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Effects on fertility

Link to relevant study records

Referenceopen allclose all

Endpoint:
two-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
2007
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Please refer to section 13 of the dataset for read across justification.
Reason / purpose for cross-reference:
read-across source
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
not applicable
Principles of method if other than guideline:
Not applicable
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Source: Harlan Sprague-Dawley Breeding Laboratories, Harlan Sprague-Dawley, Inc., Indianapolis, IN, USA
- Age at arrival to laboratory: 30-35 days
- Housing: Animals were group-housed (two animals of the same sex/cage) in polycarbonate cages with stainless-steel wire lids until cohabitation.
- Diet: Rodent chow(Lab Diet, Richmond Standard, PMI Feeds, Inc., St. Louis, MO), ad libitum
- Water: Deionized water, ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 70-78 °F
- Humidity: 50-55 %
- Air changes: 1/10 min
- Photoperiod : 12 h light/12 h dark cycle
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: 97 % Zinc chloride was dissolved in milli-Q water.
Details on mating procedure:
- Length of cohabitation: 21 days
- Proof of pregnancy: Conception (Day 0 of gestation) was checked daily in the mornings by looking for the presence or absence of copulatory plugs.
- After the cohabitation period, the mated females were separated from the males.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Not applicable
Duration of treatment / exposure:
2 generations: Dosing (7 days/week) started after two weeks of acclimation and was continued for males and females for 77 days prior to cohabitation. Dosing was continued throughout the periods of cohabitation (21 days) for both sexes. Dosing of female rats was continued throughout the gestation (21 days) and lactation (21 days) periods. The doses for both sexes were adjusted weekly according to changes in body weight.
Frequency of treatment:
Once daily, 7 days/week
Remarks:
Doses / Concentrations:
7.5, 15, 30 mg/kg bw/day
Basis:
nominal conc.
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dosage levels were derived from a 14-day dose range finding study. The maximum tolerated dose (MTD) of Zinc chloride was set at 60 mg/kg bw/day in rats. In order to prevent a large effect of zinc-induced toxicity on non-reproductive tissues interfering with the interpretation of pure reproductive toxicity, the high-dose group (group 4) was set at 1/2 (30 mg/kg bw/day) of the established MTD. Likewise, the mid-dose group (group 3) was at 1/4 (15 mg/kg bw/day) of the established MTD and the lowest dose group (group 2) was 1/8 (7.50 mg/kg bw/day) of the established MTD.
Positive control:
No data
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT AND FOOD CONSUMPTION: Yes
- Food efficiency = (body weight gain/amount of diet consumed) × 100

OTHER:
HAEMATOLOGY AND CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to necropsy, the F0 males and at Day 21 of lactation, all F0 females and one male and one female F1 offspring were anesthetized with a combination of intraperitoneal Pentothal and Isoflo via inhalation. Blood samples for hematology and clinical chemistries were collected in heparinised 3mL syringes via cardiac puncture.
- Blood Chemistry parameters: Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, amylase, blood urea nitrogen, creatinine, cholesterol, sodium, potassium, chloride, calcium, phosphorus, albumin, total protein, total bilirubin, and glucose using Roche Cobas Mira S Chemistry Analyser (Roche Diagnostic System, Inc., Somerville, NJ).
Oestrous cyclicity (parental animals):
No data
Sperm parameters (parental animals):
No data
Litter observations:
STANDARDISATION OF LITTERS
- Performed on Day 4 postpartum: yes
- Maximum of 8 pups/litter (4 sex/litter); excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring: Total litter size, number of stillborn pups per sex, sex distribution, pup body weight and the presence of any obvious external congenital anomalies.
- Body weights of pups were recorded on Days 0, 4, 7, 14 and 21.
- Sex ratio (%) = (the total number of males on the day of weaning)/ (the total number of females on the day of weaning) × 100
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals, as soon as possible after the last litters in each generation were produced.
- Maternal animals: All surviving animals, after the last litter of each generation were weaned.

HISTOPATHOLOGY / ORGAN WEIGHTS:
- Organ weights: During the necropsy, organ weights were recorded for the kidneys, liver, brain, pituitary, adrenals, pancreas, thymus, spleen, testes, epididymides, prostate, and seminal vesicles. Fo male organ weights were also adjusted to body weight for statistical analysis.

Histopathology:
- Tissue samples collected from organs listed above for histopathologic evaluation were fixed in either Bouins solution (all reproductive tissues) or 10% neutral buffered formalin (all other tissues). After fixation, the tissue samples were trimmed, processed, embedded in paraffin, cut at 6 μm and stained with hematoxylin and eosin.
Postmortem examinations (offspring):
At the end of cohabitation for the parental F1 males and lactation for the F1 females, the animals were anesthesized, sacrificed and their organ weights were recorded like their F0 parents.

GROSS EXAMINATION OF DEAD PUPS: No
Statistics:
- Kruskal-Wallis test followed by the Mann-Whitney U test for pair-wise comparisons to detect the difference between treatment group and control means.
- ANOVA for analysing body-weight change, fertility, litter size, pups’ viability, pups’ body weight, postpartum dam weight and organ weight data between different treatment groups.
- Dunnett’s and/or Duncan’s multiple comparison procedures.
- When the ANOVA revealed significant differences among the treatment groups, Dunnett's and/or Duncan's multiple comparison procedures were utilized to pinpoint the specific treatment differences. Differences were considered statistically significant if p≤ 0.05.
Reproductive indices:
- Fertility index (%) = (number of females delivering/number of females cohabited) × 100
Offspring viability indices:
- Live birth index (%) = (number of live pups at Day 0/number of pups born) × 100
- 4-day survival index (%) = (number of live pups on Day 4/number of pups alive on Day 0) × 100
- 21-day (weaning) survival index (%) = (number of pups alive on Day 21/number of pups alive on Day 4) × 100
- Litter Size = Number of pups/number of pregnant females
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS):
- Aggression/hyperactivity throughout the study in both F0 males and females, hair loss behind the ears in males, vaginal discharges in low and high dose females; 0, 8, 20 and 12 % mortality in males were observed in control, low, mid and high dose groups, respectively and 12, 24, 28 and 24 % mortality in females were observed in control, low, mid and high dose groups, respectively.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS):
- All treated F0 males experienced significant reduction in body weight after the 1st week of dosing and this trend continued up to the end of the experiment. The total weight gain of males was significantly reduced (dose dependent) in the low-, mid- and high-dose groups. In the F0 females, total weight gain and percent reduction in the low- mid- and high-dose groups were not significantly different from the control.
- Zinc chloride treatment to F0 and F1 males and females caused no significant effects on their feed efficiencies when compared to their control groups.

HEMATOLOGY AND CLINICAL CHEMISTRY:
- None of the hemogram or leukogram values of both F0 and F1 males and females among the treated groups were different from those of the control groups. However, there was a trend toward decreased values of Packed Cell Volume (PCV). The clinical chemistry findings in males and females of both generations did not show any significant difference from those of their controls. However, in mid- and high-dose males of both generations, there seemed to a trend toward elevated values of Amylase, Alkaline phosphatase and glucose.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS):
- In F0 rats, Zinc chloride treatment caused a significant reduction on the fertility, litter size, and the viability indices (Days 0 and 4) were significantly reduced at the high-dose group compared to control.

