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Toxicological information

Carcinogenicity

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Description of key information

Read across approach

In the absence of substance-specific data, the carcinogenicity of diarsenic trioxide is assessed based on reviews and/or data for inorganic arsenic compounds.

Diarsenic trioxide is readily soluble in water (17.8 g/L at 20°C). Upon dissolution in water, it reacts acidically to trivalent arsenite ions which are not subject to any relevant degree of oxidation for up to 72 hours (Klawonn, 2010). Read-across from toxicological data on inorganic arsenites to diarsenic trioxide is justified without restrictions. However, it is also known that in the human body, inorganic arsenic compounds are converted apart from As(III) also to As(V). Upon becoming systemically available, As(V) is rapidly partly converted to As(III). As(III) species are considered to be more toxic and bioactive than As(V) species. The difference in toxicological potency between As(III) and As(V) cannot be quantified exactly and may vary between routes of exposure and/or type of toxicological effects. Generally, risk assessments are conducted for "inorganic arsenic compounds" as a group, and do not differentiate between various species.Following a conservative approach, the toxicity of diarsenic trioxide is therefore considered to be determined by the release of soluble inorganic species (trivalent arsenites and pentavalent arsenates) which do not differ substantially in potency and may be interconverted both in the environment and in the body. Consequently, it is justified to apply read across to soluble inorganic arsenic compounds to evaluate the systemic effects, including carcinogenicity, of diarsenic trioxide.

General remarks

A large number of investigations on the carcinogenicity of inorganic arsenic compounds are available, and these have been reviewed on several occasions by renowned scientific organizations. Given the overwhelming volume of information, only selected individual Robust Study Summaries (RSS) were developed. The following paragraphs summarise the available data in animals and humans.

When evaluating the results of the animal and human studies, it is important to remember that there are considerable differences in arsenic biotransformation between species and between individuals of a same species (see section on Toxicokinetics). Also, a number of aspects raise issues regarding the usefulness of some studies for quantifying, comparing and interpreting results, especially regarding relevance to humans and risk assessment. These include definition of the arsenic species analysed, concentrations/doses, types of cells, simulation of natural exposure for example (Cohenet al., 2013). Therefore, for the hazard assessment, preference is given to human data.

Studies in animals

In their most recent monograph, the IARC (2012) states that many animal studies have been reported with essentially negative results but these studies suffer from inadequacies in experimental design such as too few animals, too short duration, poor survival and too low levels of exposure.

A 2-year (104-week) carcinogenicity dose–response study was conducted with sodium arsenite (NaAsO2) administered via drinking water to Sprague-Dawley rats at concentration of 0, 50, 100 and 200 mg/L ad libitum. The authors concluded that, under the conditions of their study, sodium arsenite induced sparse benign and malignant tumours amongst treated rats. They noted that the types of tumours observed were infrequent in the strain of Sprague-Dawley rats of the colony used in their laboratory (Soffritti et al., 2006).

Studies on inhalation exposure in animals with inorganic arsenicals are not available. Investigations involving intra-tracheal administration of arsenite in hamsters elicited formation of lung tumours (adenoma and/or carcinoma) (ATSDR, 2007; IARC, 2004) but this route of administration is not of relevance for human health risk assessment.

With respect to animal-to-human extrapolation however, rodents are generally recognised as a poor model system for arsenic and cancer. ATSDR (2007) summarised some of the major drawbacks of animals as a model of arsenic toxicity, which include the following: (i) the metabolism of arsenic in humans (significant formation of methylated forms) is unlike that of most other mammalian species and the ratio of inorganic to organic arsenic excreted also varies between species; (ii) rats sequester arsenic in their erythrocytes and thus are not a suitable model for human toxicity.

Evidence in humans

Inorganic arsenic at high exposures is recognised to be a human carcinogen, affecting mainly the urinary bladder, lungs and skin. Also, a positive association has been observed between exposure to inorganic arsenic compounds and cancer of the kidney, liver and prostate (IARC, 2004; NRC, 1999 and 2001). Selected pivotal studies and their interpretation with regard to human cancer risk assessment are presented below.

Oral route:

The latency period for the onset of cancer in humans is approximately 30-50 years. For this reason, most epidemiological studies on arsenic-induced carcinogenicity originate from countries such as Taiwan, USA, Chile and Argentina, where environmentally mediated exposure has been prevalent for more than 50 years.

