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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
20 mg/kg bw/day
Species:
rat
Additional information

The reproductive toxicity of zinc compounds has been investigated in one and two generation reproductive toxicity studies in which rats or mice were dosed by gavage or via the diet with soluble zinc compounds (i. e., zinc chloride, zinc sulphate) at exposure levels up to 14 mg Zn/kg bw/day (gavage) or 200 mg Zn/kg bw/day (diet) (Khan et al.,2001, 2003, 2007; Samanta et al, 1986). Further information on potential effects of zinc compounds on male or female reproductive organs could be retrieved from subchronic toxicity studies as conducted by Maita et al.(1981) and Edwards and Buckley (1995).

Maita et al. (1981) reported that mice and rats fed with zinc sulphate in dietary concentrations up to 30,000 mg/kg feed did not produce adverse effects on either male or female sex organs after 13 weeks of exposure. This dietary level was equal to ca. 1100 mg or 565 mg Zn/kg bw/day for mice and rats, respectively. Edwards and Buckley (1995) showed that rats exposed to 13 or 60 mg Zn/kg bw/day in the diet over a period of 90 days did not show any detrimental effects on sex organs. In the exposure group of 335 mg Zn/kg bw/day, all males showed hypoplasia in testes and seminiferous tubules in males hypoplastic uterus in females, but these findings are not considered reliable as the animals of this high dose group were generally of poor health conditions and killed for humane reasons prior to study termination.

In addition to those key reproductive toxicity studies(Khan et al.,2001, 2003, 2007; Samanta et al, 1986), some additional studies indicating high oral doses of zinc (i.e., exposures greater that 25 mg day/kg bw/day) to impair fertility as indicated by a decreased number of implantations sites and increased number of resorptions are of note:

A study was carried out to determine the effect of zinc supplementation on the number of implantation sites and resorptions in pregnant rats. The control group consisting of 12 pregnant females was maintained on 10 % vegetable protein diet (containing 30 ppm zinc) from Day 1 through Day 18 of pregnancy. The experimental group consisting of 13 animals was also maintained on the same diet, but received additionally 150 ppm zinc as a 2% zinc sulphate solution administered daily orally. All the animals were sacrificed on Day 18 of pregnancy, and their uteri examined for implantation sites and resorptions. Of a total number of 101 implantation sites in the 12 control animals there were two resorptions, one in each of two animals. In marked contrast, in the 13 zinc supplemented animals, there were 11 resorptions out of 116 implantations. Eight of the animals had at least one resorption each. This difference was statistically significant. The result indicates that oral administration of moderately high levels of zinc (150 ppm) may be associated with harmful effects in the course of pregnancy of rat (Kumar et al., 1976). The low protein diet may have affected the physiology of the animals resulting in an increased sensitivity for zinc. As this hypothesis cannot be further assessed and also considering the limited available study information, this study is only of limited validity for the assessment of effects of zinc exposure on fertility (EU RAR, 2004).

Another study aimed at determining the effect of post-coitum, and pre- and post-coitum dietary zinc supplementation on the conception in the Charles-Foster rat. In the post-coitum study (test 1), two groups of 15 pregnant rats were fed 0 and 4,000 ppm zinc as zinc sulphate in diet (i.e., approximately 200 mg Zn/kg bw/day) from day 1 through day 18 of pregnancy. In the pre- and post-coitum study (test 2), two groups of 15 female rats were treated with same doses for 21 days pre-mating period, maximum 5 days of mating period and 18 days of post-coitum period. All the females were sacrificed on Day 18 of gestation and uterus content and fetuses were examined. In test 1, significant decrease in the incidences of conception and number of implantation sites per mated female was observed in the treatment group with respect to the control group. However, the difference in implantation sites when considered per pregnant female was not significant. In test 2, no significant difference in incidences of conception and implantation sites was observed in the control and treatment groups. In both the tests, there was no treatment-related change in the fetal and placental weights, stillbirths and malformed fetuses were absent and the number of resorption sites was negligible. Based on these results, dietary zinc supplementation at 4,000 ppm did not affect the fetal growth in pregnant rats. This dose, however, altered the normal conception when started after coitus but showed no effect when initiated sufficient time before coitus (Pal et al., 1987).