ORGAN WEIGHTS (PARENTAL ANIMALS):
- In F0 males, the unadjusted weights of the brain in the mid and high-dose groups, the liver and kidney in all treated groups, the spleen in the high-dose group, and the seminal vesicles in the mid- and high-dose groups were significantly different from the control. When organ weights of F0 males were adjusted for body weight, the brain in the mid- and high-dose groups, the liver and kidney in all treated groups, the spleen in the high-dose group, and the seminal vesicles in the mid- and high-dose groups remained significantly different from their controls. The unadjusted organ weights of F0 females revealed significant differences for the spleen and uterus in the high-dose group. Following the adjustments of F0 female organ weights for body weight, the spleen and the uterus in the high-dose group remained significantly different from their controls.

GROSS PATHOLOGY (PARENTAL ANIMALS):
- Gross findings related to Zinc chloride treatment in males were primarily seen in the target organ systems (digestive, hematopoietic-lymphoreticular, and reproductive) already established for zinc. Digestive system lesions in the gastrointestinal tract (GIT) (distention, discoloration/hemorrhage and ulceration) and pancreas (smaller than usual) were mostly seen in rats given the two highest doses. Hematopoietic-lymphoreticular system lesions (small spleens and thymuses) were also scattered among the groups of treated males. In the reproductive tract of the males, the only gross changes noted were small prostates and small seminal vesicles (one each) in the high-dose group. Gross lesions in treated females generally paralleled those observed in their male counterparts.

HISTOPATHOLOGY (PARENTAL ANIMALS):
- In males, the most biologically meaningful lesions were found in the reproductive system (prostatic acinar atrophy and inflammation) and the hematopoietic-lymphoreticular system (splenic lymphoid depletion and hemosiderosis and thymic atrophy) of treated groups. No significant changes in clinical pathology values or organ weights correlated with these lesions. None of the microscopic changes in target organs were of great magnitude. All unscheduled deaths were confined to the treated groups, the majority of them probably being related to toxicity, but histomorphologic confirmation of this was not noted. The histopathology observed among the treated females was similar to that seen in the males, except that no lesions were seen in the reproductive system. The correlations and biological interpretations were also very similar.

OTHER FINDINGS (PARENTAL ANIMALS):
- Postpartum dam body weight: The F0 and F1 post-partum dam weights in all dose groups were significantly different from their control groups.
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 7.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Remarks on result:
other: not reported
Remarks on result:
not measured/tested
Clinical signs:
effects observed, treatment-related
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings:
effects observed, treatment-related
VIABILITY (OFFSPRING):
- The F1 males experienced 0, 12, 8, and 4 % mortality in the control, low-, mid- and high-dose groups, respectively. The mortality among the F1 females was 0, 8, 12, and 20 % in the control, low-, mid- and high-dose groups, respectively.

CLINICAL SIGNS (OFFSPRING):
- Aggression/hyperactivity was observed throughout the study in both F1 males and females of treated groups.

BODY WEIGHT (OFFSPRING):
- The F1 males in the mid- and high-dose groups experienced a significant reduction in body weight after the 1st week of dosing and the low-dose group experienced a similar reduction after the 2nd week of dosing. These trends continued up to the end of the experiment. The total weight gain of F1 males was significantly reduced (dose dependent) in the low, mid-, and high-dose groups. The F1 females in the low-dose group experienced significant reductions in body-weight gain on weeks 15, 16, and F1 females in the mid-dose group experienced a similar reduction in body-weight gain weeks 3 through 17, This was also true for females in the highest dose group for weeks 1 through 17. The body weights of F1 and F2 pups at Day 21 in the high-dose group were significantly lower compared to their control.

ORGAN WEIGHTS (OFFSPRING):
- In F1 males, the unadjusted weights of the brain, spleen, and prostate in all treated groups, the liver, adrenal,
testis and seminal vesicles in mid-dose and the kidney in high-dose were significantly different from their controls. When the organ weights of F1 males were adjusted for body weight, the brain, spleen, and prostate in all treated groups, the liver, adrenal and seminal vesicles in mid-dose group, and kidney in high-dose group remained significantly different from their controls. The unadjusted organ weights of F1 females that were different from their controls included the brain and spleen in low- mid- and high-dose groups and the kidneys in the high-dose group. Following the adjustments of F1 female organ weights for body weight, the brain and spleen in all dose groups and kidneys in high dose groups were significantly different from controls.

GROSS PATHOLOGY (OFFSPRING):
- Gross findings related treatment in males were primarily seen in the target organ systems (digestive, hematopoietic-lymphoreticular, and reproductive) already established for zinc. Digestive system lesions in the gastrointestinal tract (GIT) (distention, discoloration/hemorrhage and ulceration) and pancreas (smaller than usual) were mostly seen in rats given the two highest doses. Hematopoietic-lymphoreticular system lesions (small spleens and thymuses) were also scattered among the groups of treated males. In the reproductive tract of the males, the only gross changes noted were small prostates and small seminal vesicles (one each) in the high-dose group. Gross lesions in treated females generally paralleled those observed in their male counterparts.

HISTOPATHOLOGY (OFFSPRING):
- In F1 males, the most biologically meaningful lesions were found in the reproductive system (prostatic acinar atrophy and inflammation) and the hematopoietic-lymphoreticular system (splenic lymphoid depletion and hemosiderosis and thymic atrophy) at 30 mg/kg bw/day. These results indicated that Zinc chloride exposure has only mild effects on the reproductive performance of rats. No significant changes in clinical pathology values or organ weights correlated with these lesions. None of the microscopic changes in target organs were of great magnitude. All unscheduled deaths were confined to the treated groups, the majority of them probably being related to toxicity, but histomorphologic confirmation of this was not noted. The histopathology observed among the treated females was similar to that seen in the males, except that no lesions were seen in the reproductive system. The correlations and biological interpretations were also very similar.

OTHER FINDINGS (OFFSPRING):
- Reproductive performance: F1: No significant difference was seen in the weaning index and sex ratios in F1 pups. In F1 generation rats, Zinc chloride treatment resulted in a significant reduction on fertility, viability (Day 0) and litter size in the high-dose group compared to control. However, the treatment showed no effect on viability index, weaning index and sex ratios of F2 pups.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 7.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Remarks on result:
not measured/tested
Reproductive effects observed:
not specified

None

Conclusions:
Under the test conditions, the No Observed Adverse Effect Level (NOAEL) of read across substance Zinc chloride was 7.5 mg/kg bw/day in rats. Similar results can be expected for zinc dimethacrylate.



Executive summary:

