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Key value for chemical safety assessment

Effects on fertility

Additional information

Inhalation route (humans): no studies were located regarding reproductive effects in humans after inhalation exposure to inorganic arsenicals (ATSDR, 2007).

 

Inhalation route (animals): the effect of diarsenic trioxide on reproductive performance was investigated in female (CD) rats exposed to 0.08–20 mg As/m3(preliminary study) or 0.2–8 mg As/m3(definitive study) for 6h daily from 14 days prior to mating through gestation day 19. No changes occurred in the precoital interval (time to mating), mating index (percentage of rats mated), or fertility index (percentage of matings resulting in pregnancy), thus yielding a NOAEL of 8 mg As2O3/m3(Holson et al. 1999; cited in ATSDR, 2007).

 

Oral route (humans): ingestion of arsenic in drinking water has been associated with adverse reproductive outcomes in humans. For example, a study of 96 women in Bangladesh who had been drinking water containing ≥0.10 mg As/L (approx. 0.008 mg As/kg/day) for 5–10 years reported a significant increase in spontaneous abortions, stillbirth and preterm birth compared to a non exposed group (Ahmad et al., 2001; cited in ATSDR, 2007). A significant association between concentrations of arsenic in the water >0.05 mg/L (approximately 0.006 mg As/kg/day) and spontaneous abortions were found in another study of 533 women from Bangladesh (Milton et al. 2005; cited in ATSDR, 2007). A study of 202 women from West Bengal (India) reported that exposure to arsenic concentrations of arsenic ≥0.2 mg/L in drinking water (approximately 0.02 mg As/kg/day) during pregnancy were associated with a 6-fold increased risk of stillbirth (von Ehrenstein et al. 2006; cited in ATSDR, 2007). An earlier study of 286 women in USA found no significant association between arsenic in the drinking water (0.0016 mg/L; approximately 0.00005 mg As/kg/day) and spontaneous abortions (Aschengrau et al. 1989; cited in ATSDR, 2007).

 

Oral route (animals): reproductive performance was not affected in female rats that received gavage doses of 8 mg As/kg/day (as As2O3) from 14 days prior to mating through gestation day 19 (Holson et al. 2000; cited in ATSDR, 2007). Reproductive indices that were evaluated included the precoital interval (time to mating), mating index (percentage of rats mated), and fertility index (percentage of matings resulting in pregnancy). In a 3-generation study in mice given sodium arsenite in drinking water at an average dose of 1 mg As/kg/day, there was a significant increase in the incidence of small litters and a trend toward a decreased number of pups per litter in all three generations of the treated group (Schroeder and Mitchener 1971; cited in ATSDR, 2007).


Short description of key information:
See short description of key information on developmental toxicity / teratogenicity.

Effects on developmental toxicity

Description of key information
Chronic exposure of women via drinking water and inhalation has been suggested as being associated with developmental toxicity and an impairment of birth outcome. Inorganic arsenic has also been shown to be embryotoxic and teratogenic in experimental animals; however, most studies have used high parenteral arsenic dosing, which might have involved maternal toxicity. Only recently experimental studies without maternal toxicity have shown foetal growth retardation, neurotoxicity and alteration in pulmonary structure following oral dosing at relevant exposure levels, often in the form of arsenate. Due to the major differences between species, direct extrapolation to humans cannot be made. However, the comparison of the susceptibility to arsenic of various species during embryonic and foetal development appears to indicate the importance of metabolism for developmental toxicity. Overall,reproduction toxicity may be considered secondary to the carcinogenicity of arsenic. Thus, effect levels and DNELs have not been established for this end-point.
Additional information

Inhalation route (humans): developmental effects associated with occupational and environmental exposure to airborne arsenic have been investigated in a series of studies at the Ronnskar copper smelter in northern Sweden. In comparison to a northern Swedish reference population, female employees of the smelter had a significantly increased incidence of spontaneous abortion, and their children had a significantly increased incidence of congenital malformations and significantly decreased average birth weight. Increased incidence of spontaneous abortion and decreased average birth weight of children were also found in populations living in close proximity to the smelter. However, while these data are suggestive of developmental effects associated with occupational and environmental exposure from the smelter, the reported effects are not large, the analyses include only limited consideration of potential confounders (e.g., smoking), and there are no data relating the apparent effects specifically to arsenic exposure (Nordström et al. 1978a, 1978b, 1979b; cited in ATSDR, 2007). A case-control study of stillbirths in the vicinity of a Texas arsenic pesticide factory that included an estimation of environmental arsenic exposures using atmospheric dispersion modelling and multiple regression analysis considering arsenic exposure, race/ethnicity, maternal age, median income, and parity as explanatory variables reported a statistically significant increase in the risk of stillbirth in the highest exposure category (>100 ng As/m3, midpoint=682 ng/m3). However, further analysis showed that this increase in risk was limited to people of Hispanic descent, who the researchers speculated may be an especially sensitive population due to a genetic impairment in folate metabolism. Also, the interpretation of this study is limited by small numbers of cases and controls in the high exposure group, lack of data on smoking, potential confounding exposures to other chemicals from the factory, and failure to take into account previous years of deposition in the exposure estimates (Ihrig et al., 1998; cited in ATSDR, 2007).

