Registration Dossier

Administrative data

Description of key information

It is generally considered that trivalent arsenic compounds are more toxic than the pentavalent forms, at least at high doses. Oral exposure to inorganic arsenic has a number of effects, including cardiovascular, respiratory, gastrointestinal, haematological, immune, reproductive, and nervous systems. More recent studies have focussed on the immune, reproductive and nervous systems (ATSDR, 2007). However, overall repeated dose toxicity may be considered secondary to the carcinogenicity of arsenic. Thus, effect levels and DNELs have not been established for this end-point.

Key value for chemical safety assessment

Mode of Action Analysis / Human Relevance Framework

Additional information

Inhalation route (humans):

 

Respiratory effects:

Workers exposed to arsenic dusts in air often experience irritation to the mucous membranes of the nose and throat which may lead to laryngitis, bronchitis or rhinitis, and very high exposures characteristic of workplace exposures in the past can cause perforation of the nasal septum. However, despite these known respiratory irritant effects of arsenic, there have been few systematic investigations of respiratory effects in humans exposed to arsenic, none are considered to be conclusive as to the relationship between inhaled inorganic arsenic and respiratory disease (ATSDR, 2007).

 

Cardiovascular effects

There is some evidence from epidemiological studies that inhaled inorganic arsenic can produce effects on the cardiovascular system, but such following oral exposure to arsenic are better characterised (ATSDR, 2007).

 

Gastrointestinal effects:

Several case studies have reported nausea, vomiting, and diarrhoea in workers with acute arsenic poisoning following occupational inhalation exposure. Although gastrointestinal effects are not typically associated with arsenic poisoning by inhalation, such effects are a common feature of oral ingestion of high doses of arsenic. Exposure levels were not reliably estimated for any of these cases (ATSDR, 2007).

 

Dermal effects:

Dermatitis has frequently been observed in industrial workers exposed to inorganic arsenic in the air, with the highest rates occurring in the workers with the greatest arsenic exposure. However, limited quantitative information is available regarding the exposure levels that produce such dermatitis, and co-exposure by the dermal route makes a dose-response analysis difficult. The highest arsenic exposure (0.384-0.034 mg As/m3) were affected bygrossly pigmentation, hyperkeratinisation multiple warts. NOAEL values for dermal irritation have however not been identified (ATSDR, 2007).

 

Neurological effects:

There is some evidence from epidemiological studies that inhaled inorganic arsenic can produce neurological effects: studies of copper smelter workers at the ASARCO smelter (USA), a power station in Slovakia and the Ronnskar smelter (Sweden) have demonstrated peripheral neurological effects in workers associated with arsenic trioxide exposure (ATSDR, 2007). However, the associated exposures are apparently difficult to quantify.

 

Other organ systems:

There is no reliable evidence in humans that inhaled inorganic arsenic produces effects on other important organ systems such as liver, kidneys or the haematological, immunological and musculoskeletal system.

 

 

Inhalation route (animals):

 

Respiratory and gastrointestinal effects:

Respiratory symptoms such as rales (8 mg As/m3), laboured breathing and gasping (20 mg As/m3) were observed in a developmental study in rats with inhalation exposure to arsenic trioxide dust, with no symptoms at 2 mg As/m3. Since this sort of response is produced by a number of respirable particulate materials, it is likely that the inflammatory response is not specifically due to arsenic. Upon autopsy, some of the animals exposed to 20 mg As/m3exhibited severe hyperaemia and plasma discharge into the intestinal lumen, whereas exposure to 8 mg As/m3did not produce gross gastrointestinal lesions (Holson et al. 1999; ATSDR, 2007).

 

Immunological effects:

Female mice exposed to arsenic trioxide aerosol for 3 hours showed a concentration-related decrease in pulmonary bactericidal activity presumably as a result of injury to alveolar macrophages, and a corresponding concentration-related increase in susceptibility to introduced respiratory bacterial pathogens (Aranyi et al., 1985; cited in ATSDR, 2007).

 

Other organ systems:

There is no reliable evidence in animals that inhaled inorganic arsenic produces effects on other important organ systems such as liver, kidneys, skin or the haematological, immunological, cardiovascular and musculoskeletal system (ATSDR, 2007).