In a two-generation study conducted similarly to OECD Guideline 416, the read across substance Zinc chloride was administered to groups of Sprague-Dawley rats (25/sex/dose) at 7.5, 15 and 30 mg/kg bw/day by oral gavage. Treatment was started after two weeks of acclimation and was continued for males and females for 77 days prior to cohabitation. Treatment was continued throughout the periods of cohabitation (21 days) for both sexes. Treatment of female rats was continued throughout the gestation (21 days) and lactation (21 days) periods. Control group animals received deionised water. During the study, data was recorded on mortality, clinical signs, body weight change, food consumption, haematology, blood chemistry, and reproductive performance. All animals were subjected to a gross necropsy examination, selected organs were weighed and histopathological evaluation of selected tissues was performed. The clinical condition of offspring, litter size and survival, sex ratio and offspring bodyweight were assessed and macroscopic pathology investigations were undertaken. Exposure of F0 and F1 parental rats to test material showed significant reduction in fertility, viability (Days 0 and 4), and the body weight of F1 and F2 pups from the high-dose group but caused no effects on litter size, weaning index, and sex ratio. Aggression/hyperactivity was observed throughout the study in both F0 and F1 males and females of treated groups. Exposure of Zinc chloride to F0 and F1 parental males resulted in a significant reduction in their body weights, and the F0 and F1 parental females did not show any significant difference in their body weights compared to their control groups. However, the postpartum dam weights of both F0 and F1 female rats were significantly reduced compared to their controls. Zinc chloride treatment to F0 and F1 males and females caused no significant effects on their feed efficiencies when compared to their control groups. Exposure of test material to F0 and F1 generation parental animals resulted in non significant change in clinical pathology parameters, except the alkaline phosphatase level, which showed an upward trend in both sexes of both generations. In F0 rats, reduction of brain, liver, kidney, spleen and seminal vesicles weights of males and in the spleen and uterus of females were observed. In F1 rats, reduction of brain, liver, kidney, adrenal, spleen, prostate and seminal vesicles weights of males and in spleen and uterus of females were observed. Gross lesions were observed in gastro-intestinal (GI) tract, lymphoreticular/ hematopoietic and reproductive tract in parental rats in both generations. Digestive system lesions in the gastrointestinal tract (GIT) (distention, discoloration/hemorrhage and ulceration) and pancreas (smaller than usual) were mostly seen in rats given the two highest doses. Hematopoietic-lymphoreticular system lesions (small spleens and thymuses) were also scattered among the groups of treated males. In the reproductive tract of the males, the only gross changes noted were small prostates and small seminal vesicles (one each) in the high-dose group. Gross lesions in treated females generally paralleled those observed in their male counterparts. In both F0 and F1 males, the histopathological lesions were found in the reproductive system (prostatic acinar atrophy and inflammation) and the hematopoietic-lymphoreticular system (splenic lymphoid depletion and hemosiderosis and thymic atrophy) of treated groups. No significant changes in clinical pathology values or organ weights correlated with these lesions and none of the microscopic changes in target organs were of great magnitude. All unscheduled deaths were confined to the treated groups, the majority of them probably being related to toxicity, but histomorphologic confirmation of this was not noted. The histopathology observed among the treated females was similar to that seen in the males, except that no lesions were seen in the reproductive system. Under the test conditions, the No Observed Adverse Effect Level (NOAEL) of read across substance Zinc chloride was 7.5 mg/kg bw/day in rats (Khan, 2007). Similar results can be expected for zinc dimethacrylate.

Endpoint:
one-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
1986
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Please refer to section 13 of the dataset for read across justification.
Reason / purpose for cross-reference:
read-across source
Qualifier:
no guideline followed
Principles of method if other than guideline:
Males rats were fed diet supplemented with the test material for specific period and then mated with normal females. Males were sacrificed after mating and effect on sperm motility/viability and zinc concentration in reproductive organs observed. Females were allowed to have full term gestation and effect on conception and litter viability were determined.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: Charles-Foster
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 162 g
- Diet: Crushed rat feed of Hindustan Lever (India), ad libitum
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Mixing appropriate amounts with (Type of food): Crushed rat feed
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 1 day
- Proof of pregnancy: Sperm in vaginal smear (mating performed only once irrespective of results)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
30-32 days before mating to males only
Frequency of treatment:
Daily, ad libitum
Details on study schedule:
Following the day of mating, males were sacrificed and sperm was immediately collected from epididymis for motility and viability studies. Reproductive organs were dissected out for estimation of zinc. Mated females were allowed to have full term gestation.
Remarks:
Doses / Concentrations:
4000 ppm zinc as zinc sulfate
Basis:
nominal in diet
No. of animals per sex per dose:
Control group: 15
Treatment group: 18
Control animals:
yes, plain diet
Details on study design:
None
Positive control:
None
Parental animals: Observations and examinations:
No data
Oestrous cyclicity (parental animals):
No data
Sperm parameters (parental animals):
Parameters examined in male parents:
- Sperm motility and viability

Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
- Number of pups, stillbirths, live births and malformation
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All animals sacrificed following the day of mating and reproductive organs (testis, epididymis, seminal vesicle and prostate) were dissected out for estimation of zinc
- Maternal animals: Not sacrificed; mated females were allowed to have full term gestation.
Postmortem examinations (offspring):
No data
Statistics:
Fisher's one sided T test
Reproductive indices:
None
Offspring viability indices:
None
Clinical signs:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
effects observed, treatment-related
Reproductive performance:
effects observed, treatment-related
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): Motility of the sperm was significantly reduced in the zinc treated rats at all time intervals viz. 30 min., 2 h and 4 h. The percentage reduction as compared to the controls was 8.5, 25 .3 and 29 .0 respectively. Sperm viability was unaffected. (See Table 7.8.1/3 for details)

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): Mating by zinc treated males caused significant lowering of incidence of conception and number of live births per mated female. Only 11 females conceived out of 18 mated by zinc treated males whereas all females mated with control rats conceived. (See Table 7.8.1/1 for details)

OTHER FINDINGS (PARENTAL ANIMALS): Zinc content was significantly increased only in the testis (25 %) and sperm (18 %) of the zinc treated rats. (See Table 7.8.1/2 for details)
Key result
Dose descriptor:
LOAEL
Remarks:
zinc
Effect level:
ca. 4 000 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: overall effects sperm characterization; other: zinc concentration in reproductive organs
Key result
Dose descriptor:
LOAEL
Remarks:
Not treated but mated with males fed 4000 ppm zinc
Effect level:
ca. 4 000 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: overall effects incidence of conception
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
VIABILITY (OFFSPRING): No stillbirth in any of the groups.

OTHER FINDINGS (OFFSPRING): No malformed litter in any of the groups.
Key result
Dose descriptor:
LOAEL
Remarks:
Offsprings of 4000 ppm zinc treated males
Generation:
F1
Effect level:
ca. 4 000 ppm
Sex:
male/female
Basis for effect level:
other: overall effects live births; offspring malformation
Reproductive effects observed:
not specified

Table 7.8.1/1: Outcome of mating by zinc treated male rats

 

Mating males

 

 

Control

Experimental

Number of females mated

15

18

Number of females conceived

15

11

Normal live litter

 

 

Total number

101

61

Number / mated female

6.73

3.38*

*Difference was significant at 5% level

Table 7.8.1/2: Zinc content of the reproductive tissues of zinc treated male rats

 

Control

Experimental

Testis

28.1± 1.63 (15)

35.3 ± 2.13 (18)*

Epididymis

58.3 ± 3.46 (10)

61.4 ± 6.63 (10)

Seminal vesicle

24.4 ± 3.25 (10

33.8 ± 5.96 (10)

Prostate (whole)

48.8 ± 6.90 (10)

51.7 ± 6.36 (10)

Sperm

559 ± 14.8 (10)

658 ± 24.7 (10)*

Results expressed as Mean ± SEM in µg/g, except for sperm in µg/g dw, for the number of rats shown in parentheses. * P < 0.02

Table 7.8.1/3: Motility and viability of the sperm of zinc treated rats

 

Control (15)

Experimental (18)

Motility (Emmen's unit)

 

 

30 min

25.9 ± 0.57

23.7 ± 0.47*

2 hours

23.7 ± 0.58

17.7 ± 1.15**

4 hours

17.2 ± 1.10

12.2 ± 1.42*

% viable at 4 hours

55.7 ± 4.80

49.0 ± 4.60

Values expressed as Mean ± SEM for the number of rats shown in parentheses.* P < 0.01 ; **P<0.001

Conclusions:
Under the test conditions, dietary zinc supplementation at 4000 ppm reduced male fertility in rats. Similar results can be expected for zinc dimethacrylate.
Executive summary:

A study was conducted to determine the effects of the read across substance zinc sulphate on male fertility in Charles-Foster rats. 4000 ppm zinc as zinc sulfate was fed to 18 test males in diet for 30-32 days. 15 control males were fed normal diet for the same duration. All animals mated with individual normal females once between Day 30 and 32. After mating, males were sacrificed for sperm characterization and zinc concentration analysis in different reproductive organs. Mated females were allowed to have full term gestation. Mating by treated males caused significant lowering of incidence of conception and number of live births per mated female. However, no stillbirth or malformed litter was observed. Motility of the sperm was significantly reduced in the treated rats but viability was unaffected. Zinc content was significantly increased only in the testis and sperm of the treated rats. The results indicate that dietary zinc supplementation at 4000 ppm reduced male fertility in rats under the conditions of the study (Samantha, 1986). Similar results can be expected for zinc dimethacrylate.