The available information suggests that high oral doses of zinc (i. e., exposure levels greater than 20 mg Zn/kg bw/day) may adversely affect spermatogenesis and result in impaired fertility indicated by decreased number of implantation sites and increased number of resorptions (US EPA, 2005). However, these effects were only observed in the presence of maternal toxicity as seen in the one or two generation studies conducted by Khan et al.(2001, 2003, 2007) or, in case of the study conducted by Kumar et al. (1976), when other study non-zinc relevant study specificities could have impacted the study outcome.

Overview of experimental key studies on fertility

Test substance

Method

Results

Remarks

Reference

Zinc chloride

One-generation study in rats administered zinc chloride at doses of 0, 3.6, 7.2, 14.4 mg Zn/kg bw/d in water over one generation by gavage. Exposure started 77 days prior to mating

As of 3.6 mg Zn/kg bw/day:

P - Mortality; body weight gain; fertility indext; thymus atrophy

F1 - litter size (non significant); number of surviving pubs (non significant);

As of 7.2 mg Zn/kg bw/day:

P – hemosidosis of spleen; lymphocyte deficiency

F1 - number of surviving pubs; BW gain (PND 21)

2 (reliable with restrictions)

key study

Khan et al., 2001

Zinc chloride

One-generation study in mice administered zinc chloride at doses of 0, 0.75, 1.5 and 3, mg Zn/kg bw/d (male)respectively, 0. 1.5, 3 and 6, mg Zn/kg bw/d (female) in water with 1.5mL HNO3/l over one generation by gavage. Exposure started 49 days prior to mating

0.75 resp. 1.5 mg Zn/kg bw/day:

P- Mortality; body weight gain; abs./rel. Liver/thymus/ spleen weight; fertility indext; number pregnancies

F1- litter size (non significant); number of surviving pubs (non significant);

1.5 resp. 3 mg Zn/kg bw/day:

P- body weight gain; F1– 14day survival index;

3 resp. 6 mg Zn/kg bw/day:

F1– only 1 birth; 9 still births.

2 (reliable with restrictions)

key study

Khan et al., 2003

Zinc chloride

Two-generation study in rats administered zinc chloride at doses of 7.5, 15and 30 mg zinc chloride/kg bw/d (3.6, 7.2 and 14.4 mg Zn/kg bw/day) in water over two successive generations via the oral route. Application procedure not specified but likely oral gavage. Exposure started 77 days prior to mating.

As of 3.6 mg Zn/kg bw/day:

P - Mortality; body weight gain; abs/rel liver/kidney weight; lesions in GI tract, inflammation in prostate

F1 - Mortality; body weight gain; abs/rel brain/prostate/spleen weight;

F2 – no effects

7.2 mg Zn/kg bw/day:

P – abs./rel. brain/seminal vesicle weight;F1 - abs/rel liver/adrenal/seminal vesicle weight

F2 – no effects

14.4 mg Zn/kg bw/day:

P – abs./rel. Spleen/uterus weight;

F1 - body weight gain (PND21); abs/rel kidney weight; litter size and #surviving pubs until PND4;

F2 – body weight gain (PND21); abs/rel kidney weight; litter size and number surviving pubs until PND4;

Maternal toxicity at any dose level. The NOAEL for fertility and development toxicity is about 15 mg ZnCl2/kg bw/d, this corresponds to 7.2 mg Zinc/kg bw/day. No NOAEL for systemic toxicity could be derived.

2 (reliable with restrictions)

key study

Khan et al., 2007

Zinc sulphate

Charles foster rats fed with a diet containing 4000ppm Zn (in form of zinc sulphate); exposure equals 200 mg Zn/kg bw exposure started 30-32 days prior to mating.