Cancer risk assessment for arsenic has mostly used these oral studies, covering principally exposure via drinking water, as a basis to determine the shape of the carcinogenicity dose-response curve (linear or non-linear) and establish a reasonable threshold. Both points are still the subject of scientific debate (see for example the exchanges between Burgoon and Cohen published in the 2016-2017 Archives of Toxicology).

Previous assessments of cancer via the oral (drinking water) route include:

-         Tseng et al. (1968, 1977), ecological study on the incidence of skin cancer and morbidity in southwest Taiwan

-         Chen et al. (1985, 1992) and Wu et al.(1989), ecological studies of cancer of bladder and lungs in southwest Taiwan

-         Chiou et al. (2001), cohort study on the incidence cancer of the bladder in in northeast Taiwan

-         Ferrecio et al. (2000), case-control study on the incidence of lung cancer in Chile

These studies focused on populations exposed to high arsenic concentrations and pointed to a possible linear dose-response relationship between ingestion of arsenic via drinking water and cancer (UBA, 2007).

In 2006, a comprehensive study was conducted by Ahsan et al. (2006) in Araihazar (Bangladesh), designated the “Health Effects of Arsenic Longitudinal Study” (HEALS), which overcomes many of the major shortcomings often attributed to epidemiological studies, such as limited number of subjects and thus the statistical power, as well as inadequate control of actual exposures. The study: i) addresses a large number of subjects (n = 11,746), ii) covers a wide range of arsenic concentrations in drinking water (0.1-864 µg/L), and iii) properly characterises exposure to arsenic (not only was the arsenic in well water analysed, but also drinking water consumption monitored and most relevant, creatinine-adjusted urinary arsenic excretion as monitored for each enrolled participant). This prospective cohort study is quite unique in a way that almost 100 percent of the drinking water for this population comes from one or two wells with relatively stable concentrations of arsenic which were also analysed across the study. These data were correlated with collected usage data, average duration of well use, past exposure history and total urinary arsenic concentration measured on 11 224 HEALS participants. This proper characterisation of the population exposure to arsenic made it one of the useful studies for the purpose of risk assessment. Compared with drinking water containing <8.1 µg/L of arsenic, the study concludes that drinking water containing 8.1-40.0, 40.1-91.0, 91.1-175.0, and 175.1-864.0 µg/L was associated with adjusted prevalence odds ratios of premalignant skin lesions of 1.91 (95% confidence interval (CI): 1.26, 2.89), 3.03 (95% CI: 2.05, 4.50), 3.71 (95% CI: 2.53, 5.44) and 5.39 (95% CI: 3.69, 7.86), respectively. The effect seemed to be influenced by gender, age, and body mass index. The value of 8.1 µg As/L (rounded to 8 µg/L) could be seen as a NOAEL for the study.

Work by Lamm et al. (2003 and 2006) does not support the linear dose-response hypothesis and the authors extrapolate a threshold for carcinogenicity of 160 µg/L based on epidemiological data from Taiwan.In 2015, Lamm et al. conducted an exhaustive review of published literature on the association of lung cancer and drinking water arsenic levels and the risk from arsenic exposures in the range of 1 ppb to 1 ppm, covering a total of 202 citations from 1981 through 2015. The final set of studies was comprised of three from Chile, two from Taiwan and one from the US, involving two ecological studies, three case-control studies and one cohort study. The authors applied regression analysis to examine the relationship between the relative risk and arsenic exposure over a drinking water concentration range of 1 - 1000 µg/L. They concluded that the analysis of the data from the ecological studies was as informative as the analysis of the non-ecological studies (i.e. case-control and cohort studies). All analyses generally indicated no increased risk for lung cancer at exposures below about 100–150 µg/L.

