Arsenic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

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 al., 2000).  

- 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 As^IIItoxicity 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 As^IIItreatment 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).

Short description of key information:
No multi-generation studies investigating potential effects of arsenic acid or parent compounds on fertility are available but data on reproductive organs have been gathered from literature.
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.
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.

Effects on developmental toxicity

Description of key information

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.

Additional information

A review article was published by Wang et al. (2006) describing the reproductive and developmental effects of arsenic and analogues.

 

Inorganic arsenicals, As^IIIand As^Vwere 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 As^IIIin drinking water (Chattopadhyay et al., 2002).

- 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 As^IIItreatments. 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 al., 1987).

- 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).

Justification for classification or non-classification

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 literature.

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.