 

 

 

Oral route (humans):

 

There are a large number of studies in humans and animals on the toxic effects of ingested arsenic. In humans, most cases of toxicity have resulted from accidental, suicidal, homicidal, or medicinal ingestion of arsenic-containing powders or solutions or by consumption of contaminated food or drinking water. In many cases, the exact chemical form of arsenic is not known; however, it is presumed that the most likely forms are either inorganic arsenate [As(+5)], inorganic arsenite [As(+3)] or a mixture of both.

 

Respiratory effects:

Bronchitis and sequelae (bronchiectasis, bronchopneumonia) have been observed in patients and at autopsy in some chronic poisoning cases (Guha Mazumder et al. 2005; Milton and Rahman 2002; Rosenberg 1974; Tsai et al. 1999; Zaldívar 1974; Zaldívar and Guillier 1977). Bronchopneumonia secondary to arsenic-induced bronchitis was considered to be the cause of death in one young child who died after several years of exposure to an average dose of 0.08 mg As/kg/day (Zaldívar and Guillier 1977). Decrements in lung function, measured as decreased FEV1, FVC, and FEF25–75 have also been reported in subjects exposed to 0.1–0.5 mg As/L in the drinking water and exhibiting skin lesions (von Ehrenstein et al. 2005). In general, however, respiratory effects have not been widely associated with repeated oral ingestion of low arsenic doses. Nevertheless, a few studies have reported minor respiratory symptoms, such as cough, sputum, rhinorrhea, and sore throat, in people with repeated oral exposure to 0.03–0.05 mg As/kg/day (Ahmad et al. 1997; Mizuta et al. 1956) (ATSDR, 2007).

 

Cardiovascular effects

A number of studies in humans indicate that arsenic ingestion may lead to serious effects on the cardiovascular system. Characteristic effects on the heart from both acute and long-term exposure include altered myocardial depolarization (prolonged QT interval, nonspecific ST segment changes) and cardiac arrhythmia (Cullen et al. 1995; Glazener et al. 1968; Goldsmith and From 1986; Heyman et al. 1956; Little et al. 1990; Mizuta et al. 1956; Moore et al. 1994b; Mumford et al. 2007). A significant dose-related increase in the prevalence of cardiac electrophysiological abnormalities was observed in residents of Inner Mongolia, China; the incidences of QT prolongation were observed in 3.9, 11.1, and 20.6% of the residents with drinking water levels of <21, 110–300, and 430–690 μg/L, respectively (Mumford et al. 2007). Most dramatic is "Blackfoot Disease," a condition that is endemic in an area of Taiwan where average drinking water levels of arsenic range from 0.17-0.80 ppm (Tseng 1977), corresponding to doses of about 0.014–0.065 mg As/kg/day (IRIS 2007). The disease is characterised by a progressive loss of circulation in the hands and feet, leading ultimately to necrosis and gangrene (Chen et al. 1988b; Ch’i and Blackwell 1968; Tseng 1977, 1989; Tseng et al. 1968, 1995, 1996). Despite other factors being suspected of playing a role in the etiology of this disease (Ko 1986; Lu et al. 1990; Yu et al. 1984), the clear association between the occurrence of Blackfoot Disease and the intake of elevated arsenic levels indicates that arsenic is at least a contributing factor.

