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EC number: 231-901-9
CAS number: 7778-39-4
A review article was published by Wang
et al. (2006) describing the reproductive and developmental effects of
arsenic and analogues.
Male reproductive toxicity:
Arsenite given through drinking water or by
i.p. injection interferes spermatogenesis and lowers levels of
testosterone and gonadotrophin causes male reproductive toxicity; these
results suggest that arsenic may act on the brain or pituitary as well
as directly on the germ cells (Chinoy et al., 2004; Pant et al., 2001,
2004; Sarkar et al., 2003).
- Male mice exposed to sodium arsenite in
drinking water at up to 533.90μmol/L for 35 days
showed reproductive toxicity without clinical effects. AsIII-treated
mice did not show changes in body weight, testes weight, or accessory
sex organ weights. However, at 533.90μmol/L, the
activity of 17β-hydroxysteroid dehydrogenase (HSD) was
decreased and conversely, the activities of lactate dehydrogenase (LDH)
andγ-glutamyltranspeptidase (γGT) were increased
in the testes. LDH was used as a marker of Leydig cell function, andγGT
as a marker of Sertoli cell function. AsIII-treated mice also showed
decreases in sperm count and motility along with an increase in abnormal
sperm (Pant et al., 2001).
- Swiss albino mice were given sodium
arsenite at 53.39μmole/L (equivalent to 4 ppm
arsenic) via drinking water for 365 days, causes decreased testicular
weights, sperm count and sperm motility and the percentage of abnormal
sperm was increased. It also affects the activities of marker testicular
enzymes which ultimately causes damage to germ cells (Pant et al., 2004).
- Sodium arsenite was administered to Wistar
rats via i.p. injections at 4, 5, or 6 mg/kg/day for 26 days. At 5 and 6
mg/kg/day, relative testicular weight, accessory sex organ weights and
epididymal sperm counts were decreased. Arsenic induced low levels of LH
and FSH might be the trigger of suppressed testosterone synthesis, leads
to increased spermatid degeneration (Sarkar et al., 2003).
Male Swiss mice were administered with arsenic trioxide orally at 0.5
mg/kg for 30 days, affects the spermatogenesis, cholesterol metabolism
and testicular testosterone level. Co-exposures to arsenic and fluoride
(NaF) found that the recovery from arsenic and fluoride-induced effects
can be facilitated by ascorbic acid, calcium, and vitamin E, which
suggests that arsenic and fluoride induced reproductive toxicity was at
least in part mediated by oxidative stress (Chinoy et al., 2004).
Female reproductive toxicity:
In female mice and rats, inorganic arsenic
suppresses ovarian steroidogenesis, prolongs diestrus, and degenerates
ovarian follicular and uterine cells. It also increases meiotic
aberrations in oocytes, and decreases cleavage and pre implantation
development (Chattopadhyay et al., 2001; Navarro et al., 2004; Zhang et
- Female Wistar rats gavaged with 10 mL of
0.4 ppm sodium arsenite daily for 28 days, causes uterine and ovarian
toxicity, prolonged diestrous (due to low estradiol), decreased relative
ovarian and uterine weights and affects the neuroendocrine regulation of
female sex hormones (decreased LH, FSH, and estradiol). Decreased FSH
level may contribute to the degeneration of ovarian follicles. It also
causes uterine cell degeneration may be due to low ovarian estradiol
and/or increased production of reactive oxygen species after arsenic
treatment. The primary cause of AsIIItoxicity in the female
reproductive system could be arsenic induced changes in the levels of
catecholamines in the brain, which lowers gonadotrophin synthesis and
secretion (Chattopadhyay et al., 2001, 2003).
- Female CD-1 mice were injected with 0, 8,
or 16 mg/kg sodium arsenite i.p. every 2 days for a total of 7
injections over 14 days followed by injections of equine and human
chorionic gonadotrophins overlapping the end of AsIIItreatment
to induce superovulation. AsIII induces oocyte meiotic aberrations and
could subsequently decrease oocyte fertilization, preimplantation
development, and embryo viability. Some of these arsenic effects on
oocytes were observed at 8 mg/kg, which was a previously established
maternal no-observed-adverse-effect level (NOAEL) (Navarro et al., 2004).
In conclusion, exposure to inorganic arsenic and analogues via oral or intraperitoneal route has shown developmental toxicity in rats and mice and maternal inhalation or oral ingestion of inorganic arsenic affected fetal development and behavior, but did not cause malformations.
Inorganic arsenicals, AsIIIand AsVwere
reported to be more toxic than organic arsenicals to embryos/fetuses
(National Research Council 1999).
