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The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Read-across: WoE, rat, OECD 421, GLP, NOAEL = 1000 mg/kg bw (Longobardi 2013)

Read-across: WoE, rat, feeding study, NOAEL = 1212.12 mg/kg bw/d (Pal and Pal 1987)

Link to relevant study records

Referenceopen allclose all

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
assessment report
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Four high dose females (nos. 92510061, 92510067, 92510071 and 92510075) were sacrificed for humane reasons on Day 21/22 of gestation. At despatch to necropsy these animals had pale appearance, decreased activity, piloerection and/or were cold to touch. At necropsy examination they were all pregnant.
At post mortem examination, all females showed pale colour of the kidneys and reduced size of the spleen and thymus. In addition some females also showed multiple depressed dark areas in the glandular region of the stomach with associated yellow mucoid contents in the ileum and jejunum and/or distended duodenum with gas contents and/or pale colour of the liver.
Such changes were considered to be treatment-related.
Treatment-related changes were noted in the kidneys, spleen, thymus and stomach. The observed renal injury involved the nephrons, unit of the kidney, morphologically characterised by degeneration of some glomeruli (sclerosis) and the majority of renal tubules, sometimes associated with subacute inflammatory reactions. The renal tubules showed lined cells, in some instances basophilic with presence of exfoliated cells and/or amorphous material (crystal-like) in their lumen. Focal tubular necrosis in the papilla, associated with pelvic dilatation (hydronephrosis) and hyperplasia of the pelvic lining epithelium were also reported in female no. 92510075.
Moreover, mild to marked lymphoid depletion or red pulp depletion and atrophy were noted in the spleen and in the thymus and ulceration or erosion in the glandular mucosa of the stomach was also reported in the four unscheduled dead females. These changes were considered stress-related.
All females mated. Only one control female (no. 92510005) was sacrificed 26 days post coitum and found not pregnant at necropsy.
The number of females with live pups on Day 4 postpartum was: 8 in the control group, 10 in each of the low and mid-dose groups, 6 in the high dose group. Total litter loss was observed in a single female from the control group (no. 92510019).
Male animals did not show any signs of toxicological significance during the whole study. No significant clinical signs were seen in the female animals killed at the end of the study.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Four females dosed at 1000 mg/kg/day were sacrificed for humane reasons on Day 21/22 of gestation due to the presence of a number of clinical signs (pale appearance, decreased activity, piloerection and/or cold to touch).
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No significant changes in body weight were observed in the treated animals when compared to controls. Reductions in body weight and body weight gain (these being also statistically significant) were observed in the treated males during the mating treatment period. These reductions, which were not dose-related, were not considered to be toxicologically significant. No significant changes were observed in the females.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No effects on food consumption were observed in the males. Slight and occasionally also significant at statistical analysis reductions were seen in the high dose females on Day 20 post coitum (-13%) and on Day 4 post partum (-19%).
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Four high dose females (nos. 92510061, 92510067, 92510071 and 92510075) were sacrificed for humane reasons on Day 21/22 of gestation. At despatch to necropsy these animals had pale appearance, decreased activity, piloerection and/or were cold to touch.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related changes were seen in selected organs/tissues evaluated in high dose males or females receiving the test substance, sacrificed at the end of treatment period, nor in the abnormalities detected at post mortem.
Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and to the integrity of the various cell types within the different stages; regular layering in the germinal epithelium was noted.
Histopathological findings: neoplastic:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
Oestrus cycle number before pairing was slightly reduced in the high dose females (2.2) when compared to controls (2.7).
The mean pre-coital interval and the number of copulation plugs were similar between control and treated groups.
All females mated. However, one female of the control group (no. 92510005) was found not pregnant.
A copulatory index of 100% was observed for both sexes from all groups. The fertility index in the treated groups (100%) was higher than in controls animals (90%). The number of females, with live pups on Day 4postpartum was: 8 in the control group, 10 in each of the low and mid-dose groups and 6 in the high dose group.
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
No treatment-related differences were noted in implantation number, pre-birth loss data and gestation length between control and treated groups.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: fertility and reproduction paramters
Dose descriptor:
NOEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
Remarks on result:
other: systemic toxicity
Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality:
not examined
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined
Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs that could be related to treatment were reported at the examination of pups during the lactation period.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
No significant differences in pup loss were observed among the surviving treated dams and the controls.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Four females from the high dose group were sacrificed for humane reasons at the end of gestation period.
No significant differences in total litter size, live litter size, mean pup weights and pup loss were observed among the surviving treated dams and the controls.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No relevant differences between control and treated groups were noted at necropsy in the decedent pups.
No significant abnormalities were recorded in the pups sacrificed on Day 4 post partum.
Histopathological findings:
not examined
Other effects:
no effects observed
Description (incidence and severity):
Sex ratios:
No treatment-related effects were seen on sex ratios.
Males percentage at birth appeared to be slightly reduced in the high dose when compared to other groups, but this reduction was considered to be not toxicologically relevant.
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: fertility and reproduction parameters
Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality / viability:
not examined
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Other effects:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Reproductive effects observed:
no
Conclusions:
Treatment-related effects indicating systemic toxicity were observed in some pregnant females dosed at 1000 mg/kg/day.
No changes were observed in males at any dose and in females dosed at 100 and 300 mg/kg/day.
No adverse effects on sexual function and fertility or in developmental parameters and lactation were observed at any of the dose levels investigated.
The dose level of 300 mg/kg/day is considered to be the NOEL for systemic toxicity, while 1000 mg/kg/day is the NOAEL for fertility and reproduction parameters.
Executive summary:

A study according to OECD Guideline 422 and GLP was performed to investigate the repeated dose toxicity of the test item when administered orally to male and female Sprague Dawley rats. Groups of 10 males and 10 females received the test item, by gavage at dosages of 100, 300 and 1000 mg/kg/day. A similarly constituted group of animals received the vehicle alone (purified water) and acted as a control. All doses were administered at a constant volume of 10 mL/kg body weight.

Males were treated for 2 weeks prior to pairing and during pairing of all females until the day before necropsy, for a total of 4 consecutive weeks. Females were treated for 2 weeks prior to pairing, during pairing and throughout the gestation and lactation periods until Day 3 post partum.

The following investigations were performed on all groups: body weight, clinical signs, food consumption, oestrous cycle, mating performance, litter observation, macroscopic observations, organ weights and histopathological examination of abnormalities. Histopathological examination of testes, epididymides and ovaries was performed only on control and high dose groups.

Mortality and fate of females

Four high dose females were sacrificed for humane reasons on Day 21/22 of gestation. At despatch to necropsy these animals had pale appearance, decreased activity, piloerection and/or were cold to touch. At necropsy examination they were all pregnant. Pale colour of the kidneys, reduced size of the spleen and thymus, multiple depressed dark areas in the glandular region of the stomach with associated yellow mucoid contents in the ileum and jejunum and/or distended duodenum with gas contents and/or pale colour of the liver were also observed.

Histopathological examination revealed treatment-related changes in the kidneys (nephrons, unit of the kidney, morphologically characterised by degeneration of some glomeruli and the majority of renal tubules, sometimes associated with subacute inflammatory reactions), spleen and thymus (lymphoid depletion or red pulp depletion and atrophy) and stomach (ulceration or erosion in the glandular mucosa). Only one control female was found not pregnant at necropsy.

The number of females with live pups on Day 4 post partum was: 8 in the control group, 10 in each of the low and mid-dose groups, 6 in the high dose group.

Clinical signs

No signs of toxicological significance were observed in animals from the control, low and mid-dose groups and in the surviving female animals from the high dose group.

Body weight and body weight gain

No changes of toxicological significance were observed in body weight and body weight gain in treated males and females when compared to controls.

Food consumption

No effects on food consumption were observed in the males and in low and mid-dose females. Reduced food consumption was seen in the high dose females during the post coitum period.

Oestrus cycle, mating performance and reproductive parameters

Mean oestrus cycle was slightly reduced in the females dosed at 1000 mg/kg/day (approximately 2 in the 15 day pre-mating period) when compared to controls (approximately 3).