Arsenic exposure in Taiwan has also been associated with an increased incidence of cerebrovascular and microvascular diseases (Chiou et al. 1997; Wang et al. 2002, 2003) and ischemic heart disease (Chang et al. 2004; Chen et al. 1996; Hsueh et al. 1998b; Tsai et al. 1999; Tseng et al. 2003). Hypertension, defined as a systolic blood pressure of ≥140 mm Hg in combination with a diastolic blood pressure of ≥90 mm Hg, was associated with estimated lifetime doses of approximately 0.055 mg As/kg/day (0.25 mg/L in water) in a study of people in Bangladesh (Rahman et al. 1999), whereas no significant association was found with estimated doses of 0.018 mg As/kg/day (0.75 mg/L in water). Wang et al. (2003) found an increased incidence of microvascular and macrovascular disease among subjects in Taiwan living in an arseniasis-endemic area in which the water of artesian wells had arsenic concentrations >0.35 mg/L (estimated doses of >0.03 mg As/kg/day). An additional study of Taiwanese subjects reported a significant increase in incidence of hypertension associated with concentrations of arsenic in the water >0.7 mg/L (estimated doses of >0.06 mg As/kg/day) (Chen et al. 1995). Studies in Chile indicate that ingestion of 0.6–0.8 ppm arsenic in drinking water (corresponding to doses of 0.02-0.06 mg As/kg/day, depending on age) increases the incidence of Raynaud's disease and of cyanosis of fingers and toes (Borgoño and Greiber 1972; Zaldívar 1974, 1977; Zaldívar and Guillier 1977). Autopsy of five children from this region who died of apparent arsenic toxicity showed a marked thickening of small and medium sized arteries in tissues throughout the body, especially the heart (Rosenberg 1974). In addition, cardiac failure, arterial hypotension, myocardial necrosis, and thrombosis have been observed in children who died from chronic arsenic ingestion (Zaldívar 1974), as well as adults chronically exposed to arsenic (Dueñas et al. 1998). Likewise, thickening and vascular occlusion of blood vessels were noted in German vintners exposed to arsenical pesticides in wine and in adults who drank arsenic-contaminated drinking water (Roth 1957; Zaldívar and Guillier 1977). A survey of Wisconsin residents using private wells for their drinking water found that residents exposed for at least 20 years to water concentrations of >10 μg As/L had increased incidences of cardiac bypass surgery, high blood pressure, and circulatory problems as compared with residents exposed to lower arsenic concentrations (Zierold et al. 2004). Similarly, Lewis et al. (1999) reported increased mortality from hypertensive heart disease in both men and women among a cohort exposed to arsenic in their drinking water in Utah, as compared with the general population of Utah. Limitations in the study included lack of evaluation of smoking as a confounder and of other dietary sources of arsenic, and the lack of a dose-response for hypertensive heart disease. Another ecological study (Engel and Smith 1994) found significant increases in deaths from arteriosclerosis, aortic aneurysm, and all other diseases of the arteries, arterioles, and capillaries among U.S. residents with arsenic drinking waters of >20 μg/L; the increase in deaths from congenital anomalies of the heart and other anomalies of the circulatory system also observed in this subpopulation limits the interpretation of the findings (ATSDR, 2007).

 

Gastrointestinal effects:

Clinical signs such as gastrointestinal irritation, including nausea, vomiting, diarrhoea, and abdominal pain, are observed in groups or individuals with longer-term, lower-dose exposures (e.g., Borgoño and Greiber 1972; Cebrián et al. 1983; Franzblau and Lilis 1989; Guha Mazumder et al. 1988, 1998a; Haupert et al. 1996; Holland 1904; Huang et al. 1985; Mizuta et al. 1956; Nagai et al. 1956; Silver and Wainman 1952; Wagner et al. 1979; Zaldívar 1974), but effects are usually not detectable at exposure levels below about 0.01 mg As/kg/day (Harrington et al. 1978; Valentine et al. 1985). These symptoms generally decline within a short time after exposure ceases. More severe symptoms (hematemesis, hemoperitoneum, gastrointestinal hemorrhage, and necrosis) have been reported in some people with long-term ingestion of 0.03–0.05 mg As/kg/day as a medicinal preparation (Lander et al. 1975; Morris et al. 1974) (ATSDR, 2007).

 

Haematological effects:

Anaemia and leukopenia are common effects of arsenic poisoning in humans, and have been reported following intermediate (Franzblau and Lilis 1989; Heyman et al. 1956; Nagai et al. 1956; Wagner et al. 1979), and chronic oral exposures (Chakraborti et al. 2003a; Glazener et al. 1968; Guha Mazumder et al. 1988; Hopenhayn et al. 2006; Kyle and Pease 1965; Tay and Seah 1975) at doses of 0.002 mg As/kg/day or more. These effects may be due to both a direct cytotoxic or haemolytic effect on the blood cells (Armstrong et al. 1984; Fincher and Koerker 1987; Goldsmith and From 1986; Kyle and Pease 1965; Lerman et al. 1980) and a suppression of erythropoiesis (Kyle and Pease 1965; Lerman et al. 1980). However, haematological effects are not observed in all cases of arsenic exposure (EPA 1981b; Harrington et al. 1978; Huang et al. 1985; Silver and Wainman 1952) (ATSDR, 2007).

