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EC number: 231-901-9 | CAS number: 7778-39-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicological Summary
- Administrative data
- Workers - Hazard via inhalation route
- Workers - Hazard via dermal route
- Workers - Hazard for the eyes
- Additional information - workers
- General Population - Hazard via inhalation route
- General Population - Hazard via dermal route
- General Population - Hazard via oral route
- General Population - Hazard for the eyes
- Additional information - General Population
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 6 µg/m³
- Most sensitive endpoint:
- carcinogenicity
DNEL related information
- Overall assessment factor (AF):
- 1
- Modified dose descriptor starting point:
- NOAEC
Acute/short term exposure
DNEL related information
Local effects
Acute/short term exposure
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 85 µg/kg bw/day
- Most sensitive endpoint:
- carcinogenicity
DNEL related information
- Overall assessment factor (AF):
- 1
- Modified dose descriptor starting point:
- NOAEL
Acute/short term exposure
DNEL related information
Workers - Hazard for the eyes
Additional information - workers
For the derivation of a DNEL for arsenic acid, carcinogenicity appears as the critical end-point with lowest NOAEL and will therefore be used to derive the DNEL. Rat and mouse, the two rodents which are normally used for chemical carcinogenicity testing appear as very poor and insensitive models to evaluate arsenic carcinogenicity potential. However, there is evidence from a large number of epidemiological studies that inhalation and oral exposure to inorganic arsenic increases the risk of lung cancer. Among these epidemiological studies on the carcinogenic potential of arsenic, only few of them are dealing with pentavalent (or non specified) mineral arsenic and are of sufficient quality to allow derivation of a NOAEL (or LOAEL).
For inhalation exposure, most studies involved workers exposed primarily to arsenic trioxide dust in air at copper smelters and despite some good studies with some information on dose effect relationship, these studies have many shortcomings and do not allow the definition of a reliable NOAEL for arsenic acid to derive a relevant DNEL. The more reliable is a study by Jarup et al, (1989) in which the cause-specific mortality was followed through 1981 in a cohort of 3,916 male Swedish smelter workers employed for at least 3 months from 1928 through 1967. Arsenic levels in the air of all workplaces within the smelter were estimated for three different time periods. Using this exposure matrix and detailed information of the work history, cumulative arsenic exposure could be computed for each worker. Standardized mortality ratios (SMRs) were calculated for several dose categories using age-specific mortality rates from the county where the smelter was situated. A positive dose-response relationship was found between cumulative arsenic exposure and lung cancer mortality with an overall SMR of 372 (304-450, 95% confidence interval). The lung cancer mortality was related to the estimated average intensity of exposure to arsenic but not to the duration. SMR’s ranged from 271 (<0.25 mg year/m3) to 1137 (<100 mg*year/m3). However, smoking pattern was not recorded in this study and there was some indication that it was different from the reference population. This may explain the lack of dose response until 50 mg*years/m3in this study. Therefore no reliable NOAEL can be estimated from this study and the LOAEL is probably <50 mg*years/m3.
As these cancers are also present after oral absorptionof excessive amount of inorganic arsenic, mainly in drinking water, the NOAEL derived from these studies will be used to derive also the inhalation DNEL. The three main cancer types which have been identified in these studies and for which NOAEL can be derived from epidemiological studies are skin, bladder and lungs.