Christoforidou et al. (2013) carried out a systematic review of the existing literature (2000-2013) examining the association between the risk of bladder cancer in humans and exposure to arsenic through drinking water. They considered eight ecological studies, six case-control studies, four cohort studies and two meta-analyses to be of relevance (the majority of the studies were carried out in areas with high arsenic concentrations in drinking water such as southwestern and North-Eastern Taiwan, Pakistan, Bangladesh, Argentina (Cordoba Province), USA (South-Eastern Michigan, Florida, Idaho) and Chile). Most of the studies reported higher risks of bladder cancer incidence or mortality in areas with high arsenic concentrations in drinking water compared to the general population or a low arsenic exposed control group. The reliability of these studies was somewhat limited in that arsenic exposure was assessed at the individual level only in half of them, only three of them assessed exposure using a biomarker and only five out of eight ecological studies adjusted for potential confounders except for age. In contrast, all cohort and case-control studies adjusted for cigarette smoking. One conclusion of the authors was that the majority of the studies provided evidence of statistically significant increases in bladder cancer risk at high concentrations of arsenic (>50μg/L). It was however also noted that, in the case-control studies, an increased bladder cancer risk with arsenic in drinking water was only observed among smokers. One of the meta-analysis studies (Mink et al., 2008) which performed a stratified analysis on smoking status concluded that arsenic exposure at low concentrations (<100 – 200 μg/L) alone did not seem to be an important independent risk factor for bladder cancer.

Lynch et al. (2017) conducted an analysis to determine the most appropriate cancer endpoints, studies and models to support an oral carcinogenicity assessment of inorganic arsenic, taking into consideration factors that affect the apparent potency across geographically and culturally distinct populations. Overall, they found that the incremental risks of bladder and lung cancer associated with inorganic arsenic were relatively low. They concluded that mode of action evidence supports there being a threshold, but that making a robust quantitative demonstration of a threshold using epidemiological data is difficult.

Tsuji et al. (2019) evaluated the epidemiology of cancers of the urinary bladder, lung and skin and non-cancer skin changes for consistency with a calculated threshold value of value of 50–100 µg/L in drinking water (about 65 µg/L) based on extensive investigations in mode of action analysis, in in vitro studies (>0.1 µM) and in animal studies (>2 mg/L in drinking water or 2 mg/kg of diet). The authors focused on studies involving low-level exposures to inorganic arsenic primarily in drinking water (approximately <150 µg/L). Based on the relevant epidemiological studies with individual-level data, a threshold level for inorganic arsenic in the drinking water for these cancers was estimated to be around 100 µg/L, with strong evidence that it is between 50 and 150 µg/L, consistent with the value calculated based on mechanistic, in vitro and in vivo investigations.

Boffetta and Borron (2019) conducted a systematic review and a dose-response meta-analysison risk estimates of lung and bladder cancer for exposure to arsenic in drinking water up to 150 µg/L using a 2-stage approach based on a random-effects model. Their findings provide evidence of a lack of an increased risk of lung and bladder cancer for exposure to arsenic in drinking water up to 150 µg/L, the highest concentration studied.

Inhalation route:

Several studies have been reported in the past that document the association between inhalation exposure to arsenic and lung cancer, more specifically to arsenic trioxide dust in air at copper smelters. These have previously been described in detail (ATSDR, 2007) and are therefore addressed here only briefly:

-         a cohort study of works in the Asarco copper refinery in Washington, USA (Enterline et al., 1987)

-         a cohort study in the Anaconda copper refinery in Montana, USA (Lee-Feldstein et al., 1983 and 1986)

-         a study in a collective of Swedish copper refinery workers (Järup et al., 1989).

The most recent and reliable study is considered to be the one by Lubin et al. (2008) which is an updated evaluation of the cohort of workers in the Anaconda (USA) refinery. This latter investigation relates to the most recent data with the highest number of man-years and also an attempt at a more thorough exposure assessment. However, imprecision inherent to such retrospective exposure estimates cannot be excluded and altogether these occupational epidemiological studies do not allow to identify a clear NOAEL.