 

Hepatic effects:

A number of studies in humans exposed to inorganic arsenic by the oral route have noted signs or symptoms of hepatic injury. Clinical examination often reveals that the liver is swollen and tender (Chakraborty and Saha 1987; Franklin et al. 1950; Guha Mazumder et al. 1988, 1998a; Liu et al. 2002; Mizuta et al. 1956; Silver and Wainman 1952; Wade and Frazer 1953; Zaldívar 1974), and analysis of blood sometimes shows elevated levels of hepatic enzymes (Armstrong et al. 1984; Franzblau and Lilis 1989; Guha Mazumder 2005; Hernández-Zavala et al. 1998). These effects are most often observed after repeated exposure to doses of 0.01–0.1 mg As/kg/day (Chakraborty and Saha 1987; Franklin et al. 1950; Franzblau and Lilis 1989; Guha Mazumder et al. 1988; Mizuta et al. 1956; Silver and Wainman 1952; Wade and Frazer 1953), although doses as low as 0.006 mg As/kg/day have been reported to have an effect following chronic exposure (Hernández-Zavala et al. 1998). Histological examination of the livers of persons chronically exposed to arsenic has revealed a consistent finding of portal tract fibrosis (Guha Mazumder 2005; Guha Mazumder et al. 1988; Morris et al. 1974; Piontek et al. 1989; Szuler et al. 1979), leading in some cases to portal hypertension and bleeding from oesophageal varices (Szuler et al. 1979); cirrhosis has also been reported at an increased frequency in arsenic-exposed individuals (Tsai et al. 1999). Several researchers consider that these hepatic effects are secondary to damage to the hepatic blood vessels (Morris et al. 1974; Rosenberg 1974), but this is not directly established (ATSDR, 2007).

 

Dermal effects:

One of the most common, characteristic effects of arsenic ingestion is a pattern of skin changes that include generalized hyperkeratosis and formation of hyperkeratotic warts or corns on the palms and soles, along with areas of hyperpigmentation interspersed with small areas of hypopigmentation on the face, neck, and back. These and other dermal effects have been noted in a large majority of human studies involving repeated oral exposure (e.g., Ahmad et al. 1997, 1999b; Ahsan et al. 2000; Bickley and Papa 1989; Borgoño and Greiber 1972; Borgoño et al. 1980; Cebrián et al. 1983; Chakraborti et al. 2003a, 2003b; Chakraborty and Saha 1987; Foy et al. 1992; Franklin et al. 1950; Franzblau and Lilis 1989; Guha Mazumder et al. 1988, 1998a, 1998b, 1998c; Guo et al. 2001a; Haupert et al. 1996; Huang et al. 1985; Lander et al. 1975; Liu et al. 2002; Lüchtrath 1983; Milton et al. 2004; Mizuta et al. 1956; Morris et al. 1974; Nagai et al. 1956; Piontek et al. 1989; Rosenberg 1974; Saha and Poddar 1986; Silver and Wainman 1952; Szuler et al. 1979; Tay and Seah 1975; Tseng et al. 1968; Wade and Frazer 1953; Wagner et al. 1979; Wong et al. 1998a, 1998b; Zaldívar 1974, 1977). In cases of low-level chronic exposure (usually from water), these skin lesions appear to be the most sensitive indication of effect, so this end point is considered to be the most appropriate basis for establishing a chronic oral MRL. This is supported by the finding that other effects (hepatic injury, vascular disease, neurological effects) also appear to have similar thresholds. Numerous studies in humans have reported dermal effects at chronic dose levels generally ranging from about 0.01-0.1 mg As/kg/day (Ahmad et al. 1997; Bickley and Papa 1989; Borgoño and Greiber 1972; Borgoño et al. 1980; Cebrián et al. 1983; Chakraborty and Saha 1987; Foy et al. 1992; Franklin et al. 1950; Guha Mazumder et al. 1988; Huang et al. 1985; Lüchtrath 1983; Piontek et al. 1989; Silver and Wainman 1952; Tseng et al. 1968; Zaldívar 1974, 1977). However, in a study with detailed exposure assessment, all confirmed cases of skin lesions ingested water containing >100 μg/L arsenic (approximately 0.0037 mg As/kg/day) and the lowest known peak arsenic concentration ingested by a case was 0.115 μg/L (approximately 0.0043 mg As/kg/day) (Haque et al. 2003). Another large study reported increased incidence of skin lesions associated with estimated doses of 0.0012 mg As/kg/day (0.023 mg As/L drinking water) (Ahsan et al. 2006). Several epidemiological studies of moderately sized populations (20–200 people) exposed to arsenic through drinking water have detected no dermal or other effects at average chronic doses of 0.0004–0.01 mg As/kg/day (Cebrián et al. 1983; EPA 1981b; Guha Mazumder et al. 1988; Harrington et al. 1978; Valentine et al. 1985), and one very large study detected no effects in any person at an average total daily intake (from water plus food) of 0.0008 mg As/kg/day (Tseng et al. 1968). This value has been used to calculate a chronic oral MRL for inorganic arsenic of 0.0003 mg/kg/day (ATSDR, 2007).