200 mg Zn/kg bw/day

P – Zn-concentration in testis and sperm; sperm mobility; number of pregnancies

F1 – number of live births

2 (reliable with restrictions)

key study

Samanta et al., 1986

Effects on Fertility, Human information

In reviews by the World Health Organisation in the Environmental Health Criteria for Zinc (WHO, 2001) and by the US Agency for Toxic Substances and Disease Registry in the Toxicity Profile for Zinc (ATSDR, 2005), existing human studies which examined the responses of women to zinc supplementation during pregnancy have been summarised. Studies on large controlled trials that were conducted to investigate the effects of dietary zinc supplementation in healthy pregnant women were peer reviewed. The reviewers concluded that zinc at a rate of 20mg/day and 30 mg/day did not result in any adverse reproductive effects during pregnancy (Hunt et al.,1984; Kynast and Saling et al.,1986).Two exemplar studies are summarised in the following:

A double blind trial was conducted in 56 pregnant women at risk of delivering a small for gestational-age baby to determine the effects of dietary zinc supplementation during the last 15-25 weeks of pregnancy following administration of 22.5 mg zinc/day. No adverse reproductive effects were observed (Simmer et al.,1991).

Pregnant women who received 0.3 mg zinc/kgbw/day as zinc sulphate capsules during the last two trimesters did not exhibit any changes in maternal body weight gain, blood pressure, postpartum haemorrhage or infection, inidicating no adverse reproductive effects (Mahomed et al.,1989).


Short description of key information:
A range of studies have been conducted to assess the effects of zinc on fertility and reproductive performance, most of them with very soluble zinc chloride and zinc sulphate. A complete overview and review of available fertility studies is available in the EU risk assessment of zinc compounds (EU RAR, 2004), the review of the of health effects of zinc compounds by the US Agency for Toxic Substances and Disease Registry (ATSDR, 2005), the toxicological review of zinc and compounds by the US Environmental Protection Agency (US EPA, 2005) or the review by the WHO (WHO, 2001). The results of the key experimental studies addressing potential effects of zinc compounds on fertility are summarised in the CSR.

Effects on developmental toxicity

Description of key information
Several prenatal toxicity studies are available that examined the developmental toxicity of various zinc compounds in rats, mice, rabbit or hamsters up to dietary exposure levels of 200 mg Zn/kg bw/day or 50 mg Zn/kg bw/day by gavage (for details see Table developmental toxicity studies). No developmental toxicity has been observed in these studies and there NOAEL’s have been established at the highest doses tested.
Although some developmental effects such as decreases in body weights or decrease in individual organ weights were observed in F1 and/or F2 generations in the one or two generation reproductive toxicity studies conducted by Khan et al. (2007) at high exposure levels, these observations are, however, not suitable for risk assessment or hazard classifications as they were always accompanied with maternal toxicity. Moreover, no developmental toxicity was observed at non-maternally toxic doses in a teratogenicity study in which CF-1 albino mice were administered intraperitoneally 0, 12.5, 20.5 and 25 mg/kg on Day 11 of gestation (test 1) and at 20.5 mg/kg on Days 8 -11 of gestation (test 2) (Chang et al., 1979).
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: 11 -14 weeks
- Weight at study initiation: 146.0 - 192.1 g
- Fasting period before study: no
- Housing: individually, dust-free wooden bedding, enrichment: wooden gnawing blocks
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

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

Route of administration:
inhalation: aerosol
Type of inhalation exposure (if applicable):
nose/head only
Vehicle:
air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: flow-past nose-only exposure system, individually exposure of each rat, exhaled air is immediately exhausted
- Method of holding animals in test chamber: individual acrylic tubes
- Source and rate of air: conditioned and compressed air, 6 m3/h
- System of generating particulates/aerosols: feeding system and high-pressure, high-velocity pressurized air dispersion with computerized control
- Temperature, humidity, pressure in air chamber: 22 +/- 2°C, 50 +/- 20%,
- Air flow rate: 6 m3/h
- Method of particle size determination: cascade impactor/ Marple impactor
- Treatment of exhaust air: disposal in compliance with local, federal and state regulations