No significant differences between groups were observed in pre-coital interval and copulation plugs, as well as in the reproductive parameters (copulatory index and fertility index).

Implantation, pre-birth loss data and gestation length

No treatment-related differences were noted in implantation number, pre-birth loss data and gestation length between control and treated groups.

Litter data and sex ratios

Litter data and sex ratios were unaffected by treatment.

Pre-weaning clinical signs of pups

Clinical signs were comparable between treated and control groups.

Necropsy findings in decedent pups and in pups sacrificed on Day 4 post partum No treatment-related effects were seen.

Organ weights

No toxicologically relevant changes were observed in organ weights.

Macroscopic observations

No relevant changes were detected at post mortem examination in treated animals killed at end of treatment period, when compared with controls.

Microscopic observations

No treatment-related changes were seen in selected organs/tissues evaluated in high dose males or females receiving the test item, sacrificed at the end of treatment period, or in the abnormalities detected at post mortem.

Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and to the integrity of the various cell types within the different stages; regular layering in the germinal epithelium was noted.

The source substance contains the major organic moieties of the target substance. Therefore, the results are also applicable to the target substance.

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
assessment report
Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
Weight of the placenta was not significantly different between the experimental group and their respective control group.
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined
Description (incidence and severity):
Regarding the test without ZnSO4 gavage prior to mating, 12 out of 15 animals of the control group and the treated group were mated, of which 12 and 5 females, respectively, conceived during the study.
Regarding the test with ZnSO4 gavage prior to mating, 11 out of 18 animals of the control group and 15 out of 18 animals of the treated group were mated, of which 10 and 14 females, respectively, conceived during the study.
When zinc was first added to the food after coitus, the "implanation sites per pregnant female was lower in the zinc treated group (5.0) than in the control rats (7.0), however the difference was not significant (t-test). Implantation sites per mated female were 7.0 in the control group and 2.1 in the zinc fed experimental group."
When zinc treatment started 21 to 26 days prior to mating there was no significant difference in incidentes of conception between the treated group and the control group. Also, there was no significant difference between the two groups regarding implantation sites expressed per mated or pregnant female. Also, the mean fetal and placental weights were similar.
Dose descriptor:
NOAEL
Effect level:
24 242.4 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: see section "Decription of reproductive performance" and "details on results (P0)"
Remarks on result:
other: dosage of zinc for 21-26 day prior to mating
Dose descriptor:
NOAEL
Effect level:
24 242.4 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: see section "Decription of reproductive performance" and "details on results (P0)"
Remarks on result:
other: no dosage of zinc prior to mating
Dose descriptor:
NOAEL
Effect level:
1 212.12 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: see section "Decription of reproductive performance" and "details on results (P0)"
Remarks on result:
other: converted from ppm using the conversion factor for female rats of 0.05 Lehman, A.J. (1954)
Critical effects observed:
no
Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality:
not examined
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined
Remarks on result:
not measured/tested
Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality / viability:
not examined
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Other effects:
no effects observed
Description (incidence and severity):
No stillbirth or malformation of the fetuses for either of the tests was detected.
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Dose descriptor:
NOEL
Generation:
F1
Effect level:
24 242.4 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: "Other effect" as well as the descrption of the other effects (see above)
Dose descriptor:
NOEL
Generation:
F1
Effect level:
1 212.12 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: see section "Description of reproductive performance" and "details on results"
Remarks on result:
other: converted from ppm using the conversion factor for female rats of 0.05 Lehman, A.J. (1954)
Critical effects observed:
no
Remarks on result:
not measured/tested
Reproductive effects observed:
no

The target substance contains 16.5 % Zn ions. Therefore, the hazard value for Zn ion is converted to the target substance considering a Zn content of 16.5 %.

