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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

A two generation reproductive toxicity study was conducted in rats. This study was considered relevant in a read-across approach.

Under the test conditions, administration of test material (ZnCl2) to adult male and female rats throughout maturation, mating, gestation and early lactation resulted in significant effects (general toxicity) on adults and offspring at 30 and 15 mg/kg/d. Although effects were seen at 7.5 mg/kg/d, these were considered to be toxicologically non significant and is therefore considered to be the "No Observed Adverse Effect Level" (NOAEL). Considering possible reproductive effect, a NOAEL is fixed about 15 mg ZnCl2/kg bw/d. This could be considered as equivalent to 50.15 mg ZnGlc/kg bw/d (for Zinc Gluconate). The possible adverse effects on reproductive performance observed are seen only at dose level causing marked systemic toxicity. Consequently they are not considered relevant for classification purposes.

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key 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:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
The read-across hypothesis is instantaneous dissociation of zinc gluconate into zinc cations (Zn2+) and gluconate anions in aqueous media (environmental compartments and body fluids). Thus, for endpoints where no zinc gluconate data exist, the assessment of the (eco-) toxicological effects can be based on available data of dissociable zinc compounds and gluconate derivatives.
The assessment of human and environmental toxicology is mainly based on the zinc ion, which is considered to be toxicologically more relevant than the gluconate ion (see complete justification report attached).
All of the zinc based read-across partners have in common that they dissociate into zinc and the respective counter ion in aqueous media as described above. The same is true for all of the gluconate based read-across partners, as they dissociate into the gluconate anion and the respective counter ion in aqueous media.
The gluconate derivatives are tentatively ignored for the purpose of this read-across due to the role of gluconates as common additives or nutritional supplements in food and due to the fact that gluconate/gluconic acid is a ubiquitous metabolic product/substrate in mammals with proven low toxicity. As a normal metabolic product of glucose metabolism, 25–30 g are being produced daily in humans. It can safely be concluded that systemic toxicity need not be expected to arise from gluconates/gluconic acid when assessing the potential effects of zinc gluconate. Nevertheless, the lack of toxicological relevance of gluconates is addressed in sufficient detail in the final read-across report targeted at supporting this dossier.
When resorting to dissociable zinc read-across partners, there is a risk of confounding effects that might actually be attributable to the counter ion. The dissociation products of the aforementioned zinc compounds are glycerol, sulphate and chloride ions. The counter ions of the gluconates are sodium, calcium and manganese. All these ions play an important role in the physiology of man and other species. Considering this information, the respective counter ions (calcium, sodium, manganese) are unlikely to contribute to any confounding effects hence do need to be further addressed in this report.

Taking into account the global approach and the detailed explanation (including data matrix and analysis for each endpoint) provided in the report attached, the present read-across is considered relevant.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The most consistent finding was aggression/hyperactivity throughout the study in both males and females. Other less frequently seen observations noted are hair loss behind the ears in males, and vaginal discharges in low and high dose females.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
The males experienced 0, 8, 20, and 12% mortality in control, low-, mid- and high-dose groups, respectively.
The mortality among the females was 12, 24, 28, and 24% for the control, low-, mid- and high-dose groups, respectively.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The ZnCl2-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.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
ZnCl2-treatment to F0 and F1 males and females caused no significant effects on their feed efficiencies when compared to their control groups.
Food efficiency:
no effects observed
Description (incidence and severity):
ZnCl2-treatment to F0 and F1 males and females caused no significant effects on their feed efficiencies when compared to their control groups.
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
None of the hemogram or leukogram values of both Fo and F1 males and females among the ZnCl2-treated groups were different from those of the control groups. However, there was a trend toward decreased values of Packed Cell Volume (PCV).
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
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 Amyl, ALK, and GLu.
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
The most consistent finding was aggression/hyperactivity throughout the study in both males and females.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
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 ZnCl2-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 ZnCl2-treated groups, the majority of them probably being related to toxicity, but histomorphologic confirmation of this was not noted. The histopathology observed among the ZnCl2-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.
Histopathological findings: neoplastic:
no effects observed
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Postpartum dam body weight: The F0 and F1 post-partum dam weights in all dose groups were significantly different from their control groups.
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
In F0 rats, ZnCl2 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. However, no significant difference was seen in the weaning index and sex ratios F1 pups (Table 5). The body weight of F1 pups at day 21 in the high-dose group was significantly lower compared to their control.
Key result
Dose descriptor:
NOAEL
Effect level:
15 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Overall effects for fertility and development toxicity. It is about 15 mg ZnCl2/kg bw/d, this corresponds to 7.2 mg Zinc/kg bw/day.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The most consistent finding was aggression/hyperactivity throughout the study in both males and females. Other less frequently seen observations noted are hair loss behind the ears in males, and vaginal discharges in low and high dose females.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
The males experienced 0, 12, 8, and 4% mortality in the control, low-, mid- and high-dose groups, respectively.
The mortality among the females was 0, 8, 12, and 20% in the control, low-, mid- and high-dose groups, respectively.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
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 17. 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.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
ZnCl2-treatment to F0 and F1 males and females caused no significant effects on their feed efficiencies when compared to their control groups.
Food efficiency:
no effects observed
Description (incidence and severity):
ZnCl2-treatment to F0 and F1 males and females caused no significant effects on their feed efficiencies when compared to their control groups.
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
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 Amyl, ALK, and GLu.
Urinalysis findings:
not examined
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In F1 males, the unadjusted weights of the brain, spleen, and prostate in all ZnCl2-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 ZnCl2-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 pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Gross findings related to ZnCl2-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 ZnCl2-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 ZnCl2-treated females generally paralleled those observed in their male counterparts.
Histopathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
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 30.00 mg/kg/day ZnCl2-treated groups. These results indicated that ZnCl2 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 ZnCl2-treated groups, the majority of them probably being related to toxicity, but histomorphologic confirmation of this was not noted. The histopathology observed among the ZnCl2-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 effects:
effects observed, treatment-related
Description (incidence and severity):
No significant difference was seen in the weaning index and sex ratios in F1 pups. In F1 generation rats, ZnCl2 treatment resulted in a significant reduction on fertility, viability (Day 0) and litter size in the high-dose group compared to control. However, ZnCl2 treatment showed no effect on viability index, weaning index and sex ratios of F2 pups.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
The most consistent finding was aggression/hyperactivity throughout the study in both males and females.
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
15 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Overall effects for fertility and development toxicity. It is about 15 mg ZnCl2/kg bw/d, this corresponds to 7.2 mg Zinc/kg bw/day.
Key result
Reproductive effects observed:
no