 

Neurological effects:

A large number of epidemiological studies and case reports indicate that ingestion of inorganic arsenic can cause injury to the nervous system. Repeated exposures to low levels (0.03–0.1 mg As/kg/day) are typically characterised by a symmetrical peripheral neuropathy (Chakraborti et al. 2003a, 2003b; Foy et al. 1992; Franzblau and Lilis 1989; Guha Mazumder et al. 1988; Hindmarsh et al. 1977; Huang et al. 1985; Lewis et al. 1999; Mizuta et al. 1956; Muzi et al. 2001; Silver and Wainman 1952; Szuler et al. 1979; Wagner et al. 1979). Neurological effects were not generally found in populations chronically exposed to doses of 0.006 mg As/kg/day or less (EPA 1981b; Harrington et al. 1978; Hindmarsh et al. 1977).There is emerging evidence suggesting that exposure to arsenic may be associated with intellectual deficits in children: for example, Wasserman et al. (2004) conducted a cross-sectional evaluation of intellectual function in 201 children 10 years of age whose parents were part of a larger cohort in Bangladesh. After adjustment for confounding factors, a dose-related inverse effect of arsenic exposure was seen on both performance and Full-Scale subset scores; for both end points, exposure to ≥50 μg/L resulted in statistically significant differences (p<0.05) relative to the lowest exposure group (<5.5 μg/L). A study of 351 children age 5–15 years from West Bengal, India, found significant associations between urinary arsenic concentrations and reductions in scores of tests of vocabulary, object assembly, and picture completion; the magnitude of the reductions varied between 12 and 21% (von Ehrenstein et al. 2007). In this cohort, the average lifetime peak arsenic concentration in well water was 0.147 mg/L. However, no clear pattern was found for increasing categories of peak arsenic water concentrations since birth and children’s scores in the various neurobehavioral tests conducted. Furthermore, using peak arsenic as a continuous variable in the regression models also did not support an adverse effect on the tests results (ATSDR, 2007).

 

Renal effects:

Most case studies of chronic arsenic toxicity do not report clinical signs of significant renal injury, even when other systems are severely impaired (e.g., Cullen et al. 1995; Franzblau and Lilis 1989; Jenkins 1966; Kersjes et al. 1987; Mizuta et al. 1956; Silver and Wainman 1952) (ATSDR, 2007).

 

Other organ systems:

No reliable studies of musculoskeletal or immunological effects in humans after oral exposure to inorganic arsenicals have been reported (ATSDR, 2007).