P0

conc. level (f) (Zn) = 4000 ppm

conc. level (f) (target substance; Zn/0.165) = 24242.4 ppm

conc. level (converted from ppm) (Zn) = 200 mg/kg bw/day

conc. level (converted from ppm) (target substance; Zn/0.165) = 1212.12 mg/kg bw/day

F1

NOEC (m/f) (Zn) = 4000 ppm

NOEC (m/f) (target substance; Zn/0.165) = 24242.4 ppm

NOEC (f) (Zn) = 200 mg/kg bw/day

NOEC (f) (target substance; Zn/0.165) = 1212.12 mg/kg bw/day

Conclusions:
For the female parent, the dose of 4,000 ppm zinc showed either no effects (in case of dosage start prior to mating) or a slight effect on reproduction performance (in case of dosage started after coitus).
For the F1 generation (examination of fetuses) no effect of the dosage of the female parent animal was observed.
The dosage of 4,000 ppm zinc corresponds to a target substance concentration of 24,242.4 ppm and 1,212.12 mg/kg bw/day.
Executive summary:

Anhydrous ZnSO4 was used to test the influence of zinc feeding on conception of rats. Two tests were conducted involving the dosing of female, virgin rats with zinc either after coitus or 21 to 26 days prior to mating. The dosage was continued during the pregnancy until the female rats were sacrificed on day 18 of gestation. Weight of the placenta was not significantly different between the experimental group and their respective control group. Regarding the test without ZnSO4 gavage prior to mating, 12 out of 15 animals of the control group and the treated group were mated, of which 12 and 5 females, respectively, conceived during the study.

In the test with ZnSO4 gavage prior to mating, 11 out of 18 animals of the control group and 15 out of 18 animals of the treated group were mated, of which 10 and 14 females, respectively, conceived during the study. When zinc was first added to the food after coitus, the "implanation sites per pregnant female was lower in the zinc treated group (5.0) than in the control rats (7.0), however the difference was not significant (t-test). Implantation sites per mated female were 7.0 in the control group and 2.1 in the zinc fed experimental group." When zinc treatment started 21 to 26 days prior to mating, there was no significant difference in incidents of conception between the treated group and the control group. Also, there was no significant difference between the two groups regarding implantation sites expressed per mated or pregnant female. Also, the mean fetal and placental weights were similar. No stillbirth or malformation of the fetuses for either of the tests was detected.  

For the female parent, the dose of 4,000 ppm zinc showed either no effects (in case of dosage start prior to mating) or a slight effect on reproduction performance (in case of dosage started after coitus). For the F1 generation (examination of fetuses) no effect of the dosage of the female parent animal was observed.

The NOAEL of 4,000 ppm zinc corresponds to a target substance concentration of 24,242.4 ppm and 1,212.12 mg/kg bw/day.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 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

OECD 421 (Longobardi 2013)

A study according to OECD Guideline 422 and GLP was performed to investigate the repeated dose toxicity of the test item when administered orally to male and female Sprague Dawley rats. Groups of 10 males and 10 females received the test item, by gavage at dosages of 100, 300 and 1000 mg/kg/day. A similarly constituted group of animals received the vehicle alone (purified water) and acted as a control. All doses were administered at a constant volume of 10 mL/kg body weight.

Males were treated for 2 weeks prior to pairing and during pairing of all females until the day before necropsy, for a total of 4 consecutive weeks. Females were treated for 2 weeks prior to pairing, during pairing and throughout the gestation and lactation periods until Day 3 post partum.

The following investigations were performed on all groups: body weight, clinical signs, food consumption, oestrous cycle, mating performance, litter observation, macroscopic observations, organ weights and histopathological examination of abnormalities. Histopathological examination of testes, epididymides and ovaries was performed only on control and high dose groups.

Mortality and fate of females

Four high dose females were sacrificed for humane reasons on Day 21/22 of gestation. At despatch to necropsy these animals had pale appearance, decreased activity, piloerection and/or were cold to touch. At necropsy examination they were all pregnant. Pale colour of the kidneys, reduced size of the spleen and thymus, multiple depressed dark areas in the glandular region of the stomach with associated yellow mucoid contents in the ileum and jejunum and/or distended duodenum with gas contents and/or pale colour of the liver were also observed.

Histopathological examination revealed treatment-related changes in the kidneys (nephrons, unit of the kidney, morphologically characterised by degeneration of some glomeruli and the majority of renal tubules, sometimes associated with subacute inflammatory reactions), spleen and thymus (lymphoid depletion or red pulp depletion and atrophy) and stomach (ulceration or erosion in the glandular mucosa). Only one control female was found not pregnant at necropsy.