- Female Crl:CD(SD)BR rats were orally
gavaged with arsenic trioxide from 14 days prior to mating through GD
19, did not cause neural tube defects in fetus even at maternally toxic
dose levels (10 mg/kg/day). At the highest dose tested (10 mg/kg/day),
fetal weights were decreased. There were no arsenic-induced changes in
mating index, fertility index, implantation, or fetal malformation.
Maternal NOAEL was found to be 2.5 mg/kg/day due to transient decreases
in food consumption at 5 mg/kg/day (Holson et al., 2000b).
- Sodium arsenite was administered to
pregnant rats in drinking water at 0.03, 0.3, and 3 ppm. Rats exposed at
3 ppm caused 25% neonatal death. At 0.3 and 3 ppm, decreased fetal
behavior and brain development were noticed, which demonstrated that the
brain development can be affected by in utero exposure to non maternal
lethal levels of AsIIIin drinking water (Chattopadhyay et
- SD rats were administered with sodium
arsenite in drinking water at 36.7 mg/L on GD 15 or postnatal Day 1,
until newborns were approximately 4 months old and weaned pups also
received the same AsIIItreatments. Maternal behaviors and
body weights were unaffected by either arsenic treatment. Pups in the
group exposed from GD 15 showed increased spontaneous locomotor
activities, and pups in both exposed groups showed increased numbers of
errors in a delayed alternation task in comparison to the pups in the
untreated control group. The group exposed from GD 15 had more litters
showing full pinna detachment on postnatal day 12 and low ratings on eye
opening on postnatal day 14. However, there was no difference in these
developmental indices on postnatal day 16. These data showed that
arsenic induced an asynchrony of the maturation processes during
postnatal development and caused behavioral changes, including deficits
in spontaneous locomotor activity and more errors in completing a
spatial learning task (Rodriguez et al. 2002).
- Pregnant F344 rats and CD-1 mice were
exposed up to 2.5 ppm (8 mg/m3) of arsine by inhalation for 6 h/day
during gestation days (GDs) 6-15. No developmental or reproductive
toxicity was observed, although maternal splenomegaly and evidence of
hemolysis occurred in the 2.5 ppm group. When pregnant rats were exposed
up to 5 ppm arsine during GDs 6 to 17, the arsenic concentrations in
both maternal blood and fetal liver were increased in a dose dependent
manner; indicated that the lack of arsine fetotoxicity/teratogenicity
was not due to the lack of embryonic arsenic exposure. The arsine NOAEL
for maternal toxicity (increased spleen weight in rats and mice) and
developmental toxicity (increase in average fetal body weight per litter
in rats) was 0.5 ppm. Arsine gas (AsH3) was not fetotoxic or teratogenic
in rats or mice (Morrissey et al., 1990).
- Fetal malformations were only reported
when pregnant rats and mice were i.v or i.p. injected with inorganic
arsenic at early gestation (DeSesso 2001; Stump et al., 1999).
- Maternal inhalation or oral ingestion of
inorganic arsenic affected fetal development and behavior, but did not
cause malformations (Chattopadhyay et al., 2002; DeSesso., 2001; Holson
et al., 1999, 2000b; Stump et al., 1999).
- Oral administration of arsenic at a dose
twice that used in i.p. injection resulted in a peak maternal arterial
blood arsenic concentration that was roughly only 30% of the i.p.
injection. As a result, the arsenic concentration differences in embryos
from mothers exposed to arsenic from i.p. injection and oral gavage are
even greater than those in maternal blood (DeSesso et al., 1998; Hood et
- Swiss mice were administered with single
i.p. injection of 45 mg/kg sodium arsenate on GD 8 induced fetal
malformations such as external (exencephaly and eye abnormalities),
visceral (hydrocephalus and hydronephrosis) and skeletal malformations
(Fascineli et al. 2002).
- Inhalation is the least effective means of
increasing maternal or embryonic arsenic concentrations, compared to
i.p. and i.v. injections and oral exposure (Holson et al. 2000a).
No multi-generation studies investigating potential effects of
arsenic acid or parent compounds on fertility are available but data on
reproductive organs and teratology data have been gathered from
Based on the reprotoxic effects that were ellicited on arsenic
compounds, and for precautionnary reasons, although no testing was
performed on arsenic acid itself, arsenic acid may be classified as:
- reproductive toxicant category 2 - H361, according to the CLP
Regulation (EC) N° (1272-2008), and
- Toxic to Reproduction: Category 3 - R62 and R63 according to the
Annex VI to the Directive 67/548/EEC.
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