 


 

Oral route (animals):

 

Respiratory effects:

There are only few data regarding respiratory effects in animals following oral exposure to inorganic arsenic. An infant Rhesus monkey that died after 7 days of oral exposure to a complex arsenate salt at a dose of 3 mg As/kg/day exhibited bronchopneumonia with extensive pulmonary haemorrhage, oedema, and necrosis (Heywood and Sortwell 1979). Two other monkeys in this treatment group survived a 1-year exposure period and had no gross or microscopic pulmonary lesions at sacrifice. Increased relative lung weights were seen in rats exposed to 6.66 mg As/kg/day as sodium arsenite 5 days/week for 12 weeks (Schulz et al. 2002). Chronic oral studies in dogs and rats treated with arsenate or arsenite failed to find respiratory lesions (Byron et al. 1967; Kroes et al. 1974; Schroeder et al. 1968) (ATSDR, 2007).

 

Cardiovascular effects

Similar alterations in vascular reactivity have been noted in rats given repeated oral doses of arsenic trioxide (11 mg As/kg/day) for several weeks (Bekemeier and Hirschelmann 1989), although no histological effects could be detected in the hearts of rats or dogs exposed to up to 30 mg As/kg/day as arsenate or arsenite for 2 years (Byron et al. 1967; Kroes et al. 1974; Schroeder et al. 1968). Guinea pigs exposed to arsenic trioxide for 1 day (0, 7.6, 22.7, or 37.9 mg As/kg) or 8 days (0 or 3.8 mg As/kg/day) showed prolongation of the cardiac QT interval and action potential duration (Chiang et al. 2002) (ATSDR, 2007).

 

Gastrointestinal effects:

Clinical signs of gastrointestinal irritation were observed in monkeys and rats given repeated oral doses of arsenic (6 and 11 mg As/kg/day, respectively) for 2 weeks (Bekemeier and Hirschelmann 1989; Heywood and Sortwell 1979). Haemorrhagic gastrointestinal lesions have also been reported in animal studies. A monkey that died after repeated oral treatment with 6 mg As/kg/day for approximately 1 month was found to have acute inflammation and haemorrhage of the small intestine upon necropsy (Heywood and Sortwell 1979). This lesion was not found in other monkeys that died in this study, or in the survivors. Two pregnant mice that died after repeated gavage treatment with 24 mg As/kg/day as arsenic acid had haemorrhagic lesions in the stomach (Nemec et al. 1998). Gross gastrointestinal lesions (stomach adhesions, eroded luminal epithelium in the stomach) were seen frequently in rats treated by gavage with 8 mg As/kg/day as arsenic trioxide starting before mating and continuing through the end of gestation (Holson et al. 2000). The lesions were not found in rats treated with 4 mg As/kg/day in this study. No histological evidence of gastrointestinal injury was detected in rats exposed to arsenate or arsenite in the feed for 2 years at doses up to 30 mg As/kg/day, but dogs fed a diet containing 2.4 mg As/kg/day as arsenite for 2 years had some bleeding in the gut (Byron et al. 1967; Kroes et al. 1974) (ATSDR, 2007).

 

Haematological effects:

Long-term studies found mild anaemia in dogs fed arsenite or arsenate for 2 years at 2.4 mg As/kg/day, but no haematological effect in dogs fed 1 mg As/kg/day for 2 years or 1.9 mg As/kg/day for 26 weeks (Byron et al. 1967; Neiger and Osweiler 1989). Chronic rat studies found little or no evidence of anaemia at doses up to 30 mg As/kg/day, even with co-exposure to lead (Byron et al. 1967; Kroes et al. 1974). No haematological effects were found in monkeys exposed to arsenic doses of 3–6 mg As/kg/day for 1 year (Heywood and Sortwell 1979).Exposure of rats to ≥5 ppm of arsenic (0.30 mg As/kg/day as sodium arsenite) in the drinking water for 4 weeks resulted in increased platelet aggregation, while 10 or 25 ppm (0.60 or 1.5 mg As/kg/day) was associated with increased P-selectin-positive cells and decreased occlusion time (Lee et al. 2002), representing a change in platelet function. Similarly, exposure of rats or guinea pigs to 10 or 25 ppm of arsenic as arsenite (approximate doses of 0, 0.92, or 2.3 mg As/kg/day for rats and 0, 0.69, or 1.7 mg As/kg/day for guinea pigs) in the drinking water for 16 weeks (Kannan et al. 2001) resulted in decreases in erythrocyte and leukocyte numbers (rats and guinea pigs), increased blood mean corpuscular volume and corpuscular haemoglobin mass (guinea pigs only), and decreased mean corpuscular haemoglobin concentration (rats only) (ATSDR, 2007).