The number of females with live pups on Day 4 post partum was: 8 in the control group, 10 in each of the low and mid-dose groups, 6 in the high dose group.

Clinical signs

No signs of toxicological significance were observed in animals from the control, low and mid-dose groups and in the surviving female animals from the high dose group.

Body weight and body weight gain

No changes of toxicological significance were observed in body weight and body weight gain in treated males and females when compared to controls.

Food consumption

No effects on food consumption were observed in the males and in low and mid-dose females. Reduced food consumption was seen in the high dose females during the post coitum period.

Oestrus cycle, mating performance and reproductive parameters

Mean oestrus cycle was slightly reduced in the females dosed at 1000 mg/kg/day (approximately 2 in the 15 day pre-mating period) when compared to controls (approximately 3).

No significant differences between groups were observed in pre-coital interval and copulation plugs, as well as in the reproductive parameters (copulatory index and fertility index).

Implantation, pre-birth loss data and gestation length

No treatment-related differences were noted in implantation number, pre-birth loss data and gestation length between control and treated groups.

Litter data and sex ratios

Litter data and sex ratios were unaffected by treatment.

Pre-weaning clinical signs of pups

Clinical signs were comparable between treated and control groups.

Necropsy findings in decedent pups and in pups sacrificed on Day 4 post partum No treatment-related effects were seen.

Organ weights

No toxicologically relevant changes were observed in organ weights.

Macroscopic observations

No relevant changes were detected at post mortem examination in treated animals killed at end of treatment period, when compared with controls.

Microscopic observations

No treatment-related changes were seen in selected organs/tissues evaluated in high dose males or females receiving the test item, sacrificed at the end of treatment period, or in the abnormalities detected at post mortem.

Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and to the integrity of the various cell types within the different stages; regular layering in the germinal epithelium was noted.

The source substance contains the major organic moieties of the target substance. Therefore, the results are also applicable to the target substance.

feeding study in rats (Pal and Pal 1987)

Anhydrous ZnSO4 was used to test the influence of zinc feeding on conception of rats. Two tests were conducted involving the dosing of female, virgin rats with zinc either after coitus or 21 to 26 days prior to mating. The dosage was continued during the pregnancy until the female rats were sacrificed on day 18 of gestation. Weight of the placenta was not significantly different between the experimental group and their respective control group. Regarding the test without ZnSO4 gavage prior to mating, 12 out of 15 animals of the control group and the treated group were mated, of which 12 and 5 females, respectively, conceived during the study.

In the test with ZnSO4 gavage prior to mating, 11 out of 18 animals of the control group and 15 out of 18 animals of the treated group were mated, of which 10 and 14 females, respectively, conceived during the study. When zinc was first added to the food after coitus, the "implanation sites per pregnant female was lower in the zinc treated group (5.0) than in the control rats (7.0), however the difference was not significant (t-test). Implantation sites per mated female were 7.0 in the control group and 2.1 in the zinc fed experimental group." When zinc treatment started 21 to 26 days prior to mating, there was no significant difference in incidents of conception between the treated group and the control group. Also, there was no significant difference between the two groups regarding implantation sites expressed per mated or pregnant female. Also, the mean fetal and placental weights were similar. No stillbirth or malformation of the fetuses for either of the tests was detected.  

For the female parent, the dose of 4,000 ppm zinc showed either no effects (in case of dosage start prior to mating) or a slight effect on reproduction performance (in case of dosage started after coitus). For the F1 generation (examination of fetuses) no effect of the dosage of the female parent animal was observed.

The NOAEL of 4,000 ppm zinc corresponds to a target substance concentration of 24,242.4 ppm and 1,212.12 mg/kg bw/day.