​Mode of action

The mode of action by which inorganic arsenic produces its non-carcinogenic and carcinogenic effects in various organs and systems is not entirely elucidated and still the subject of intense debate. Based on a wide body of available evidence, inorganic arsenic compounds do not appear to be mutagenic but may cause indirect DNA damage, including chromosomal aberrations, micronucleus formation and sister chromatid exchanges in vitro and in vivo. Because this indirect toxicity was observed to occur generally at high concentrations, above those that would be attained systemically in animals and humans, it does not seem to be the basis for the carcinogenicity of arsenicals, either in animals or in humans, particularly at lower doses (Tsuji et al., 2019). Instead, there is growing evidence for a mode of action involving the formation of reactive trivalent metabolites interacting with critical cell sulfhydryl groups of protein of target tissues, leading to cytotoxicity and regenerative cell proliferation. Since these proteins are constantly regenerating, this will be a threshold effect requiring the level of interaction to be greater than the active regenerative process of the proteins.The cytotoxicity results in non-cancer toxicities and the cell proliferation enhances the development of epithelial cancers. In other tissues such as vascular endothelium, different toxicities develop, not cancer. This mode of action implies a non-linear, threshold dose-response relationship for both cancer and non-cancer endpoints, requiring sufficient concentrations of trivalent arsenic to disrupt normal cell function (Cohen et al., 2013; Tsuji et al., 2019). Epidemiology supports that cytotoxicity and regenerative hyperplasia leading to bladder cancer in humans can result from the chronic inflammatory change to the bladder epithelium, such as bacterial cystitis and schistosomiasis, consistent with non-DNA reactive and thus, a threshold MoA. Also, the increased occurrence of bronchitis and bronchiectasis in populations exposed to arsenic in drinking water suggests that these diseases involving hyperplasia may be precursors to lung carcinoma in such settings. Similarly, like hair and nails, which bind arsenic, skin is rich of sulfhydryl-containing keratin. Hyperkeratosis in skin representing proliferative effects of arsenic are thought to be pre-malignant changes. Arsenic-related cancer thus appears to result from prolonged non-genotoxic effects on lung, bladder epithelial tissues and the skin.

As noted above, cancer risk assessment for inorganic arsenic has traditionally followed a linear dose-response approach using data from drinking water studies at relatively high exposure levels. However, mode of action considerations and the outcome of several recent reviews suggest the existence of a threshold for carcinogenic and non-carcinogenic effects at around 100 µg As/L in drinking water.

Although the balance of evidence suggests that the carcinogenicity hazards of arsenic and compounds may e driven by key events that each have a threshold below which they will not occur , the available data do not allow the identification of such numerical proper threshold, especially by taking into account the inhalation studies. Based on meta-analysis and epidemiology studies, a threshold dose-response relationship for both cancer and non-cancer endpoints, with a possible threshold around 100-150 µg As/L in drinking water can generally be observed. In line with the threshold concept but adopting a conservative approach, the present risk assessment has selected the NOAEL of 8 µg As/L in drinking water from the study by Ahsan et al. (2006) as a point of departure (POD) for the extrapolation of safe exposure levels in a REACH context for both workers and the general population. Further details are provided in the DNEL section.

References not cited in ATSDR (2007)

Boffetta P and Borron C (2019). Low-level exposure to arsenic in drinking water and risk of lung and bladder cancer: a systematic review and dose-response meta-analysis. Dose Response 17(3):1559325819863634. doi: 10.1177/1559325819863634. eCollection 2019 Jul-Sep. PMID: 31384239.

Christoforidou EPJ et al. (2013). Bladder cancer and arsenic through drinking water: a systematic review of epidemiologic evidence. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. 48(14):1764-75.

Cohen SM et al. (2017). Response to Druwe and Burgoon, 2016 Letter to the Editor in Archives of Toxicology. Arch. Toxicol. 91(2):999-1000.

Druwe IL and Burgoon LD (2016). Response to Cohen et al. (2016) regarding response to Druwe and Burgoon. Arch Toxicol.  90(12):3131-3132.

Lamm SH et al. (2015). A systematic review and meta-regression analysis of lung cancer risk and inorganic arsenic in drinking water. Int. J. Environ. Res. Public Health 12(12):15498-515.  

Lynch HN et al. (2017). Quantitative assessment of lung and bladder cancer risk and oral exposure to inorganic arsenic: Meta-regression analyses of epidemiological data. Environ Int.  106:178-206. Erratum in: Environ Int. 109:195-196.

National Research Council (NRC) (1999). Arsenic in drinking water: Subcommittee on arsenic in drinking water. Washington DC. National Academic Press, 310.

National Research Council (NRC) (2001). Arsenic in drinking water: 2001 update. Subcommittee on arsenic in drinking water. Washington DC. National Academic Press, 189.