Endpoint:
two-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
Please refer to section 13 of the dataset for read across justification.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3800 (Reproduction and Fertility Effects)
GLP compliance:
yes (incl. QA statement)
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: (P) 37 (±1) days at the beginning of treatment; (F1) x wks
- Weight at study initiation: (P) Males: 127.5 - 151.0 g; Females: 110.5 - 145.1 g; (F1) Males: x-x g; Females: x-x g
- Fasting period before study:
- Housing: During the study period, the rats were housed individually in Makrolon type M III cages (Becker & Co., Castrop-Rauxel, Germany), floor area of about 800 cm², with the following exceptions: 1) During overnight matings, male and female mating partners were housed together in Makrolon type M III cages. 2) Pregnant animals and their litters were housed together until PND 21 (end of lactation).
- Diet: ground Kliba maintenance diet mouse/rat “GLP” meal (Provimi Kliba SA, Kaiseraugst, Switzerland) ad libitum
- Water: ad libitum
- Acclimation period: (P) about 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): 10 or 15 times
- Photoperiod (hrs dark / hrs light): 12 / 12


IN-LIFE DATES: From: To:
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The aqueous test substance suspensions were prepared at the beginning of the administration period and thereafter at intervals that took into account the analytical results of the stability verification. For the test substance preparation, the specified amount of test substance was weighed into an Erlenmeyer flask, topped up (shortly under the marking) with 1% Carboxymethylcellulose suspension in drinking water and four drops Cremophor EL and one drop of 32% hydrochloric acid. Afterwards the preparation was filled up with 1% Carboxymethylcellulose suspension in drinking water. The Erlenmeyer flask was sealed and the preparation was intensely mixed with a magnetic stirrer. A magnetic stirrer was used to keep the preparations homogeneous during treatment of the animals.
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: overnight for a maximum of 2 weeks
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy (= GD 0)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of the test substance preparations were sent to the analytical laboratory ten times during the study period (among other things at the beginning and towards the end) for verification of the concentrations. The samples, which were taken for the concentration control analyses at the beginning of the administration period, were also used to verify the homogeneity for the samples of the low and the high concentrations (50 and 400 mg/kg bw/d). Three samples (one from the top, middle and bottom in each case) were taken for each of these concentrations from the beaker with a magnetic stirrer running.
Duration of treatment / exposure:
until one day before sacrifice
Frequency of treatment:
once daily
Details on study schedule:
- F1 parental animals not mated until 75 days after selected from the F1 litters.
- Selection of parents from F1 generation after weaning (PND 21).
- Age at mating of the mated animals in the study: [...] weeks
Remarks:
Doses / Concentrations:
0, 50, 150, 450 mg/kg/day
Basis:
nominal conc.
No. of animals per sex per dose:
F0 generation parental animals: 25
F1 generation parental aniumals: 25
Control animals:
yes, concurrent vehicle
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily on working days or once daily (Saturday, Sunday or on public holidays)


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: first day of the premating period and then once a week at the same time of the day (in the morning) until sacrifice. The following exceptions are notable for the female parental animals: 1) During each gestation period the F0 and the F1 generation parental females were weighed on the day of positive evidence of sperm (GD 0) and on GD 7, 14 and 20. 2) Females showing no positive evidence of sperm in vaginal smears were weighed once a week during the mating interval (solely for calculation of dose volume). 3) Females with litter were weighed on the day after parturition (PND 1) and on PND 4, 7, 14 and 21. 4) Females without litter were weighed once a week during the lactation phase (solely for calculation of dose volume).



OTHER:
- Food consumption: In general, food consumption was determined once a week for the male and female F0 and F1 parental animals. After the 10th test week, food consumption of the females during pregnancy (animals with evidence of sperm) was determined weekly for GD 0-7, 7-14 and 14-20. During the lactation period (animals with litter) food consumption was determined for PND 1-4, 4-7, 7-14 and 14-21.
Oestrous cyclicity (parental animals):
Estrous cycle length and normality were evaluated daily for all F0 and F1 female parental rats for a minimum of 3 weeks prior to mating. The evaluations were continued throughout the mating period until the female exhibited evidence of mating. Moreover, at the scheduled necropsy a vaginal smear was microscopically examined to determine the stage of the estrous cycle for each F0 and F1 female.
Sperm parameters (parental animals):
Parameters examined in all male parental generations:
testis weight, epididymis weight, cauda epididymis weight, prostate weight, seminal vesicles including coagulation glands weight, sperm head count in testis, sperm head count in cauda epididymis, sperm motility, sperm morphology
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- Maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded.


PARAMETERS EXAMINED
The following parameters were examined in F1 and F2 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, clinical symptoms, sexual maturation


GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities
Postmortem examinations (parental animals):
SACRIFICE AND GROSS NECROPSY
All F0 and F1 parental animals were sacrificed by decapitation under Isoflurane anesthesia. The exsanguinated animals were necropsied and assessed by gross pathology; special attention was given to the reproductive organs.

HISTOPATHOLOGY / ORGAN WEIGHTS
Weight assessment was carried out on all animals sacrificed at scheduled dates. The following weights were determined: Anesthetized animals, liver, kidneys, adrenal glands, testes, epididymides, cauda epididymis, prostate, seminal vesicles including coagulation glands, ovaries, uterus, spleen, brain, pituitary gland, thyroid glands (with parathyroid glands). The following organs or tissues of the F0 and F1 generation parental animals were fixed in 4% neutral buffered formaldehyde solution or in BOUIN’s solution, respectively: Vagina, cervix uteri, uterus, ovaries (BOUIN), oviducts, left testis (BOUIN), left epididymis (BOUIN), seminal vesicles, coagulation glands, prostate, pituitary gland, adrenal glands, liver, kidneys, spleen, brain, thyroid glands (with parathyroid glands), all gross lesions. After fixation, the organs fixed in BOUIN´s solution were embedded in Paraplast. Fixation was followed by histotechnical processing, examination by light microscopy and assessment of findings.

OTHER:
- Differential Ovarian Follicle Count (DOFC) in F1 generation: From both ovaries (”ovary 1” and “ovary 2”) of F1 female animals (control and top dose), five sections were taken from the proximal and the distal part of the ovaries, respectively, at least 100 µm apart from the inner third of the ovary. All ovarian sections were prepared and evaluated. Primordial follicles and growing follicles were counted by light microscope (magnification: 100x) on each of these slides, – according to the definitions given by Plowchalk et al. (PLOWCHALK, D. R., B. J. SMITH, and D. R. MATTISON: Assessment of Toxicity to the Ovary Using Follicle Quantitation and Morphometrics. In: Methods in Toxicology, Vol. 3, Part B: Female Reproductive Toxicology (J. J. HEINDEL and R. E. CHAPIN, Editors), p. 57-68, 1993, Academic Press). To prevent multiple counting on serial slides – especially of the growing follicles – only follicles with an oocyte with visible chromatin on the slide were counted. The number of each type of follicle was recorded individually for ovary 1 and ovary 2 of every animal on any of the slide levels (level 1-10), giving in summary the incidence of each type of the follicles by using EXCEL sheets for the reporting of the results. Finally, the results of all types of follicles were summarized for all animals per group in dose groups 10 and 13. As primordial follicles continuously develop into growing follicles, the assessment of the follicles was extended to the combined incidence of primordial plus growing follicles. In general, the fifth slide of the left and right ovary was evaluated for histological findings. Whenever the diagnosis: ”no abnormalities detected” was used for the ovaries, this implicates all functional statuses of follicles, especially corpora lutea, were present. An attempt was made to correlate gross lesions with histopathological findings.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals were sacrificed at 4 days of age. All F2 offspring were sacrificed after weaning (~ PND 21).
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
- All pups were examined externally and eviscerated; their organs were assessed macroscopically.