The possible adverse effects on reproductive performance observed are seen only at dose level causing marked systemic toxicity. Consequently they are not considered relevant for considering reproductive toxicity of the substance.

Conclusions:
Under the test conditions, administration of test material (ZnCl2) to adult male and female rats throughout maturation, mating, gestation and early lactation resulted in significant effects (general toxicity) on adults and offspring at 30 and 15 mg/kg/d. Although effects were seen at 7.5 mg/kg/d, these were considered to be toxicologically non significant and is therefore considered to be the "No Observed Adverse Effect Level" (NOAEL). Considering possible reproductive effect, a NOAEL is fixed about 15 mg ZnCl2/kg bw/d. This could be considered as equivalent to 50.15 mg ZnGlc/kg bw/d (for Zinc Gluconate).
The possible adverse effects on reproductive performance observed are seen only at dose level causing marked systemic toxicity. Consequently they are not considered relevant for classification purposes.
Executive summary:

A study was conducted to evaluate the reproductive toxicity potential of test material in rats for two generations.

Male and female rats were administered test material at the doses of 7.50, 15.00 and 30.00 mg/kg/d over two successive generations. Control group animals received deionised water. 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. Significant reduction in body weights of F0 and F1 parental males and postpartum dam weights female rats. Exposure of test material to F0 and F1 generation parental animals resulted in non-significant change in clinical pathology parameters (except the ALK level). Reduction of brain, liver, kidney, spleen and seminal vesicles weights of males and in the spleen and uterus of females was observed in F0 and F1 rats. Gross lesions were observed in gastro-intestinal (GI) tract, lymphoreticular/ hematopoietic and reproductive tract in parental rats in both generations. Reduced body fat was also recorded in F1 parental rats.

The possible adverse effects on reproductive performance observed are seen only at dose level causing marked systemic toxicity.Consequently they are not considered relevant for classification purposes.

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50.15 mg/kg bw/day
Study duration:
chronic
Species:
rat
Additional information

NOAEL reported for overall effects for fertility and development toxicity.

Effects on developmental toxicity

Description of key information

The two generation reproductive toxicity study conducted in rats (Khan et al.) described above could be considered for assessing the effects of zinc gluconate on developmental toxicity in a read-across approach.

Mode of Action Analysis / Human Relevance Framework

The two generation reproductive toxicity study was conducted in rats (Sprague-Dawley) which is a common specie used in such experimtental study and recommanded in OECD guideline. The study is well documented, meets generally accepted scientific principles and thus is considered relevant for human extrapolation.

Furthermore, human study (Mahomed et al.) confirms the conclusion of the experimental study :

A double blind trial (prospective study) was conducted on pregnant women to determine the effects zinc supplementation during pregnancy on maternal and fetal outcome.

494 women booking before 20 weeks of gestation in a hospital were prescribed either 66 mg zinc sulphate (equivalent to 20 mg elemental zinc) capsules or placebo for once daily use, starting from day of booking till delivery. Various adverse outcomes were tested, including maternal bleeding, hypertension, complications of labour and delivery, gestational age, Apgar scores, and neonatal abnormalities. The main outcome measure was birth weight.

There were no differences between the mothers and neonates of the zinc supplemented and placebo group. Under the test conditions, zinc supplementation during pregnancy did not affect maternal or fetal outcome. This study (Mahomed et al.) is juged relevant to be used in a read-across purpose.

Justification for classification or non-classification

The possible adverse effects on reproductive performance observed in the experimental two generation reproductive toxicity study (Khan et al.) are seen only at dose level causing marked systemic toxicity. Consequently they are not considered relevant for classification purposes. Furthermore, direct observation (double blind prospective study) on pregnant women showed that zinc supplementation during pregnancy did not affect maternal or fetal outcome.

Zinc gluconate is thus not classified.

Additional information