For skin, the most relevant and sensitive study is from Ashan (2006) conducted in Bangladesh. In this study the authors evaluated dose-response relations between arsenic exposure from drinking water and premalignant skin lesions by using baseline data on 11,746 participants recruited in 2000-2002. Several measures of arsenic exposure were estimated for each participant based on well-water arsenic concentration and usage pattern of the wells and on urinary arsenic concentration. In different regression models, consistent dose-response effects were observed for ail arsenic exposure measures. Control group consists in people with drinking water containing <8.1 µg/L of arsenic. Drinking water containing 8.1-40:0, 40.1-91.0, 91.1-175.0, and 175.1-864.0 µg/L of arsenic was associated with adjusted prevalence odds ratios (OR) of skin lesions of 1,91 (95% confidence interval (CI): 1.26, 2,89), 3.03 (95% CI: 2.05, 4.50), 3.71 (95% Cl: 2,53, 5.44), and 5.39 (95% CI: 3.69, 7.86), respectively. To take into account water intake, the authors used also a Cumulative Arsenic Index (well concentration * daily consumption * days of use/year). When considering this value the median of the NOAEL group is 24 g and the median of the LOEL group (prevalence OR: 1.83 and range: 1.25-2.69) is 137 mg. This is equivalent per day to 66 and 675 µg/day for NOAEL and LOAEL respectively. When arsenic urinary excretion is considered this value the median of the NOAEL group is 48.3 µg/g of creatinine and the median of the LOEL group (prevalence OR: 1.75 and range: 1.23-2.48) is 124.3 µg/g of creatinine. With the hypothesis that urinary excretion is equivalent to 60% of the intake (Buchet et al, 1981) and the creatinine excretion is 1300 mg/day for a 60 kg adult; this is equivalent per day to 1.7 and 4.5 µg/kg/day for NOAEL and LOAEL respectively. This study has identified a large number of people presenting lesions (between 57 and 242 in low and high dose group respectively) and is therefore statistically robust. However, the lesions identified were not malignant lesions and can be considered as very early indicators of arsenic overload. The 2.5% prevalence of lesions in the control group tends to indicate a high sensitivity in the lesion identification. Therefore the LOAEL in this study can be considered as the median value of the lowest category with an OR of 1.91, i.e. 24 µg/L. This value is close from the NOAEL of 0.8 µg/L derived from Tseng, 1968 (Tseng, W.P., H.M. Chu, S.W. How, J.M. Fong, C.S. Lin and S. Yeh. 1968. Prevalence of skin cancer in an endemic area of chronic arsenicism in Taiwan. J. Natl. Cancer Inst. 40: 453-463) used by EPA (*EPA. 1998d. National emissions standards for hazardous air pollutants for primary lead smelters. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 63.Fed Regist 63(74)19200. ) to derive acceptable values in drinking water.
Bladder cancer incidence has been studied by Chiou (2001). In this study the authors examined risk of transitional cell carcinoma (TCC) in relation to ingested arsenic in a cohort of 8102 residents in north-eastern Taiwan. Estimation of each study subject's individual exposure to inorganic arsenic was based on the arsenic concentration in his or her own well water. Information on duration of consumption of the well water was obtained through standardized questionnaire interviews. The occurrence of urinary tract cancers was ascertained by follow-up interview and by data linkage with community hospital records, the national death certification profile, and the cancer registry profile. Cox proportional hazards regression analysis was used to estimate multivariate-adjusted relative risks and 95% confidence intervals. There was a significantly increased incidence of urinary cancers for the study cohort compared with the general population in Taiwan (standardized incidence ratio = 2.05; 95% confidence interval (CI): 1.22, 3.24). A significant dose-response relation between risk of cancers of the urinary organs, especially TCC, and indices of arsenic exposure was observed after adjustment for age, sex, and cigarette smoking. The multivariate-adjusted relative risks of developing TCC were 1.9, 8.2, and 15.3 for arsenic concentrations of 10.1-50.0, 50.1-100, and >100 pg/L, respectively, compared with the referent level of <10.01µg/L. However, this was significant only for the highest exposure group (>100 µg/L ). Therefore the LOAEL in this study can be considered as100 µg/L. Two other publications report on dose effect relationship for bladder cancer: Guo et al (2000) and Bates et al (2004). Guo et al (2000) is a village based ecological study conducted in Taiwan using cancer registry and death certificates; there is no increased incidence of bladder cancer below an Arsenic water concentration of 0.64 mg/L. The next lowest dose without effect is the group with water concentration between 0.33 and 0.64 mg/L. Bates et al (2004) is a case control study conducted in Argentina. Cases were recruited in different clinics of the area and exposure was assessed by measurement of the Arsenic concentration of their residence. There found no increased incidence of bladder cancer with an Arsenic water concentration up to 200 mg/L (group between 200 and 389 µg/L). There was a potential increase in subject who ever smoked and were exposed more that 50 years to arsenic but the significance of that is unclear.