 

Hepatic effects:

Studies in dogs or mice have not detected clinically significant hepatic injury following exposure to either arsenite or arsenate (Byron et al. 1967; Fowler and Woods 1979; Kerkvliet et al. 1980; Neiger and Osweiler 1989; Schroeder and Balassa 1967), although enlargement of the common bile duct was noted in rats fed either arsenate or arsenite in the diet for 2 years (Byron et al. 1967; Kroes et al. 1974) and lipid vacuolation and fibrosis were seen in the livers of rats exposed to 12 mg As/kg/day as arsenate in the drinking water for 6 weeks (Fowler et al. 1977). Similarly, fatty changes and inflammatory cell infiltration were seen in the livers of both normal and metallothionein-null mice exposed to 5.6 mg arsenic/kg/day in the drinking water for 48 weeks (Liu et al. 2000).

 

An increase in indices of peroxidation was reported in rats dosed with approximately 0.02 mg As/kg/day for 60 days from drinking water containing 2.5 mg sodium arsenite/L (Bashir et al. 2006); absolute liver weight was also increased at this dose level. Exposure of guinea pigs to 0.69 or 1.7 mg As/kg/day in the drinking water for 16 weeks, but not in rats exposed to 0.92 or 2.3 mg As/kg/day, resulted in increases in delta-aminolaevulinic acid synthetase (ALAS) levels (Kannan et al. 2001). Exposure of BALB/C mice to 0.7 mg arsenic/kg/day in the drinking water for 15 months resulted in increased liver weights, changes in liver enzymes (glutathione S-transferase, glutathione reductase, catalase, glucose-6-phosphate dehydrogenase, glutathione peroxidase), fatty liver, and fibrosis (Santra et al. 2000) (ATSDR, 2007).

 

Dermal effects:

Dermal lesions similar to those observed in humans have not been noted in oral exposure studies in monkeys (Heywood and Sortwell 1979), dogs (Byron et al. 1967), or rodents (Schroeder et al. 1968) (ATSDR, 2007).

 

Neurological effects:

Neurological effects have also been observed in animal studies: Rodriguez et al. (2001) evaluated neurobehavioral changes in male Sprague-Dawley rats exposed to 0, 5, 10, or 20 mg As/kg/day as sodium arsenite by gavage for 2 or 4 weeks; significant effects were seen in spontaneous locomotor activity and the food pellet manipulation test in the high-dose animals, while no effects were seen in the low- or mid-dose rats. Decreased performance in open field tests were also seen in rats exposed to 26.6 mg As/kg/day, but not to 13.3 mg/kg/day or less, as sodium arsenite for 4 weeks (Schulz et al. 2002); curiously, the behavioural changes were no longer present at 8 and 12 weeks of exposure, which may suggest an adaptive response. Heywood and Sortwell (1979) reported salivation and uncontrolled head shaking in two monkeys given several doses of 6 mg As/kg/day as arsenate, while no such effects were noted in monkeys given 3 mg As/kg/day for 2 weeks. Nemec et al. (1998) observed ataxia and prostration in pregnant female rabbits treated with 1.5 mg As/kg/day repeatedly during gestation, but not in rabbits treated with 0.4 mg As/kg/day.(ATSDR, 2007).

 

Other organ systems:

No reliable studies of musculoskeletal or immunological effects in humans after oral exposure to inorganic arsenicals have been reported (ATSDR, 2007). Studies in animals also indicate that the kidney is not a major target organ for inorganic arsenic (Byron et al. 1967; Schroeder and Balassa 1967; Woods and Southern 1989) (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 repeated dose toxicity, are also observed, but occur at much higher doses. Therefore, a separate classification for “specific target organ toxicity - repeated” 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).