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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
2006
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Data from review article
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
review article or handbook
Title:
Unnamed
Year:
2006

Materials and methods

Principles of method if other than guideline:
Data from review article
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Inorganic arsenic and structural analogues including arsenite and arsenic trioxide

Test animals

Species:
other: rats and mice
Strain:
other: Swiss albino mice; CD-1 mice; Wistar rats
Sex:
male/female

Administration / exposure

Route of administration:
other: oral: gavage or drinking water; intraperitoneal
Vehicle:
water
Details on mating procedure:
No data
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Not applicable
Frequency of treatment:
Not applicable
Details on study schedule:
Not applicable
No. of animals per sex per dose:
Not applicable

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

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 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 AsIII treatment 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).

Applicant's summary and conclusion

Conclusions:
In conclusion, exposure to inorganic arsenic and analogues via oral or intraperitoneal route has shown adverse effects on reproduction in mice and rats.
Executive summary:

A review article was published by Wang et al. (2006) describing the reproductive and developmental effects of arsenic and analogues. Exposure to inorganic arsenic and analogues through drinking water or by i.p. injection causes male reproductive toxicity by interfering spermatogenesis and lowering levels of testosterone and gonadotrophin. This suggested 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). 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).  

 

In conclusion, exposure to inorganic arsenic and analogues via oral or intraperitoneal route has shown adverse effects on reproduction in mice and rats.