Lung cancer incidence has been studied by Buchet et al (1998). A cohort study was conducted to analyse the statistics of mortality in Belgian population previously exposed to As from natural (drinking water) and/or industrial (nonferrous metal smelter emissions) sources. Mortality data and underlying causes were obtained from the Belgian National Institute of Statistics. A moderately increased absorption of As, leading to a 3- to 4- fold higher urinary excretion (35 µg/day as compared with 6-10 µg As/day in nonexposed subjects) did not enhance the mortality by diseases of the nervous system, liver and heart, and cancers. An increase in mortality by lung cancer, however, was observed in men but not women living around zinc smelters but might be related to past occupational exposure and/or smoking habits. In conclusion, a low to moderate level of environmental exposure to inorganic arsenic does not seem to affect the causes of mortality, suggesting in particular nonlinearity of the dose-response relationship for arsenic and cancer. The excretion of 35 µg/day corresponds to a daily intake of 58 µg/day equivalent to 0.83 µg/kg for a 70 kg man. Ferreccio et al (2000) conducted a case-control study to assess the relation between lung cancer and arsenic in drinking water in northern Chile. Study identified 152 lung cancer cases (1994-1996) and 419 frequency-matched hospital controls. Information on drinking water sources, cigarette smoking, and other variable was obtained through standardized questionnaire interviews. Logistic regression analysis revealed a clear trend in lung cancer odds ratios and 95% confidence intervals (CIs) with increasing concentration of arsenic in drinking water, as follows: 1, 1.6 (95% CI = 0.5-5.3), 3.9 (95% CI = 1.2-12.3), 5.2 (95% CI = 2.3-11.7), and 8.9 (95% CI = 4.0-19.6), for arsenic concentrations 0-10 µg/L , 10-29 µg/L , 30-49 µg/L , 50-99 µg/L and 200-400 µg/L respectively. There was evidence of synergy between cigarette smoking and ingestion of arsenic in drinking water; the odds ratio for lung cancer was 32.0 (95% CI = 7.2-198.0) among smokers exposed to more than 200 µg/L of arsenic in drinking water (lifetime average) compared with nonsmokers exposed to less than 50 µg/L. Under the conditions of the study, an association was found between ingestion of inorganic arsenic at more than 75 µg/L (arithmetic mean of the 60-89 µg/L group) and risk of human lung cancer and the NOAEL can be estimated at 29 µg/L.
Derivation of NOAEL from these studies:
According to DNEL/DMEL derivation for human data document
Threshold effects
… If the exposure range categories form a continuum and the number of individuals in the exposure category showing no effect is sufficient to exclude an effect, the NOAEL lies in the lowest exposure category with an effect but one can’t know at which exact value within this category. If the exposure categories form a continuum, the upper exposure limit of the range of exposures in the no-effect category is the same as the lower limit of the range of exposure in the lowest category showing an effect. In the absence of more details on the distribution of exposures this value should be used as a NOAEL.
This has been used for some studies like Guo et al (2000) and Guo et al (2000). However it was not possible for some studies like Ahsan where the NOAEL was define by the boundaries of the lowest exposure subgroup. In this case, the median value of the groups have been used.
Table 1: NOAEL summaries:
Author |
Target |
NOAEL |
LOAEL |
Remarks |
Ahsan, 2006 |
Premalignant skin lesions |
1.7 µg/kg bw day |
4.5 µg/kg bw day |
Median value of the group with the lowest increase |
Buchet 1998 |
Lung carcinoma |
≥0.83 µg/kg bw day |
|
No effect in a population with a mean urinary excretion of 35 µg/day |
Chiou 2001 |
Bladder cancer |
75 µg/L |
>100 µg/L |
|
Guo, 2000 |
Bladder cancer |
64 µg/L |
|
Highest value of the group with no significant increased incidence.Very small number of cases |
Bates, 2004 |
Bladder cancer |
>200 µg/L |
|
No effects up to >200µg/L but very small number of cases. |
Ferreccio, 2000 |
Lung Cancer |
29 µg/L |
40 µg/L |
Highest value of the group with no significant increased incidence. Issue with selection of controls which may have lead to OR overestimate in the low ranges. |
Jarup, 1989 |
Lung Cancer |
<50 mg years/m3 |
Lack of reliable information on smoking pattern of many subjects |
The lowest NOAEL is found with Ferreccio et al (2000). However, the issues with control selection cast some doubts about the precision of this case-control study. The best estimate seems then to be the study by Ahsan et al (2006) which have the advantage of having measured exposure as µg/L, an integrated value over the year and individual exposure values. The latest will be used to derive the DNEL.