Tsuji, JS et al. (2019). Dose-response for assessing the cancer risk of inorganic arsenic in drinking water: the scientific basis for use as a threshold. Crit. Rev. Toxicol. https://doi.org/10.1080/10408444.2019.1573804.

 

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2004 to 2006
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
A long-term carcinogenicity bioassay on sodium arsenite (NaAsO2) was performed. NaAsO2 was administrated with drinking water at concentrations of 200, 100, 50, or 0 mg/L, for 104 weeks to Sprague-Dawley rats (50/sex/group), 8 weeks old at the start of the study. The animals were monitored until spontaneous death at which time each animal underwent complete necropsy. Histopathological evaluation of all pathological lesions and of all organs and tissues collected was routinely performed on each animal. Also, drinking water and feed consumption were monitored during the study as well as body weight. Lastly, the animals were clinically examined during the study.
GLP compliance:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 8 weeks old
- Housing: animals were housed in groups of five in makrolon cages (41 cm X 25 cm X 15 cm) with stainless-steel wire tops and a shallow layer of white wood-shavings as bedding.
- Diet: standard Corticella diet (Corticella S.p.A., Bologna, Italy)
- Water (ad libitum): tap water

ENVIRONMENTAL CONDITIONS
- Temperature: 21 ± 2°C
- Relative humidity: 50 - 60%
- Photoperiod (hrs dark / hrs light): 12/12 (natural and artificial light sources)

After weaning at 4 -5 weeks of age, the experimental animals were randomized in order to have no more than one male and one female from each litter in the same group.
Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
Each morning, leftover solution from the previous day was removed and glass drinking bottles were washed and refilled with fresh solution.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
ad libitum
Post exposure period:
no data
Remarks:
Doses / Concentrations:
0, 50, 100 or 200 mg/L
Basis:
nominal in water
based on test substance
No. of animals per sex per dose:
50/sex/group
Control animals:
yes, concurrent no treatment
Details on study design:
NaAsO2 was administrated with drinking water at concentrations of 200, 100, 50, or 0 mg/L, for 104 weeks to Sprague-Dawley rats (50/sex/group), 8 weeks old at the start of the study. The animals were monitored until spontaneous death at which time each animal underwent complete necropsy. Histopathological evaluation of all pathological lesions and of all organs and tissues collected was routinely performed on each animal. Also, drinking water and feed consumption were monitored during the study as well as body weight. Lastly, the animals were clinically examined during the study.
Positive control:
no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: the animals were clinically examined for gross changes every 2 weeks for the duration of the study.

DETAILED CLINICAL OBSERVATIONS: No data

DERMAL IRRITATION: No data

BODY WEIGHT: Yes
- Time schedule for examinations: body weight was measured individually once weekly for the first 13 weeks and then every 2 weeks until 111 weeks of age. Measurement of body weight contiuned every 8 weeks until the end of the experiment.

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Mean daily feed consumption was measured once weekly per cage for the first 13 weeks, and then every 2 weeks until 111 weeks of age.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION: Yes
- Time schedule for examinations: mean daily drinking water was measured once weekly per cage for the first 13 weeks, and then every 2 weeks until 111 weeks of age.

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER: extensive historical data are available on the tumor incidence among untreated rats.
Sacrifice and pathology:
The biophase ended at 159 weeks, with the death of the last animal at 167 weeks of age. Upon, death, all animals underwent complete necropsy. Histopathology was routinely performed on the following organs and tissues of each animal from each group: skin and subcutaneous tissue, the brain (three sagittal sections), pituitary gland, Zymbal glands, salivary glands, Harderian glands, cranium (five sections, with oral and nasal cavities and external and internal ear ducts), tongue, thyroid, parathyroid, pharynx, larynx, thymus and mediastinal lymph nodes, trachea, lung and mainstem bronchi, heart, diaphragm, liver, spleen, pancreas, kidneys, adrenal glands, esophagus, stomach (fore and glandular), intestine (four levels), urinary bladder, prostate, gonads, interscapular brown fat pad, subcutaneous and mesenteric lymph nodes, and other organs or tissues with pathological lesions. All organs and tissues were preserved in 70% ethyl alcohol, except for bones, which were fixed in 10% formalinand the decalcified with 10% formaldehyde and 20% formic acid in water solution. The normal specimens were trimmed, following SOP. Trimmed specimens were processed as paraffin blocks and 3 - 5 µm sections of every specimen were obtained. Sections were routinely stained with Hematoxylin-Eosin.
Statistics:
Mutilple tumors of different types and sites, of different types in the same site, of the same types in bilateral organs, of the same types in the skin, subcutaneous tissue or mammary glands, or at distant sites of diffuse tissue (i.e., bones aand skeletal muscle) were plotted as single/independent tumors. Multiple tumors of the same type in the same tissue and organ, apart from those mentioned above, were plotted only once.
Three statistical tests were used to analyze neoplastic and non-neoplastic lesion incidence data. The Chi-square test and the Fisher's exact test (HAseman, 1978)* were used to evaluate differences in tumor incidence between treated and control groups. The Cochran-Armitage trend test (Armitage, 1971; Gart et al., 1979)** was used to test for linear trends in tumor incidence.