HISTOPATHOLOGY / ORGAN WEIGHTS
Animals with notable findings or abnormalities were further evaluated on a case-by-case basis, depending on the type of finding noted. After the scheduled sacrifice the brain, spleen and thymus of 1 pup/sex and litter from the F1 and F2 pups were weighed. Normally, the first male and the first female pups/litter were taken for these determinations. For the calculation of the relative organ weights, the pup body weights, determined routinely during the in-life phase on PND 21, were used.
Reproductive indices:
- Male reproduction data: The mating partners, the number of mating days until vaginal sperm could be detected in the female, and the gestational status of the female were noted for F0 and F1 breeding pairs. For the males, mating and fertility indices were calculated for F1 and F2 litters according to the following formulas: Male mating index (%) = (number of males with confirmed mating)/(number of males placed with females) x 100. Male fertility index (%) = (number of males proving their fertility)/(number of males placed with females) x 100.
- Female reproduction and delivery data: The mating partners, the number of mating days until vaginal sperm were detected, and gestational status were recorded for F0 and F1 females. For the females, mating, fertility and gestation indices were calculated for F1 and F2 litters according to the following formulas:
Female mating index (%) = (number of females mated)/(number of females placed with males) x 100.
Female fertility index (%) = (number of females pregnant)/(number of females mated) x 100.
Gestation index (%) = (number of females with live pups on the day of birth)/(number of females pregnant) x 100.
The total number of pups delivered and the number of liveborn and stillborn pups were noted, and the live birth index was calculated for F1 and F2 litters according to the following formula:
Live birth index (%) = (number of liveborn pups at birth)/(total number of pups born) x 100.
The implantations were counted and the postimplantation loss (in %) was calculated according the following formula:
Postimplantation loss (%) = (number of implantations – number of pups delivered)/(number of implantations) x 100.
Offspring viability indices:
The number and percentage of dead pups on the day of birth (PND 0) and of pups dying between PND 1-4, 5-7, 8-14 and 15-21 (lactation period) were determined; however, pups, which died accidentally or had to be sacrificed due to maternal death, were not included in these calculations. The number of live pups/litter was calculated on the day after birth, and on lactation days 4, 7, 14, and 21. Furthermore, viability and lactation indices were calculated according to the following formulas:
Viability index (%) = (number of live pups on day 4 (before culling) after birth)/(number of live pups on the day of birth) x 100.
Lactation index (%) = (number of live pups on day 21 after birth)/(number of live pups on day 4 (after culling) after birth) x 100.
Test group 03 (400 mg/kg bw/d):
P PARENTAL ANIMALS:
CLINICAL EXAMINATIONS/ REPRODUCTIVE PERFORMANCE/ CLINICAL PATHOLOGY/ PATHOLOGY
- Statistically significantly decreased food consumption in parental males during premating weeks 5 - 10 (up to 7%)
- Statistically significantly decreased food consumption in parental females during premating weeks 1 - 3 (up to 6%), weeks 5 - 8 (up to 7%) and weeks 9 - 10 (about 6%)
- Statistically significantly decreased food consumption in parental females during gestation days 0 - 7 (about 10%)
- Statistically significantly decreased food consumption in parental females during lactation days 4 - 7 (about 7%)

F1 PARENTAL ANIMALS:
CLINICAL EXAMINATIONS/ REPRODUCTIVE PERFORMANCE/ CLINICAL PATHOLOGY PATHOLOGY
- Statistically significantly decreased food consumption in parental males during premating weeks 0 - 1 (about 14%) and weeks 8 - 10 (up to 7%)
- Statistically significantly decreased food consumption in parental females during premating weeks 0 - 1 (about 10%) and weeks 9 - 10 (about 8%)
- Statistically significantly decreased food consumption in parental females during gestation days 0 - 14 (up to 8%)
- Statistically significantly decreased body weights in parental males during weeks 0 - 5 (up to 17%) and weeks 10 - 11 (up to 6%)
- Statistically significantly decreased body weights in parental females during premating weeks 0 - 1 (up to 17%)

Test group 02 (150 mg/kg bw/d):
P PARENTAL ANIMALS:
CLINICAL EXAMINATIONS/ REPRODUCTIVE PERFORMANCE/ CLINICAL PATHOLOGY PATHOLOGY
- Statistically significantly decreased food consumption in parental females during premating weeks 1 - 2 (about 5%)
- Statistically significantly decreased food consumption in parental females during gestation days 0 - 7 (about 7%)

F1 PARENTAL ANIMALS:
CLINICAL EXAMINATIONS/ REPRODUCTIVE PERFORMANCE/ CLINICAL PATHOLOGY PATHOLOGY
- no test substance-related adverse effects/findings

Test group 01 (50 mg/kg bw/d):
P PARENTAL ANIMALS:
CLINICAL EXAMINATIONS/ REPRODUCTIVE PERFORMANCE/ CLINICAL PATHOLOGY PATHOLOGY
- no test substance-related adverse effects/findings

F1 PARENTAL ANIMALS:
CLINICAL EXAMINATIONS/ REPRODUCTIVE PERFORMANCE/ CLINICAL PATHOLOGY PATHOLOGY
- no test substance-related adverse effects/findings
Key result
Dose descriptor:
NOAEL
Remarks:
general, systemic toxicity
Effect level:
ca. 50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
food consumption and compound intake
Remarks on result:
other: Generation: P and F1 parental animals (migrated information)
Key result
Dose descriptor:
NOEL
Remarks:
fertility and reproductive performance
Effect level:
ca. 400 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance
Key result
Dose descriptor:
NOEL
Remarks:
developmental toxicity
Effect level:
ca. 400 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose tested
Remarks on result:
other: Generation: F1 and F2 progeny (migrated information)
Test group 03 (400 mg/kg bw/d):
F1 PUPS:
CLINICAL EXAMINATIONS/ SEXUAL MATURATION/ PUP ORGAN WEIGHTS/ GROSS FINDINGS
- no test substance-related adverse effects/findings

Test group 02 (150 mg/kg bw/d):
F1 PUPS:
CLINICAL EXAMINATIONS/ SEXUAL MATURATION/ PUP ORGAN WEIGHTS/ GROSS FINDINGS
- no test substance-related adverse effects/findings

Test group 01 (50 mg/kg bw/d):
F1 PUPS:
CLINICAL EXAMINATIONS/ SEXUAL MATURATION/ PUP ORGAN WEIGHTS/ GROSS FINDINGS
- no test substance-related adverse effects/findings
Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
ca. 400 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Clinical examinations/ sexual maturation/ pup organ weights/ gross findings
Test group 03 (400 mg/kg bw/d):
F2 PUPS:
CLINICAL EXAMINATIONS/ SEXUAL MATURATION/ PUP ORGAN WEIGHTS/ GROSS FINDINGS
- no test substance-related adverse effects/findings