According to DNEL/DMEL derivation for human data document:
Ad 1. Intraspecies differences
Part of the population is suspected to be more susceptible to cancer due to genetic properties (such as having specific polymorphisms).The NOAEL for arsenic acid is derived from a large variety of population from E.U., Asia and South America which is expected to cover most of the variability in the general population. In addition, the final NOAEL from which the DNEL is derived has been determined from the effects of exposure in the general population, many of these people having been exposed also during childhood and infancy. This population is therefore expected to be at least and probably more variable than an healthy adult worker population which will be the target for the DNEL. Therefore there is no need to use AFs for extrapolation of a DNEL derived from the general population to one subgroup (in this case a worker population).
The DNEL approach has been chosen instead of the DMEL approach for two main reasons:
· Despite a very large number of mutagenicity studies conducted with different forms of Arsenic, a direct effect of arsenic on DNA has never been demonstrated
· Arsenic in a natural element widely present in earth crust with a widely present background exposure and the effects of very low level of exposure as positive or negative have never been elucidated.
There is a sufficient diversity and sufficiently large population studied to consider that the intraspecies differences are fully covered. Many of these studies have considered populations which have been exposed from infancy to adult age and in whatever circumstances and in many cases with a less than adequate nutritional status. In addition for some of these populations a significant part of the exposure may have been to trivalent arsenic known to be much more toxic than pentavalent arsenic.
In all these studies, well water as drinking water and also as cooking water. When using Ahsan study, it seems that correspondence between Time weighted well As concentration/cumulative index/Arsenic in urine corresponds to water intake in the range of 4-5 litres. For 3 litres/day, 64 µg/L will corresponds for a 60kg adult to 3,2 µg/kg bw/day and 29 µg/L will corresponds for a 60kg adult to 1,45 µg/kg bw/day. Therefore the value of 1.7 µg/kg bw day in the study from Buchet can be use to derive the DNEL without intra or between species difference. The oral DNEL for chronic exposure is therefore 1.7 µg/kg bw day.
Dermal penetration human skin (in vitro) has been studies by Wester et al (1993). Water solutions of arsenic-73 at a low (trace) level of 0.000024μg/cm2 and a higher dose of 2.1μg/cm2were prepared for comparative analysis. In vitro percutaneous absorption of the low dose from water with human skin resulted in 24-hr receptor fluid (phosphate-buffered saline) accumulation of 0.93±1.1% dose and skin concentration (after washing) of 0.98±0.96%. Combining receptor fluid accumulation and skin concentration gave a combined amount of 1.9%. Washing with soap and water readily removed residual skin surface arsenic, both in vitro and in vivo. Therefore, a penetration coefficient of 2% will be used to derive a dermal DNEL.
Chronic dermal DNEL = 1.7 µg/kg bw day (Oral DNEL) / 2% = 85 µg/kg bw day.
No reliable quantitative information can be taken from the existing epidemiological studies where inhalation was said to be the main route of exposure.A common limitation of these studies is confounding exposure to other chemicals, such as sulfur dioxide, and cigarette smoking.In addition, none of these studies has considered dermal exposure which is expected to be significant in environment where significant amount of dust may have deposited on equipment surfaces. For these reasons, chronic inhalation DNEL will be derived from oral DNEL. An assessment factor of two will be added considering that in the case of inhalation, exposure will be directly on one of the potential target, the lungs.
Chronic inhalation DNEL:: 1.7 µg/kg bw day * 70 kg / 2 (AF) * 10 m3/day : 6 µg/m3
The levels set for chronic DNEL’s will oblige to very strict OC and RMM. No acute or subchronic DNEL’s are considered necessary.
Substance will not be sold in a form making exposure possible to the general public. Therefore no consumer DNEL’s are considered necessary.
Table 1: DNEL derivation summary:
|
Oral |
Dermal |
Inhalation |
Professional |
|
|
|
Acute |
NDR |
NDR |
NDR |
Repeated dose |
NDR |
NDR |
NDR |
Chronic |
1.7 µg/kg bw day |
85 µg/kg bw day |
6 µg/m3 |
Consumers |
|
|
|
Acute |
NDR |
NDR |
NDR |
Repeated dose |
NDR |
NDR |
NDR |
Chronic |
NDR |
NDR |
NDR |
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
DNEL related information
- Overall assessment factor (AF):
- 1
Acute/short term exposure
DNEL related information
Local effects
Acute/short term exposure
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Acute/short term exposure
DNEL related information
General Population - Hazard via oral route
Systemic effects
Acute/short term exposure
DNEL related information
General Population - Hazard for the eyes
Additional information - General Population
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