References *, **

* HASEMAN, J.K. 1978. Exact sample sizes with the Fisher-Irwin test for 2×2 tables. Biometrics 34: 106–109.
** ARMITAGE, P. 1971. Statistical Methods in Medical Research. JohnWiley & Sons. New York.
** GART, J.J., K.C. CHU & R.E. TARONE. 1979. Statistical issues in interpretation of chronic tests for carcinogenicity. J. Natl. Cancer Inst. 62: 957–974.
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
Differences in survival rates were observed in both males and females; a slight decrease in the survival rate was observed in males treated at 200 and 100 mg/L, particularly from 40 weeks of age until 88 weeks of age, whereas in females, a decrease in survival rate was observed from 104 weeks of age until the end of the experiment.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A dose related difference in mean body weight was observed in males. The difference was more evident in the males treated at 200 mg/L (circa 15% when compared with controls). Differences in mean body weight were also observed in females of the groups treated at 200 and 100 mg/L. Mean body weight was about 20% less in females treated at 200 mg/L compared with control and about 10% less in females treated at 100 mg/L. No treatment-related differences in body weight were observed in females treated at 50 mg/L.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
A dose-related lower intake of feed was also observed in both male and female rats. This difference was less marked between the group treated at 50 mg/L and the control in both males and females.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
A dose-related lower intake of water containing various levels of NaAsO2 was observed in both male and female rats. In females, water consumption became similar between the group treated at 50 mg/L and the control after 88 weeks of age.
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Long-term exposure of sodium arsenite administered in drinking water to Sprague-Dawley rats has been shown to induce toxic effects on the kidneys at concentrations as high as 200 mg/L and, to a lesser extent 100 mg/L and 50 mg/L. Nephropathies were characterized by diffuse acute/chronic inflammation, tubular enlargement with deposits of ialin casts and marked fibrosis around glomeruli with distension of Bowman’s space.
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The main oncologic results of the experiment are attached below in the field "Attached background material" (Tables 1 and 2). Among males treated at 100 mg/L, a slightly increased incidence of animals bearing malignant tumors and a statistically significant increased number of total malignant tumors (P < 0.05) were observed when compared to controls. Sparse very infrequent benign and malignant tumors were observed in the treated groups, namely, one adenocarcinoma of the lung in a male treated at 200 mg/L; one carcinoma of the kidney and one papilloma of the pelvis in a male treated at 100 mg/L and two papillomas of the renal pelvis in another rat treated at the same dose. Renal pelvis papillomas were also observed in two males treated at 50 mg/L. Among females treated at 100 mg/L, a slightly increased incidence of animals bearing malignant tumors and an increased number of total malignant tumors were observed when compare to controls. Among the females treated at 200 mg/L, one adenocarcinoma of the lung was observed. The same group also included two animals bearing kidney adenomas, two bearing kidney carcinomas, and one bearing a renal pelvis carcinoma. In the group treated at 100 mg/L, three animals were observed bearing kidney adenomas, one bearing a kidney carcinoma and one bearing a renal pelvis papilloma. One animal bearing a bladder carcinoma was also observed among the females treated at 100 mg/L.
Other effects:
not specified
Details on results:
HISTORICAL CONTROL DATA
It must be noted that among the untreated Sprague-Dawley rats used in study experiment laboratories over the last 20 years (2265 males and 2274 females), the overall incidence of lung adenomas was 0.2% in males (range: 0–2.0%) and 0.1% in females (range: 0–1.0%), while the overall incidence of lung carcinomas was 0.1% in both males (range: 0–1.0%) and females (range: 0–1.3%). The overall incidence of the kidney adenomas was 0.1% in males (range: 0–1.3%) and 0.2% in females (range: 0–2.0%), while the overall incidence of kidney carcinomas was 0.2% in males (range: 0–0.3%) and 0.3% in females (range: 0–1.8%). With regard to historical data on the transitional cell epithelium of the renal pelvis and ureter, no papillomas were observed in either males or females, while only one carcinoma was observed in a female (overall incidence: 0.04% and range: 0–1.0%). No carcinomas in the transitional cell epithelium of the bladder were observed in either males or females.
Key result
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Conclusions:
Under the conditions of their study, sodium arsenite induced sparse benign and malignant tumours amongst treated rats.
Executive summary:

A 2-year (104-week) carcinogenicity dose–response study was conducted with sodium arsenite (NaAsO2) administered via drinking water to Sprague-Dawley rats (50/sex/group, 8 weeks old at the start of the study) at concentration of 0, 50, 100 and 200 mg/L ad libitum. Mean daily drinking water and feed consumption were measured once weekly per cage for the first 13 weeks, then every 2 weeks until 111 weeks of age. Body weight was measured individually once weekly for the first 13 weeks, then every 2 weeks until 111 weeks of age (however, dose levels expressed in mg/kg bw/day are not provided in the publication). The rats were maintained until spontaneous death, at which time each animal underwent complete necropsy. Histopathological evaluation of all pathological lesions and of all organs and tissues collected was routinely performed.

A dose-related lower intake of water was observed in both male and female rats. In females, water consumption became similar between the group treated at 50 mg/L and the control after 88 weeks of age. A dose-related lower intake of feed was also noted in both male and female rats. This difference was less marked between the group treated at 50 mg/L and the control. A dose-related difference in mean body weight was observed in males. The difference was more evident at 200 mg/L (circa 15% when compared with controls). Mean body weight in females was about 20% less at 200 mg/L compared with control and about 10% less at 100 mg/L. No treatment-related differences in body weight were observed in females at 50 mg/L. A slight decrease in the survival rate was observed in males at 200 and 100 mg/L, particularly from 40 to 88 weeks of age, whereas in females, a decrease in survival rate was observed from 104 weeks of age until the end of the experiment.

Among males treated at 100 mg/L, a slightly increased incidence of animals bearing malignant tumors and a statistically significant increase in number of total malignant tumors (p<0.05) were observed when compared to controls. One adenocarcinoma of the lung was seen at 200 mg/L, one carcinoma of the kidney and one papilloma of the pelvis at 100 mg/L and two papillomas of the renal pelvis in another rat at the same dose. Renal pelvis papillomas were also observed in two males at 50 mg/L.

Among females treated at 100 mg/L, a slightly increased incidence of animals bearing malignant tumors and an increased number of total malignant tumors were observed when compared to controls. Three animals were found bearing kidney adenomas, one bearing a kidney carcinoma and one bearing a renal pelvis papilloma. One animal with a bladder carcinoma was also noted in this group. At 200 mg/L, one adenocarcinoma of the lung was observed. The same group also included two animals bearing kidney adenomas, two bearing kidney carcinomas and one bearing a renal pelvis carcinoma.

The authors concluded that, under the conditions of their study, sodium arsenite induced sparse benign and malignant tumours amongst treated rats. They noted that the types of tumours observed were infrequent in the strain of Sprague-Dawley rats of the colony used in their laboratory (Soffritti et al., 2006).

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

In their most recent monograph, IARC (2012) conclude that there is sufficient evidence in humans for the carcinogenicity of mixed exposure to inorganic arsenic compounds, including for example the soluble arsenic trioxide and arsenite salts. These compounds cause cancer of the urinary bladder, lung and skin. Also, a positive association has been observed between exposure to inorganic arsenic compounds and cancer of the kidney, liver and prostate.

In the EU, diarsenic trioxide and arsenic acid and its salts are subject to a harmonised hazard classification as Carc. 1A - H350 (May cause cancer) according to Regulation (EC) No. 1272/2008.

Additional information