TEST ATMOSPHERE
- Brief description of analytical method used: gravimetrically by filter samples
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentrations of the inhalation atmospheres of test group 1 – 3 were analyzed by gravimetrical analysis. Daily means were calculated based on two measured samples per concentration and exposure. From the daily mean values of each concentration, mean concentrations and standard deviations for the entire study were derived. In these groups, the constancy of concentration in each inhalation system was continuously monitored using scattered light photometers.
In the control group (test group 0) no sample was analyzed over the study period. The analyses were carried out at the Inhalation Laboratory of the Experimental Toxicology and Ecology of BASF SE.
Details on mating procedure:
The animals were paired by the breeder (“time-mated”) and supplied on GD 0 (= detection of vaginal plug/sperm). The animals arrived on the same day (GD 0) at the experimental laboratory.
Duration of treatment / exposure:
6 hours on 14 consecutive days
Frequency of treatment:
daily
Duration of test:
from implantation to one day prior to the expected day of parturition
Dose / conc.:
0.3 mg/m³ air
Dose / conc.:
1.5 mg/m³ air
Dose / conc.:
7.5 mg/m³ air
No. of animals per sex per dose:
25 pregnant females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: request of the sponsor
- Rationale for animal assignment: random
The inhalation route was selected since it is relevant in terms of potential human exposure.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once a day

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed on gestation day (GD) 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20.
The corrected body weight gain was calculated after terminal sacrifice (terminal body weight on GD 29 minus weight of the unopened uterus minus body weight on GD 6).

FOOD CONSUMPTION
The consumption of food was recorded for GD 1-3, 3-6, 6-8, 8-10, 10-13, 13-15, 15-17, 17-19 and 19-20.

POST-MORTEM EXAMINATIONS: Yes / No / No data
- Sacrifice on gestation day #20
- Organs examined: Organ weights of the lungs, the unopened uterus and the placentas were determined. For each dam, corpora lutea were counted and number and distribution of implantation sites (differentiated by resorptions, live and dead fetuses) were determined. The fetuses were removed from the uterus, sexed, weighed and further investigated for external, soft tissue and skeletal (incl. cartilage) findings. Larynx, lungs, mediastinal and tracheobronchial lymph nodes, trachea and nasal cavities were examined histopathologically in the control and high-dose groups.


Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter
Statistics:
clinical and fetal examination:
Simultaneous com-parison of all dose groups with the control group using the DUNNETT-test (two-sided) for the hypothesis of equal means
Pairwise comparison of each dose group with the control group using FISHER'S EXACT test (one-sided) for the hypothesis of equal proportions
Pairwise comparison of each dose group with the control group using the WILCOXON-test (one-sided) for the hypothesis of equal medians

Pathology:
Non-parametric one-way analysis using KRUSKAL-WALLIS test (two-sided). If the resulting p-value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using the WILCOXON test for the hypothesis of equal medians
Historical control data:
used to interprete results of present study
Dose descriptor:
NOAEC
Effect level:
1.5 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
7.5 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
no effects observed
Dose descriptor:
NOAEC
Effect level:
7.5 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
external malformations
skeletal malformations
visceral malformations
Abnormalities:
not specified
Developmental effects observed:
not specified

The following test substance-related adverse effects/findings were noted:

 

 

Test group 3 (7.5 mg/m3):

 

·        Increase in absolute and relative lung weights (up to 47%)

·        Moderate alveolar lipoproteinosis in all animals examined

·        Slight, diffuse inflammation in all animals examined

·        Minimal to slight focal hemorrhage in three of ten animals

·        No test substance-related adverse effects on gestational parameters or fetuses

 

 

Test group 2 (1.5 mg/m3):

 

·        No test substance-related adverse effects on dams, gestational parameters or fetuses

 

 

Test group 1 (0.3 mg/m3):

 

·        No test substance-related adverse effects on dams, gestational parameters or fetuses

 

Executive summary:

Under the conditions of this prenatal developmental toxicity study, the inhalative administration of Z-Cote HP1 to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at a dose of 7.5 mg/m3 caused moderate alveolar lipoproteinosis and slight inflammation. These histopathologic findings are regarded to be adverse in nature. The relevance for humans however is not clear.

