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Diss Factsheets

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1997
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Increment of Immune Responses in Mice Perinatal Stages After Zinc Supplementation
Author:
Lastra, M. D, Pastelin, R., Herrera, M. A., Orihuela, V. D., Aguilar, A. E.
Year:
1997
Bibliographic source:
Archives of Medical Research, Vol 28, 99 67-72, 1997

Materials and methods

Principles of method if other than guideline:
Mice received zinc acetate in drinking water at concentrations of 500 and 1000 mg/I during the periods of gestation, lactation and postweaning. The general appearance, growth curves and hematocrit were examined in treated animals.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
Zinc di(acetate)
EC Number:
209-170-2
EC Name:
Zinc di(acetate)
Cas Number:
557-34-6
IUPAC Name:
zinc diacetate
Specific details on test material used for the study:
supplier: Mallinckrodt, cat. no. 8740

Test animals

Species:
mouse
Strain:
Balb/c
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Laboratory of Immunology at the School of Chemistry of the Natioal University of Mexico
- Age at study initiation: (P) 6 wks
- Weight at study initiation: (P) Females: approximately 22 g;
- Fasting period before study: not specified
- Housing: Plastic cages equipped with steel covers and sterile sawdust on the floor were used.
- Diet: ad libitum (Blue-Bonnet, 2000 Biomex)
- Water (e.g. ad libitum): not specified
- Acclimation period: not specified

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on mating procedure:
After mating, the males were separated from the females. The pregnant females were housed individually.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
One group of female, pregnant mice were exposed to Zn Acetate during gestation and lactancy. Another group of female, pregnant mice were exposed to Zn Acetate during gestation, lactancy and post-weaning.
Frequency of treatment:
daily with drinking water
Doses / concentrationsopen allclose all
Dose / conc.:
500 ppm
Remarks:
Zinc
Dose / conc.:
1 000 ppm
Remarks:
Zinc
No. of animals per sex per dose:
30 animals per group
Control animals:
yes

Examinations

Litter observations:
STANDARDISATION OF LITTERS
- Litter: 6 to 8 pups/litter; amount of pups adjusted to 6 per litter.

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number of pups, stillbirths, live births, presence of gross anomalies, physical abnormalities, growth curves.
Statistics:
ANOVA with p value < 0.05 was considered significant.
Reproductive indices:
6 to 8 pups/litter

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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 examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
"The hematocrit values were slightly reduced in the groups that received 1000 mg/l both after 21 and 42 days."
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
"The concentration of Zn remained constant over the first 21 days,increasing significantly during the post-weaning period. An increasing tendency was observed in the treated mice at 42 days of age, the period in which thymic involution is observed in the controls."
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
"A similar reproductive index was observed between the treated animals and the control group."
"The excess of zinc did not seem to alter the viability, the offspring number, or neonatal mortality."

Effect levels (P0)

open allclose all
Dose descriptor:
conc. level: see 'Remarks'
Remarks:
test concentration
Effect level:
500 mg/L drinking water
Based on:
element
Sex:
female
Basis for effect level:
haematology
clinical biochemistry
reproductive performance
other: immunological findings
Dose descriptor:
conc. level: see 'Remarks'
Remarks:
test concentration
Effect level:
1 000 mg/L drinking water
Based on:
element
Sex:
female
Basis for effect level:
haematology
clinical biochemistry
reproductive performance
other: immunological findings
Dose descriptor:
conc. level: see 'Remarks'
Remarks:
test concentration
Effect level:
28.57 mg/kg bw/day
Based on:
element
Sex:
female
Basis for effect level:
haematology
clinical biochemistry
reproductive performance
other: immunological findings
Remarks on result:
other: converted to mg/kg bw/day (please refer to 'Any other information on results incl. tables'
Dose descriptor:
conc. level: see 'Remarks'
Remarks:
test concentration
Effect level:
57 mg/kg bw/day
Based on:
element
Sex:
female
Basis for effect level:
haematology
clinical biochemistry
reproductive performance
other: immunological findings
Remarks on result:
other: converted to mg/kg bw/day (please refer to 'Any other information on results incl. tables'

Results: P1 (second parental generation)

Effect levels (P1)

Remarks on result:
not measured/tested

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Description (incidence and severity):
"The excess of zinc did not seem to alter the viability, the offspring number, or neonatal mortality."
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

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
effects observed, treatment-related
Description (incidence and severity):
"Indirect plaque forming cells (IgG) did not show any significant response to Zn treatment."
"A significant increase in lymphocytes proliferation from mice treated with doses of 500 mg/l and 1000 mg/l with respect to control mice at the end of lactancy (21 days) (p<0.05).A significant reduction in the proliferation was also observed in mice 42 days old, treated with 500 and 1000 mg/l doses."

