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EC number: 215-222-5
CAS number: 1314-13-2
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
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).
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.
of experimental key studies on fertility
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)
Khan et al., 2001
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.
Khan et al., 2003
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.
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↓
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.
Khan et al., 2007
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↓
Samanta et al., 1986
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
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.
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).
The following test substance-related
adverse effects/findings were noted:
Test group 3
in absolute and relative lung weights (up to 47%)
alveolar lipoproteinosis in all animals examined
diffuse inflammation in all animals examined
to slight focal hemorrhage in three of ten animals
test substance-related adverse effects on gestational parameters or
Test group 2
test substance-related adverse effects on dams, gestational parameters
Test group 1
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
observed adverse effect concentration (NOAEC) for prenatal developmental
toxicity is7.5 mg/m3.There
were no adverse fetal findings evident at any dose.
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
Overview of experimental key studies on
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.
30 mg/kg bw/day equalling
12mg Zn/kg bw/d (anhydrate);
6.8mg Zn/kg bw/d (heptahydrate)
Food and Drugs Research Labs., Inc, 1973*
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.
42.5 mg/kg bw/day equalling
17mg Zn/kg bw/d (anhydrate);
9.6 mg Zn/kg bw/d (heptahydrate)
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.
200 mg/kg bw/day
EU RAR, 2004
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.
88 mg/kg bw/day
32.5mg Zn/kg bw/d (anhydrate);
19.9mg Zn/kg bw/d (heptahydrate);
Females received daily doses of 0, 0.6, 2.8, 13 and 60 mg ZnSO4(unspecified)/kg bw during days 6-18 of gestation.
60 mg/kg bw/day
24mg Zn/kg bw/d (anhydrate);
13.6mg Zn/kg bw/d (heptahydrate)
Food and Drugs Research Labs., Inc, 1974*
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.
50 mg/kg bw/day
* 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.,
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:
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
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
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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