETT, C.W. (1964). New tables for multiple comparisons with a control. Biometrics, Vol. 20, 482 –491
SIEGEL, S. (1956): Non-parametric statistics for the behavioural sciences. McGraw-Hill New York
Nijenhuis, A.; Wilf, H.S.(1978): Combinatorial Algorithms. AcademicPress New York, 32-33
Hettmansperger, T.P. ( 1984); Statistical Inference based on Ranks. John Wiley & Sons New York, 132-142
International Mathematical and Statistical Libraries, Inc., 2500 Park West Tower One, Houston, Texas 77042-3020, USA, nakl-1 -nakl-3
MILLER, R.G. (1981): Simultaneous Statistical Inference Springer-Verlag New York Inc., 165-167
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
Subchronic vapor inhalation of the test substance led to the following treatment-related
adverse effects:
Test group 4 (350 ppm):
􀂾 Decreased body weight of the males (- 6.1% to - 12.8%) from study day 7 onward
􀂾 Decreased body weight change (gain) of the males (- 28.5% to - 64.8%) from study
day 7 onward
􀂾 Decreased food consumption in the male animals on study days 7 (- 13.5%),
14 (- 12.2%), and from study day 28 through to day 84 (from - 9.4% to - 13.7%)
􀂾 Decreased food efficiency in the male animals on study days 7, 28, 49 and 56
􀂾 Decrease of terminal body weights in both sexes
􀂾 Goblet cell hypertrophy/hyperplasia in the respiratory epithelium of the nasal cavity
(level I) of two females
Test group 1 (20 ppm), test group 2 (40 ppm) and test group 3 (100 ppm):
􀂾 No treatment-related findings
Dose descriptor:
NOAEC
Effect level:
100 ppm
Sex:
male/female
Basis for effect level:
other: = 352 mg/m³ for local effects and effects to body weight
Dose descriptor:
NOAEC
Effect level:
350 ppm
Sex:
male/female
Basis for effect level:
other: = 1232 mg/m³ for systemic effects in target organs other than body weight effects due to reduced food consumption
Dose descriptor:
LOAEC
Effect level:
350 ppm
Sex:
male/female
Basis for effect level:
other: = 1232 mg/m³ air; reduced food consumption and body weight gain
Dose descriptor:
LOAEC
Effect level:
350 ppm
Sex:
female
Basis for effect level:
other: = 1232 mg/m³ for local effects (goblet cell hypertrophy/hyperplasia) in the respiratory epithelium in 2/10 females
Critical effects observed:
not specified
Conclusions:
In a valid guideline study, the the no-observed adverse effect level (NOAEL) is 100 ppm for the male and female rats exposed by whole body inhalation for 90 days.
Executive summary:

In a valid guideline study acc OECD 413 ( Subchronic inhalation toxicity: 90 day exposure of rats) methacrylic acid induced signs of general toxicity as indicated by descreased body weight, body weight gain, food consumption and transiently food efficiency in the high concentration male animals. At a concentration as high as 350 ppm (1232 mg/m³), the local irritating effect was marginal, indicated by the hypertrophy/hyperplasia of the respiratory epithelium in the nasal cavity of two female animals. Substance-related changes of the sexual organs were not noted in any of the exposed animals, nor were there any changes of sperm mobility and sperm head counts. Under the current test conditions, the no-observed adverse effect level (NOAEL) in this study is 100 ppm (352 mg/m³) for the male and female rats.

NOTE: Any of data in this dataset are disseminated by the European Union on a right-to-know basis and this is not a publication in the same sense as a book or an article in a journal. The right of ownership in any part of this information is reserved by the data owner(s). The use of this information for any other, e.g. commercial purpose is strictly reserved to the data owners and those persons or legal entities having paid the respective access fee for the intended purpose.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
352 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

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 on respiratory tract, as shown in an acute inhalation study on the registered substance. 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. NOAEC in sub chronic and chronic studies on methaxcrylic acid and methyl methacrylate are comparable which shows that the no effect levels determined in subchronic studies can be used for long term risk assessment. For the methacrylate compounds, the lowest NOAEC found in sub chronic and chronic studies is 100 ppm for systemic effects, found in the 90-day study by inhalation on methacrylic acid, which is equivalent to 352 mg/m3.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Study well documented, meets generally accepted scientific principles, acceptable for assessment.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Recent GLP and OECD guideline-compliant study

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.

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.