Effect levels (F1)

open allclose all
Dose descriptor:
conc. level: see 'Remarks'
Remarks:
test concentration
Generation:
F1
Effect level:
500 mg/L drinking water
Based on:
element
Sex:
male/female
Basis for effect level:
viability
mortality
developmental immunotoxicity
Dose descriptor:
conc. level: see 'Remarks'
Remarks:
test concentration
Generation:
F1
Effect level:
1 000 mg/L drinking water
Based on:
element
Sex:
male/female
Basis for effect level:
viability
mortality
developmental immunotoxicity
Dose descriptor:
conc. level: see 'Remarks'
Remarks:
test concentration
Generation:
F1
Effect level:
28.57 mg/kg bw/day
Based on:
element
Sex:
male/female
Basis for effect level:
viability
mortality
developmental immunotoxicity
Remarks on result:
other: converted to mg/kg bw/day (please refer to 'Any other information on results incl. tables')
Dose descriptor:
conc. level: see 'Remarks'
Remarks:
test concentration
Generation:
F1
Effect level:
57 mg/kg bw/day
Based on:
element
Sex:
male/female
Basis for effect level:
viability
mortality
developmental immunotoxicity
Remarks on result:
other: converted to mg/kg bw/day (Please refer to 'Any other information on results incl. tables')

Target system / organ toxicity (F1)

Critical effects observed:
no

Results: F2 generation

Effect levels (F2)

Remarks on result:
not measured/tested

Overall reproductive toxicity

Reproductive effects observed:
no

Any other information on results incl. tables

Dose calculation

500 mg/L Zn in drinking water/day = 0.5 g Zn/g water

default values for dose calculation for female rats (according to Golde et al., 1984 and Paulussen et al., 1998, cited in ECHA Guidance R.8)

water consumption per day (female rat) = 20 mL

body weight (female rat) = 0.35 kg

Zn intake per rat per day

0.5 mg Zn/g water/day x 20 g = 10 mg Zn/day

Zn intake per body weight/day

(10 mg Zn/day) / 0.35 kg = 28.57 mg/kg bw/day

conversion factor = 0.057

Applicant's summary and conclusion

Conclusions:
No changes were observed in the general appearance, growth curves, hematocrit or signs of achromotrichia between treated and control animals. Group II and III showed a significant increase in 3H-thymidine-determined splenic lymphoproliferation, while groups V and VI exhibited an important decrease. A significant increase in plaque - forming cell response (IgM) was observed after the period of lactation in groups II and III as well as in groups V and VI. Zinc concentrations determined by atomic absorption in liver and thymus were significantly higher in all treated mice 42 days after birth. Results suggest that for carefully monitored periods and doses, oral zinc supplements might have a beneficial effect over some immune responses in the perinatal stages.
Executive summary:

In this study mice received zinc acetate in drinking water at concentrations of 500 and 1000 mg/I during the periods of gestation, lactation and post-weaning. The sequence employed in this study was (gestation/lactation/post-weaning): (I) 0/0 (II) 500/500 (III) 1000/1000 (IV) 0/0/0 (V) 500/500/500 and (VI) 1000/1000/1000 with their respective controls. Each group consists of 30 animals. No changes were observed in the general appearance, growth curves, hematocrit or signs of achromotrichia between treated and control animals. Group II and III showed a significant increase in 3H-thymidine-determined splenic lymphoproliferation, while groups V and VI exhibited an important decrease. A significant increase in plaque - forming cell response (IgM) was observed after the period of lactation in groups II and III as well as in groups V and VI. Zinc concentrations determined by atomic absorption in liver and thymus were significantly higher in all treated mice 42 days after birth. Results suggest that for carefully monitored periods and doses, oral zinc supplements might have a beneficial effect over some immune responses in the perinatal stages.