 

Inhalation route (animals): arsenic has been shown to produce developmental effects by inhalation exposure in laboratory animals, although it is unclear whether or not the effects occur only at maternally toxic doses. Mice exposed to 22 mg As/m3 (as As2O3) for 4 hours on days 9–12 of gestation had serious developmental effects (significant increases in the percentage of dead fetuses, skeletal malformations, and the number of fetuses with retarded growth), while those exposed to 2.2 mg As/m3 had only a 10% decrease in average fetal body weight, and those exposed to 0.20 mg As/m3 had no effects. However, this study is limited by failure to quantify malformations on a litter basis, discuss the nature and severity of the observed malformations, or report on the occurrence of maternal effects (Nagymajtényi et al. 1985; cited in ATSDR, 2007). No increases in fetal resorptions, fetal mortality, or malformations, and no decreases in fetal body weight occurred when rats were exposed to 0.2–8 mg As/m3 (as As2O3), 6 hours daily from 14 days prior to mating through gestation day 19 (Holson et al. 1999; cited in ATSDR, 2007).

 

Oral route (humans): chronic exposure of women to arsenic in the drinking water has been associated with infants with low birth weights in Taiwan and Chile (Yang et al. 2003; Hopenhayn et al. 2003a; cited in ATSDR, 2007). Similar associations have been made between late fetal mortality, neonatal mortality, and postneonatal mortality and exposure to high levels of arsenic in the drinking water (up to 0.86 mg/L during over a decade), based on comparisons between subjects in low- and high-arsenic areas of Chile (Hopenhayn-Rich et al. 2000; cited in ATSDR, 2007). More recently, von Ehrenstein et al. (2006 cited in ATSDR, 2007) reported no significant association between exposure to concentrations of ≥0.1 mg/L arsenic in drinking water (approximately 0.008 mg As/kg/day) (n=117; 29 women were exposed to ≥0.5 mg/L) and increased risk for neonatal death or infant mortality during the first year of life in a study of a population in West Bengal, India. No overall association between arsenic in drinking water and congenital heart defects was detected in a case-control study in Boston, although an association with one specific lesion (coarctation of the aorta) was noted (Zierler et al. 1988 cited in ATSDR, 2007). A study of 184 women with neural tube defects in the offspring living in a Texas county bordering Mexico found that exposure to levels of arsenic in the drinking water >0.010 mg/L (range or upper limit not specified) did not significantly increase the risk for neural tube defects (Brender et al. 2006 cited in ATSDR, 2007).

 

Oral route (animals): there is a considerable number of other studies in animals suggesting that ingested inorganic arsenic may produce developmental effects, which however involved such high doses that also produced overt maternal toxicity (ATSDR, 2007). For example, rats treated with a single gavage dose of 23 mg As/kg as arsenic trioxide on day 9 of gestation had a significant increase in postimplantation loss and a decrease in viable fetuses per litter, while those treated with 15 mg As/kg showed no effects (Stump et al. 1999; cited in ATSDR, 2007). Rats treated by daily gavage with 8 mg As/kg/day starting 14 days before mating and continuing through gestation had significantly reduced fetal body weights and significantly increased incidences of several skeletal variations (unossified sternebrae, slight/moderate sternebrae malalignment) that the researchers considered to be consequences of developmental growth retardation (Holson et al. 2000; cited in ATSDR, 2007). Exposure of rats to 2.93–4.20 mg As/kg/day throughout gestation and for 4 months postnatally resulted in alterations in neurobehavioral parameters in the offspring, including increased spontaneous locomotor activity and number of errors in a delayed alternation task; maternal behaviour was not affected (Rodriguez et al. 2002; cited in ATSDR, 2007). Studies in mice found increased fetal mortality, decreased fetal body weight, a low incidence of gross malformations (primarily exencephaly), and an increase in skeletal malformations in mice given single gavage doses of 23–48 mg As/kg during gestation, but with no effects at 11 mg As/kg (Baxley et al. 1981; Hood et al. 1978; cited in ATSDR, 2007). Similarly, in mice treated with 24 mg As/kg/day as arsenic acid on days 6–15 of gestation, there was a significant increase in the number of resorptions per litter (42% vs. 4% in controls) and significant decreases in the number of live pups per litter (6.6 vs. 12.3 in controls) and mean fetal weight (1.0 g vs. 1.3 g in controls), while no developmental effects were found at 12 mg As/kg/day (Nemec et al. 1998; cited in ATSDR, 2007). Hamsters treated with a single gavage dose of 14 mg As/kg during gestation also had increased fetal mortality and decreased fetal body weight, with no effect at 11 mg As/kg (Hood and Harrison 1982; cited in ATSDR, 2007). However, the most sensitive species was the rabbit, which had increased resorptions and decreased viable fetuses per litter at 1.5 mg As/kg/day and a developmental NOAEL of 0.4 mg As/kg/day, following repeated gavage dosing with arsenic acid during gestation (Nemec et al. 1998; cited in ATSDR, 2007).

Justification for classification or non-classification

Diarsenic trioxide is currently classified as “Cat 1A” human carcinogen. Carcinogenicity is the leading human health effect for diarsenic trioxide and is of concern already at low chronic doses. Other toxic effects, as considered under reproductive toxicity/developmental toxicity, are also observed, but occur at much higher doses. Therefore, a separate classification for fertility or developmental toxicity is not considered warranted. This is also in agreement with the harmonised classification in accordance with Annex I of Regulation (EC) No 1272/2008 (Index No. for As2O3: 033-003-00-0).