Test group 02 (150 mg/kg bw/d):
F2 PUPS:
CLINICAL EXAMINATIONS/ SEXUAL MATURATION/ PUP ORGAN WEIGHTS/ GROSS FINDINGS
- no test substance-related adverse effects/findings

Test group 01 (50 mg/kg bw/d):
F2 PUPS:
CLINICAL EXAMINATIONS/ SEXUAL MATURATION/ PUP ORGAN WEIGHTS/ GROSS FINDINGS
- no test substance-related adverse effects/findings
Key result
Dose descriptor:
NOEL
Generation:
F2
Effect level:
ca. 400 mg/kg bw/day
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: Clinical examinations/ sexual maturation/ pup organ weights/ gross findings
Reproductive effects observed:
not specified

- Analytics:

The various analyses:

  • demonstrated the stability of the test substance preparations over a period of 7 days at room temperature
  • confirmed the homogeneous distribution of the test substance in the vehicle (1% Carboxymethylcellulose suspension in drinking water and a few drops Cremophor EL and one drop hydrochloric acid)
  • showed that the prepared concentrations were close to the expected values ranging between 86.8 and 113.2% of the nominal concentrations

Analytical values (range):

Test group

Nominal Dose
(mg/kg bw/d)

Analytical Dose
(mg/kg bw/d)
[minimum]

Analytical Dose (mg/kg bw/d)
[maximum]

% Nominal Dose
[minimum]

% Nominal Dose
[maximum]

00 / 10

0

0

0

 

   

01 / 11

50

43.40

46.61

86.8

93.2

02 / 12

150

132.90

169.80

88.6

113.2

03 / 13

400

359.20

379.90

89.8

95.0

 

Conclusions:
Under the study conditions, the read across substance methyl methacrylate NOAEL for general, systemic toxicity was 50 mg/kg bw/day for the P and F1 parental rats, based on adverse effects on food consumption observed at the LOAEL of 150 mg/kg bw/day in the P parental females. The NOEL for fertility and reproductive performance for the P and F1 parental rats was 400 mg/kg bw/day, the highest dose tested. The NOEL for developmental toxicity, in the F1 and F2 progeny, of the test substance was 400 mg/kg bw/day, the highest dose tested. Similar results can be expected for zinc dimethacrylate.

Executive summary:

The study was performed according to OECD TG 416 in compliance with GLP. Read across substance methyl methacrylate was administered to groups of 25 male and 25 female healthy young Wistar rats (P parental generation) as an aqueous preparation by stomach tube at dosages of 0; 50; 150 and 400 mg/kg body weight/day. At least 73 days after the beginning of treatment, P animals were mated to produce a litter (F1). Mating pairs were from the same dose group and F1 animals selected for breeding were continued in the same dose group as their parents. Groups of 25 males and 25 females, selected from F1 pups to become F1 parental generation, were treated with the test substance at dosages of 0; 50; 150 and 400 mg/kg body weight/day post weaning, and the breeding program was repeated to produce F2 litter. The study was terminated with the terminal sacrifice of the F2 weanlings and F1 adult animals. Control parental animals were dosed daily with the vehicle (1% Carboxymethylcellulose suspension in drinking water and four drops Cremophor EL and one drop hydrochloric acid). The mid- and high-dose parental animals (400 mg/kg bw/d) showed clinical signs of systemic toxicity. The only relevant clinical observation was temporary salivation during a short period after dosing, which is considered to be test substance-induced. From the temporary, short appearance immediately after dosing it is likely, that this finding was induced by a bad taste of the test substance or local affection of the upper digestive tract. It is, however, not considered to be an adverse toxicologically relevant finding. In the mid- and high-dose (150 and 400 mg/kg bw/d) P generation animals, dose-related intermittent reductions of food consumption were noted, either during premating, gestation and lactation phases of this study. Less significant changes were noted for the F1 generation animals where the effects were limited to the high-dose group. High dose F1 parental males had statistically significant lower body weights during several study segments, which led to a statistically significant reduction of the mean terminal body weight resulting in secondary weight changes of brain. High dose parental females had statistically significant lower body weights during the first weeks after weaning. This weight decrease during major phases of sexual maturation led to an apparent marginal delay of vaginal patency. This minor delay did, however, not result in any corroborative pathological findings nor did it adversly effect F1 female cyclicity, fertility and reproduction. Thus, an influence of the test substance on female sexual maturation is not assumed. Pathological examinations revealed no test-substance-related changes in organ weights, gross lesions, changes in differential ovarian follicle counts or microscopic findings, apart from an increase in kidney and liver weights in male and female animals in both generations which is presumably related to the treatment. There was no histopathologic lesion observed, that could explain the weight increase. It is regarded to be an adaptive change, most likely caused by an increase in metabolic activity in the two organs, which does not lead to histopathologic findings. It is not regarded to be an adverse effect. There were no indications from clinical examinations as well as gross and histopathology, that the administration of methyl methacrylate via the diet adversely affected the fertility or reproductive performance of the P or F1 parental animals up to and including a dose of 400 mg/kg bw/day. Estrous cycle data, mating behavior, conception, gestation, parturition, lactation and weaning as well as sperm parameters, sexual organ weights and gross and histopathological findings of these organs (including differential ovarian follicle counts in the F1 females) were comparable between the rats of all test groups and ranged within the historical control data of the test facility. 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, inclusive the high-dose group (400 mg/kg bw/day). Under the study conditions, the NOAEL for general, systemic toxicity was 50 mg/kg bw/day for the P and F1 parental rats, based on adverse effects on food consumption observed at the LOAEL of 150 mg/kg bw/day in the P parental females. The NOEL for fertility and reproductive performance for the P and F1 parental rats was 400 mg/kg bw/day, the highest dose tested. The NOEL for developmental toxicity, in the F1 and F2 progeny, of the test substance was 400 mg/kg bw/day, the highest dose tested (BASF, 2009). Similar results can be expected for zinc dimethacrylate.

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.

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

Reproductive toxicity studies


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 Hydroxy (2 -methylprop-2 -enoato-O) zinc 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, 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. The clinical condition of offspring, litter size and survival, sex ratio and offspring bodyweight were assessed and macroscopic pathology investigations were undertaken.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 and reproductive/developmental toxicity were considered to be 100 mg/kg bw/day and 300 mg/kg bw/day, respectively in Crl:CD(SD) rats (Stannard, 2013). Similar results can be expected for zinc dimethacrylate.


 


A study was conducted to determine the effects of the read across substance zinc sulphate on male fertility in Charles-Foster rats. 4000 ppm zinc as zinc sulphate was fed to 18 test males in diet for 30-32 days. 15 control males were fed normal diet for the same duration. All animals mated with individual normal females once between Day 30 and 32. After mating, males were sacrificed for sperm characterization and zinc concentration analysis in different reproductive organs. Mated females were allowed to have full term gestation. Mating by treated males caused significant lowering of incidence of conception and number of live births per mated female. However, no stillbirth or malformed litter was observed. Motility of the sperm was significantly reduced in the treated rats but viability was unaffected. Zinc content was significantly increased only in the testis and sperm of the treated rats. The results indicate that dietary zinc supplementation at 4000 ppm reduced male fertility in rats under the conditions of the study (Samantha, 1986). Similar results can be expected for zinc dimethacrylate.