 

In conclusion, the no observed adverse effect concentration (NOAEC) for maternal toxicity is1.5 mg/m3.

 

The no observed adverse effect concentration (NOAEC) for prenatal developmental toxicity is7.5 mg/m3.There were no adverse fetal findings evident at any dose.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
7.5 mg/m³
Study duration:
subacute
Species:
rat
Additional information

The developmental toxicity of zinc compounds can be assessed on the basis of prenatal toxicity studies that have been conducted with soluble zinc sulphate and zinc chloride and slightly soluble zinc carbonate in rats, mice, hamsters or rabbits. Moreover, a total of three (one or two generation) reproductive toxicity studies conducted by Khan et al.(2001, 2003, 2007) provide further information on potential teratogenic effects of zinc compounds.

No prenatal toxicity was observed with either zinc sulphate, zinc chloride or zinc carbonate at exposure levels up to 50 mg Zn/kg bw/day by oral gavage or 200 mg Zn/kg bw/day if the zinc was dosed via the diet. Established NOAELs in these studies were typically at highest dose tested and systemically tolerated by the dams. Developmental effects such as decrease in body or organ weights were, however, observed in F1 and/or F2 generations in the one or two generation reproductive toxicity studies conducted by Khan et al. (2001, 2003, 2007). These studies are not considered suitable for the assessment of teratogenic effects for hazard classification or risk assessment purposes since they were always observed in the presence of maternal toxicity.

Overview of experimental key studies on developmental toxicity

Test substance*

Species

Route

Method

Result

Remark

Reference

Zinc sulphate

Mouse

CD-1

Oral

Females received daily doses of 0, 0.3, 1.4, 6.5 and 30 mg ZnSO4(unspecified)/kg bw by oral gavage during days 6-15 of gestation.

No discernible effects were seen on or maternal or foetal survival. No difference in number of abnormalities found in foetuses.

NOAEL:

30 mg/kg bw/day equalling

12mg Zn/kg bw/d (anhydrate);

6.8mg Zn/kg bw/d (heptahydrate)

2 (reliable with restrictions)

Key study

Food and Drugs Research Labs., Inc, 1973*

Zinc sulphate

Rat

Wistar

Oral

Females received daily doses of 0, 0.4, 2.0, 9.1 and 42.5 mg ZnSO4(unspecified)/kg bw by oral gavage during days 6-15 of gestation.

No discernible effects were seen on or maternal or foetal survival. No difference in number of abnormalities found in foetuses.

NOAEL:

42.5 mg/kg bw/day equalling

17mg Zn/kg bw/d (anhydrate);

9.6 mg Zn/kg bw/d (heptahydrate)

2 (reliable with restrictions)

Key study

Food and Drugs Research Labs., Inc, 1973*

Zinc sulphate

Rat

Charles Foster

Oral

Females received daily doses of 0, and 200 mg Zn/kg bw (in form of ZnSO4) in diet during days 1-18 of gestation

No discernible effects were seen on or maternal or foetal survival. A reduced number of implantations observed. No difference in number of abnormalities found in foetuses.

NOAEL:

200 mg/kg bw/day

2 (reliable with restrictions)

Key study

EU RAR, 2004

Zinc sulphate

Hamster

Oral

Females received daily doses of 0, 0.9, 4.1, 19, and 88 mg ZnSO4(unspecified)/kg bw by oral gavage during days 6-10 of gestation.

No discernible effects were seen on or maternal or foetal survival. No difference in number of abnormalities found in foetuses.

NOAEL:

88 mg/kg bw/day

equalling

32.5mg Zn/kg bw/d (anhydrate);

19.9mg Zn/kg bw/d (heptahydrate);

2 (reliable with restrictions)

Key study

Food and Drugs Research Labs., Inc, 1973*

Zinc sulphate

Rabbit

Dutch

Oral

Females received daily doses of 0, 0.6, 2.8, 13 and 60 mg ZnSO4(unspecified)/kg bw during days 6-18 of gestation.

No discernible effects were seen on or maternal or foetal survival. No difference in number of abnormalities found in foetuses.