Effects on developmental toxicity

Description of key information

Read-across: WoE, rat, OECD 421, GLP, NOAEL = 1000 mg/kg bw (Longobardi 2013)

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reason / purpose for cross-reference:
read-across source
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Basis for effect level:
clinical signs
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: absence of adverse effects on reproduction
Abnormalities:
no effects observed
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: absence of adverse effects on fertlitiy
Abnormalities:
no effects observed
Developmental effects observed:
not specified
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

OECD 421 (Longobardi 2013)

A study according to OECD Guideline 422 and GLP was performed to investigate the repeated dose toxicity of the test item when administered orally to male and female Sprague Dawley rats. Groups of 10 males and 10 females received the test item, by gavage at dosages of 100, 300 and 1000 mg/kg/day. A similarly constituted group of animals received the vehicle alone (purified water) and acted as a control. All doses were administered at a constant volume of 10 mL/kg body weight.

Males were treated for 2 weeks prior to pairing and during pairing of all females until the day before necropsy, for a total of 4 consecutive weeks. Females were treated for 2 weeks prior to pairing, during pairing and throughout the gestation and lactation periods until Day 3 post partum.

The following investigations were performed on all groups: body weight, clinical signs, food consumption, oestrous cycle, mating performance, litter observation, macroscopic observations, organ weights and histopathological examination of abnormalities. Histopathological examination of testes, epididymides and ovaries was performed only on control and high dose groups.

Mortality and fate of females

Four high dose females were sacrificed for humane reasons on Day 21/22 of gestation. At despatch to necropsy these animals had pale appearance, decreased activity, piloerection and/or were cold to touch. At necropsy examination they were all pregnant. Pale colour of the kidneys, reduced size of the spleen and thymus, multiple depressed dark areas in the glandular region of the stomach with associated yellow mucoid contents in the ileum and jejunum and/or distended duodenum with gas contents and/or pale colour of the liver were also observed.

Histopathological examination revealed treatment-related changes in the kidneys (nephrons, unit of the kidney, morphologically characterised by degeneration of some glomeruli and the majority of renal tubules, sometimes associated with subacute inflammatory reactions), spleen and thymus (lymphoid depletion or red pulp depletion and atrophy) and stomach (ulceration or erosion in the glandular mucosa). Only one control female was found not pregnant at necropsy.

The number of females with live pups on Day 4 post partum was: 8 in the control group, 10 in each of the low and mid-dose groups, 6 in the high dose group.

Clinical signs

No signs of toxicological significance were observed in animals from the control, low and mid-dose groups and in the surviving female animals from the high dose group.

Body weight and body weight gain

No changes of toxicological significance were observed in body weight and body weight gain in treated males and females when compared to controls.

Food consumption

No effects on food consumption were observed in the males and in low and mid-dose females. Reduced food consumption was seen in the high dose females during the post coitum period.

Oestrus cycle, mating performance and reproductive parameters

Mean oestrus cycle was slightly reduced in the females dosed at 1000 mg/kg/day (approximately 2 in the 15 day pre-mating period) when compared to controls (approximately 3).

No significant differences between groups were observed in pre-coital interval and copulation plugs, as well as in the reproductive parameters (copulatory index and fertility index).

Implantation, pre-birth loss data and gestation length

No treatment-related differences were noted in implantation number, pre-birth loss data and gestation length between control and treated groups.

Litter data and sex ratios

Litter data and sex ratios were unaffected by treatment.

Pre-weaning clinical signs of pups

Clinical signs were comparable between treated and control groups.

Necropsy findings in decedent pups and in pups sacrificed on Day 4 post partum No treatment-related effects were seen.

Organ weights

No toxicologically relevant changes were observed in organ weights.

Macroscopic observations

No relevant changes were detected at post mortem examination in treated animals killed at end of treatment period, when compared with controls.

Microscopic observations

No treatment-related changes were seen in selected organs/tissues evaluated in high dose males or females receiving the test item, sacrificed at the end of treatment period, or in the abnormalities detected at post mortem.

Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and to the integrity of the various cell types within the different stages; regular layering in the germinal epithelium was noted.

The source substance contains the major organic moieties of the target substance. Therefore, the results are also applicable to the target substance.

Justification for classification or non-classification

Due to the findings in the available studies, the test item needs not to be classified according to Regulation (EC) No 1272/2008.

Additional information