 


In a two-generation study conducted similarly to OECD Guideline 416, read across substance Zinc chloride was administered to groups of Sprague-Dawley rats (25/sex/dose) at 7.5, 15 and 30 mg/kg bw/day by oral gavage. Treatment was started after two weeks of acclimation and was continued for males and females for 77 days prior to cohabitation. Treatment was continued throughout the periods of cohabitation (21 days) for both sexes. Treatment of female rats was continued throughout the gestation (21 days) and lactation (21 days) periods. Control group animals received deionised water. During the study, data was recorded on mortality, clinical signs, body weight change, food consumption, haematology, blood chemistry, and reproductive performance. All animals were subjected to a gross necropsy examination, selected organs were weighed and histopathological evaluation of selected tissues was performed. The clinical condition of offspring, litter size and survival, sex ratio and offspring bodyweight were assessed and macroscopic pathology investigations were undertaken. Exposure of F0 and F1 parental rats to test material showed significant reduction in fertility, viability (Days 0 and 4), and the body weight of F1 and F2 pups from the high-dose group but caused no effects on litter size, weaning index, and sex ratio. Aggression/hyperactivity was observed throughout the study in both F0 and F1 males and females of treated groups. Exposure of Zinc chloride to F0 and F1 parental males resulted in a significant reduction in their body weights, and the F0 and F1 parental females did not show any significant difference in their body weights compared to their control groups. However, the postpartum dam weights of both F0 and F1 female rats were significantly reduced compared to their controls. Zinc chloride treatment to F0 and F1 males and females caused no significant effects on their feed efficiencies when compared to their control groups. Exposure of test material to F0 and F1 generation parental animals resulted in non significant change in clinical pathology parameters, except the alkaline phosphatase level, which showed an upward trend in both sexes of both generations. In F0 rats, reduction of brain, liver, kidney, spleen and seminal vesicles weights of males and in the spleen and uterus of females were observed. In F1 rats, reduction of brain, liver, kidney, adrenal, spleen, prostate and seminal vesicles weights of males and in spleen and uterus of females were observed. Gross lesions were observed in gastro-intestinal (GI) tract, lymphoreticular/ hematopoietic and reproductive tract in parental rats in both generations. Digestive system lesions in the gastrointestinal tract (GIT) (distention, discoloration/hemorrhage and ulceration) and pancreas (smaller than usual) were mostly seen in rats given the two highest doses. Hematopoietic-lymphoreticular system lesions (small spleens and thymuses) were also scattered among the groups of treated males. In the reproductive tract of the males, the only gross changes noted were small prostates and small seminal vesicles (one each) in the high-dose group. Gross lesions in treated females generally paralleled those observed in their male counterparts. In both F0 and F1 males, the histopathological lesions were found in the reproductive system (prostatic acinar atrophy and inflammation) and the hematopoietic-lymphoreticular system (splenic lymphoid depletion and hemosiderosis and thymic atrophy) of treated groups. No significant changes in clinical pathology values or organ weights correlated with these lesions and none of the microscopic changes in target organs were of great magnitude. All unscheduled deaths were confined to the treated groups, the majority of them probably being related to toxicity, but histomorphologic confirmation of this was not noted. The histopathology observed among the treated females was similar to that seen in the males, except that no lesions were seen in the reproductive system. Under the test conditions, the No Observed Adverse Effect Level (NOAEL) of read across substance Zinc chloride was 7.5 mg/kg bw/day in rats (Khan, 2007). Similar results can be expected for zinc dimethacrylate.


 


The study was performed according to OECD TG 416 in compliance with GLP. Read across substance methyl methacrylate was administered to groups of 25 male and 25 female healthy young Wistar rats (P parental generation) as an aqueous preparation by stomach tube at dosages of 0; 50; 150 and 400 mg/kg body weight/day. At least 73 days after the beginning of treatment, P animals were mated to produce a litter (F1). Mating pairs were from the same dose group and F1 animals selected for breeding were continued in the same dose group as their parents. Groups of 25 males and 25 females, selected from F1 pups to become F1 parental generation, were treated with the test substance at dosages of 0; 50; 150 and 400 mg/kg body weight/day post weaning, and the breeding program was repeated to produce F2 litter. The study was terminated with the terminal sacrifice of the F2 weanlings and F1 adult animals. Control parental animals were dosed daily with the vehicle (1% Carboxymethylcellulose suspension in drinking water and four drops Cremophor EL and one drop hydrochloric acid). The mid- and high-dose parental animals (400 mg/kg bw/d) showed clinical signs of systemic toxicity. The only relevant clinical observation was temporary salivation during a short period after dosing, which is considered to be test substance-induced. From the temporary, short appearance immediately after dosing it is likely, that this finding was induced by a bad taste of the test substance or local affection of the upper digestive tract. It is, however, not considered to be an adverse toxicologically relevant finding. In the mid- and high-dose (150 and 400 mg/kg bw/d) P generation animals, dose-related intermittent reductions of food consumption were noted, either during premating, gestation and lactation phases of this study. Less significant changes were noted for the F1 generation animals where the effects were limited to the high-dose group. High dose F1 parental males had statistically significant lower body weights during several study segments, which led to a statistically significant reduction of the mean terminal body weight resulting in secondary weight changes of brain. High dose parental females had statistically significant lower body weights during the first weeks after weaning. This weight decrease during major phases of sexual maturation led to an apparent marginal delay of vaginal patency. This minor delay did, however, not result in any corroborative pathological findings nor did it adversly effect F1 female cyclicity, fertility and reproduction. Thus, an influence of the test substance on female sexual maturation is not assumed. Pathological examinations revealed no test-substance-related changes in organ weights, gross lesions, changes in differential ovarian follicle counts or microscopic findings, apart from an increase in kidney and liver weights in male and female animals in both generations which is presumably related to the treatment. There was no histopathologic lesion observed, that could explain the weight increase. It is regarded to be an adaptive change, most likely caused by an increase in metabolic activity in the two organs, which does not lead to histopathologic findings. It is not regarded to be an adverse effect. There were no indications from clinical examinations as well as gross and histopathology, that the administration of methyl methacrylate via the diet adversely affected the fertility or reproductive performance of the P or F1 parental animals up to and including a dose of 400 mg/kg bw/day. Estrous cycle data, mating behavior, conception, gestation, parturition, lactation and weaning as well as sperm parameters, sexual organ weights and gross and histopathological findings of these organs (including differential ovarian follicle counts in the F1 females) were comparable between the rats of all test groups and ranged within the historical control data of the test facility. 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, inclusive the high-dose group (400 mg/kg bw/day). Under the study conditions, the NOAEL for general, systemic toxicity was 50 mg/kg bw/day for the P and F1 parental rats, based on adverse effects on food consumption observed at the LOAEL of 150 mg/kg bw/day in the P parental females. The NOEL for fertility and reproductive performance for the P and F1 parental rats was 400 mg/kg bw/day, the highest dose tested. The NOEL for developmental toxicity, in the F1 and F2 progeny, of the test substance was 400 mg/kg bw/day, the highest dose tested (BASF, 2009). Similar results can be expected for zinc dimethacrylate.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
450 mg/kg bw/day
Study duration:
subacute
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Developmental toxicity studies 


In rats, the administration of 0.4% of the read across substance ZnO (corresponding to 200 mg Zn2+/kg bw/day) via diet for 21 days prior to mating until day 15 of gestation resulted in resorption of all foetuses. Administration of 0.4% dietary Zn2+ from day 0 to day 15, 16, 18 or day 20 of gestation, but not prior to mating, resulted in decreased live fetal body weights and in 4-29% fetal resorptions. When the concentration of Zn2+ in the feed was reduced to 0.2% (corresponding to 100 mg Zn2+/kg bw /day), starting 21 days prior to mating until day 15 of gestation no resorptions or effects on fetal body weights were observed. Treatment with dietary zinc did not result in external malformations, irrespective of dose level or treatment regimen. A dose-related significant increase in liver total zinc and liver zinc concentration and a significant decrease in the liver copper concentration was found in foetuses and mothers on all zinc regiments. No other information was given with respect to the health status of the mother animals. Although some of the animals were exposed from day 21 before mating up to study termination, no data were provided on possible consequences for female fertility (Schlicker, 1968). Under the study conditions, the read across substance NOAEL 100 mg/kg bw/day is considered for maternal and developmental toxicity. Similar results can be expected for zinc dimethacrylate.