NOAEL:

60 mg/kg bw/day

equalling

24mg Zn/kg bw/d (anhydrate);

13.6mg Zn/kg bw/d (heptahydrate)

2 (reliable with restrictions)

Key study

Food and Drugs Research Labs., Inc, 1974*

Zinc carbonate

Rat

Sprague Dawley

Oral

Females received daily doses of 0, 2.5, and 50 mg Zn/kg bw (in form of ZnCO3) in diet during days 1-20 of gestation.

No discernible effects were seen on or maternal or foetal survival. No difference in number of abnormalities found in foetuses.

NOAEL:

50 mg/kg bw/day

 

2 (reliable with restrictions)

Key study

Uriu-Hare, 1989

* ZnSO4form is unspecified. The NOAEL, expressed as Zn cation, has been calculation for both anhydrate- and heptahydrate forms.

Developmental toxicity, Human information

In establishing the Environmental Health Criteria for Zinc, the World Health Organisation has reviewed and summarised existing human studies examining the responses of women to zinc supplementation during pregnancy. None of the studies indicated any significant effects on the developing foetus (WHO, 2001). Two exemplar studies are summarised in the following:

A study was conducted on pregnant women to determine the effects of nutrients during pregnancy on maternal and fetal outcome. Four hundred fifty women were observed during pregnancy and postpartum. Forty-three variables including 12 laboratory indices of maternal nutrient status were assessed. Maternal plasma zinc levels were inversely correlated with fetal weight. Blood examinations revealed a significant association between the total occurrence of fetomaternal complications or fetal distress, and lowest quartile zinc/albumin and highest quartile folate. Under the study conditions, plasma zinc was determined to be a discriminator for fetomaternal complications only in women in the lowest quartile for plasma zinc (Mukherjee et al., 1984).

A double blind trial was conducted on pregnant women to determine the effects zinc supplementation during pregnancy on maternal and fetal outcome. 494 women booking before 20 week of gestation in a hospital were prescribed either 66 mg zinc sulphate (equivalent to 20 mg elemental zinc, 0.3 mg zinc/kgbw/day) 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 (Mahomed et al.,1989).

In summary, in studies with women receiving zinc supplementation during pregnancies at levels of approximately ≤ 0.3 mg Zn/kg bw/day, no reproductive or developmental effects were observed (WHO, 2001; SCF, 2003). Evidence of zinc toxicity during human pregnancy has not been reported, but this may be due to the fact that very high exposures to zinc in human pregnancy are unusual. In contrast, zinc is necessary for normal growth and development (e.g., gene expression, vitamin metabolism) and therefore it is not surprising that zinc deficiency during pregnancy can cause a variety of adverse effects to the foetus or may result in reduced fertility or delayed sexual maturation in animals as well as in humans (EU RAR, 2004; WHO, 2001).

Zinc oxide nanomaterial:

A recent prenatal developmental study in rats performed specifically on nano-ZnO, demonstrates that maternal toxicity was evident by increase of lung weights and lung inflammations at 7.5 mg/m3. But there were no effects on reproductive parameters (conception rate, corpora lutea, implantation sites, pre- and postimplantation loss, resorptions, and dead fetuses), no increase in external and soft tissue malformations and variations resulting in a NOAEC developmental toxicity of 7.5 mg/m3.


Justification for selection of Effect on developmental toxicity: via inhalation route:
The only data available on the developmental toxicity of ZnO in pregnant rats after the inhalative administration of Z-Cote HP1 (nano-ZnO)

Justification for classification or non-classification

There is no experimental evidence that would justify a classification of zinc compounds for hazardous effects for reproductive or developmental toxicity according under the Dangerous Substance Directive 67/548/EEC or Regulation (EC) 1272-2008 on the classification, labelling and packaging of substances and mixtures. The available reproductive and developmental toxicity information has been mainly generated with soluble zinc compounds zinc chloride or zinc sulphate which ensure maximum bioavailable concentration of zinc and hence, allow the use of the information also for the assessment of the slightly soluble zinc compounds and insoluble zinc metal on a read across basis. No experimental fertility data were identified for these compounds.