 


 


Female CD-1 mice (25-30 animals/group) received daily doses of 0.3, 1.4, 6.5 and 30 mg of the read across substance ZnSO4/kg bw by gavage during days 6-15 of gestation. A control group was included. All animals were observed daily for appearance and behaviour with particular attention to food consumption and body weight. Body weights were recorded on day 0, 6, 11, 15 and 17 of gestation. The females were sacrificed at day 17. The urogenital tract of each animal was examined in detail. Between 21 and 23 females were pregnant at term in all groups. No clearly discernible effects on maternal survival, body weight gains, number of corpora lutea, implantations and resorptions were observed. The number of live litters, live and dead foetuses, the foetus weights and sex ratio were not affected by treatment. No difference in number or kind of abnormalities (in either soft or skeletal tissues) was found between exposed and control groups. It can be concluded that the administration of up to 30 mg/kg bw of unspecified zinc sulphate (≈ 12 mg or 6.8 mg Zn2+/kg bw, for anhydrate and heptahydrate, respectively) had no adverse effects on adult mice and their foetuses. Under the study conditions, the read across substance NOEL for maternal toxicity, developmental toxicity and teratogenicity was reported to be 30 mg/kg bw/day (EU, 2004). Similar results can be expected for zinc dimethacrylate.


 


Female Wistar rats (25-28 animals/group) received daily doses 0.4, 2.0, 9.1 and 42.5 mg of the read across substance ZnSO4/kg bw by gavage during days 6-15 of gestation. A control group was included. All animals were observed daily for appearance and behaviour with particular attention to food consumption and body weight. Body weights were recorded on day 0, 6, 11, 15 and 20 of gestation. The females were sacrificed at day 20. The urogenital tract of each animal was examined in detail. At term 25 females were pregnant in all groups. No clearly discernible effects on maternal survival, body weight gains, number of corpora lutea, implantations and resorptions were observed. The number of live litters, live and dead foetuses, the foetus weights and sex ratio were not affected by treatment. No difference in number or kind of abnormalities (in either soft or skeletal tissues) was found between exposed and control groups. It can be concluded that the administration of up to 42.5 mg/kg bw of unspecified zinc sulphate (≈ 17 mg or 9.6 mg Zn2+/kg bw, for anhydrate and heptahydrate, respectively) had no adverse effects on adult rats and their foetuses. Under the study conditions, the NOEL of unspecified read across substance zinc sulphate for maternal toxicity, developmental toxicity and teratogenicity was reported to be 42.5 mg/kg bw/day (≈ 17 mg or 9.6 mg Zn2+/kg bw, for anhydrate and heptahydrate, respectively) (EU, 2004). Similar results can be expected for zinc dimethacrylate.


 


Female hamsters (23-25 animals/group; outbred strain of golden hamster) received daily doses of 0.9, 4.1, 19 and 88 mg of the read across substance ZnSO4/kg bw by gavage during days 6-10 of gestation. Acontrol group was included. All animals were observed daily for appearance and behaviour with particular attention to food consumption and body weight. Body weights were recorded on day 0, 8, 10 and 14 of gestation. The females were sacrificed at day 14. The urogenital tract of each animal was examined in detail. Between 21 and 24 females were pregnant at term in all groups. No clearly discernible effects on maternal survival, body weight gains, number of corpora lutea, implantations and resorptions were observed. The number of live litters, live and dead foetuses, the foetus weights and sex ratio were not affected by treatment. No difference in number or kind of abnormalities (in either soft or skeletal tissues) was found between exposed and control groups. It can be concluded that the administration of up to 88 mg/kg bw of unspecified zinc sulphate (≈ 35.2 mg or 19.9 mg Zn2+/kg bw, for anhydrate and heptahydrate, respectively) had no adverse effects on adult hamsters and their foetuses. Under the study conditions, the NOEL of unspecified read across substance zinc sulphate for maternal toxicity, developmental toxicity and teratogenicity was reported to be 88 mg/kg bw/day (≈ 35.2 mg or 19.9 mg Zn2+/kg bw, for anhydrate and heptahydrate, respectively) (EU, 2004). Similar results can be expected for zinc dimethacrylate.


 


Female Dutch rabbits (14-19 animals/group) received daily doses of 0.6, 2.8, 13 and 60 mg of the read across substance ZnSO4/kg bw by gavage during days 6-18 of gestation. A control group was included. All animals were observed daily for appearance and behaviour with particular attention to food consumption and body weight. Body weights were recorded on day 0, 6, 12, 18 and 29 of gestation. The urogenital tract of each animal was examined in detail. The females were sacrificed at day 29. Between 10 and 12 females were pregnant at term in all groups. No clearly discernible effects on maternal survival, body weight gains, number of corpora lutea, implantations and resorptions were observed. The number of live litters, live and dead foetuses, the foetus weights and sex ratio were not affected by treatment. No difference in number or kind of abnormalities (in either soft or skeletal tissues) was found between exposed and control groups. It can be concluded that the administration of up to 60 mg/kg bw of unspecified zinc sulphate (≈ 24 mg or 13.6 mg Zn2+/kg bw, for anhydrate and heptahydrate, respectively) had no adverse effects on adult rabbits and their foetuses. Under the study conditions, the NOEL of unspecified read across substance zinc sulphate for maternal toxicity, developmental toxicity and teratogenicity was reported to be 60 mg/kg bw/day (≈ 24 mg or 13.6 mg Zn2+/kg bw, for anhydrate and heptahydrate, respectively) (EU, 2004). Similar results can be expected for zinc dimethacrylate.


In a developmental toxicity study on rabbits  according to OECD guideline 414 of the read across substance methyl methacrylate was tested for its prenatal developmental toxicity in Himalayan rabbits. The test substance was administered as an aqueous preparation to 25 inseminated female Himalayan rabbits by stomach tube at doses of 50; 150 and 450 mg/kg body weight/day on gestation days (GD) 6 through GD 28. The control group, consisting of 25 females, was dosed with the vehicle (1% Carboxymethylcellulose CB 30.000 in drinking water and a few drops Cremophor EL and one drop hydrochloric acid [1% CMC]) in parallel. A standard dose volume of 10 mL/kg body weight was used for each test group. At terminal sacrifice on GD 29, 24-25 females per group had implantation sites. No test substance-related adverse effects were observed at any of the treated dose levels. In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 450 mg/kg bw/d at nominal concentration corresponding to an actual concentration of 406 mg/kg bw/d, the highest dose tested. The no observed effect level (NOEL) for maternal toxicity is nominal 50 mg/kg bw/d (effective 41 mg/kg bw/d) based on effects on food consumption being a consequence of reduced appetite observed at the LOEL (Lowest Observed Effect Level) of 150 mg/kg bw/d (actual 132 mg/kg bw/d). The no observed adverse effect level (NOAEL) for prenatal developmental toxicity is nominal 450 mg/kg bw/d (actual 406 mg/kg bw/d). No adverse fetal findings of toxicological relevance were evident at any dose in this study (Anonymous, 2009).

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 reproductive and developmental 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.

Additional information