Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 µg/m³
Most sensitive endpoint:
carcinogenicity
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:
112 µg/kg bw/day
Most sensitive endpoint:
carcinogenicity
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Introductory note:

 

The following major cancer risk assessments have been conducted to date (UBA, 2007):

(I)A somewhat out-of-date assessment by USEPA/IRIS (1988) based on the studies by Tseng et al. (1968, 1977) on the prevalence of skin tumours in a population in southeast Taiwan (EPA, 2007).

(II) NRC based their cancer risk assessment on the studies by Chen et al. (1985, 1992) on the incidence of tumours in bladder and lungs in southwest Taiwan, using the studies by Chiou et al. (2001) and Ferreccio et al. (2000) as supportive data.

(III) In more recent assessment, the USEPA focus on the studies by Chen et al. (1985, 1992) (Morales et al. 2000; EPA, 2001).

The German UBA has (2007) performed a comprehensive evaluation of more recent investigations on cancerogenicity of arsenic via drinking water, which are not further addressed here. The DNEL derivation in this dossier is based on more recent data.

 

 

DNEL derivation (general aspects)

 

For the derivation of a DNEL for diarsenic trioxide, carcinogenicity is considered the most relevant endpoint; other effects of repeated exposure to arsenic including reproduction toxicity are considered to occur at higher exposures and therefore secondary to cancer. Since rodents (in particular rats) have a metabolic pattern that differs distinctly from humans, they are less sensitive and unsuitable as models for HH risk assessment, which is why the DNEL derivation is based on human epidemiological data only.

 

The majority of such studies focus on effects associated with elevated arsenic intakes via drinking water. In these studies, the exact speciation (tri- or pentavalent) and relative quantification of arsenic is usually lacking. However, despite that As(III) is considered moderately more toxic than pentavalent species, the difference in toxicity is anticipated to be less than an order of magnitude, and it may also be speculated that arsenic in drinking water may be a mixture of As(III/As(V), which is why direct read-across from arsenic concentrations reported in the epidemiological studies selected for DNEL derivation is justified.

 

Diarsenic trioxide is soluble, and upon dissolution the absorption via ingestion or inhalation may be considered as essentially complete. Dermal absorption through human skin has been reliably measured, yielding a conservative dermal absorption factor of 2% (Wester et al. 1993).

 

Carcinogenicity of arsenic is of systemic nature, and not dependant on the route of entry into the body. Thus, after long-term ingestion of elevated levels of arsenic in drinking water, cancer not only of the bladder is observed, but also of the lungs and skin.

 

 

Oral DNEL:

 

Several epidemiological studies have been used as point of departure for assessing the risk of cancer via drinking water intake containing arsenic. These are summarised in detail above. In a recent evaluation, the German UBA (2007) has compared all these and also summarised more recent data, concluding that despite older studies suggesting a linear dose-response, the shape of this dose-response curve and where a threshold can be established are subjects of controversy, and that overall, there is no consistent clear picture regarding the dose-response.

 

The major shortcomings of most such epidemiological studies are usually the limited number of subjects and thus the statistical power, as well as inadequate control of actual exposures. The most recent study by Ahsan et al. (2006) designated the Health Effects of Arsenic Longitudinal Study (“HEALS”) conducted in Araihazar (Bangladesh) may be considered a step forward in that it (i) addresses a large number of subjects (n=11,746), (ii) covers a wide range of arsenic concentrations in drinking water (0.1-864 ug/L), and (iii) exposure to arsenic was well characterised: not only the arsenic in well water was analysed, but also drinking water consumption monitored and most relevant, creatinine-adjusted urinary arsenic excretion as monitored for each participant enrolling in the study.

 

Using the lowest exposure group (<8 µg/L), and accounting for water intake, a cumulative arsenic index (well concentration x daily consumption x days of use/year) was derived for this group, where the arithmetic mean of intakes in this group is considered a NOAEL of 24 mg/a (LOEL 137 mg/a), corresponding to 66 and 675 µg/day for NOAEL and LOAEL, respectively. The corresponding urinary excretion in this NOAEL group is 48.3µgAs/g creatinine. Assuming that 60% of the entire arsenic intake is eliminated via urine (refer to toxicokinetic section, reference Buchet et al, 1981) and for a 60kg adult (assumed most appropriate for the Asian population studied) the default creatinine excretion is 1300mg/day, this can be recalculated to a NOAEL of 1.7µgAs/kg/day.

Given the close exposure control and the large number of participants in this study with lesions, this study is not only considered reliable and statistically robust. Since the observed lesions were not malignant, they may reasonably be considered as early indicators of arsenic intoxication.

For reasons of comparison, we note that using the same basis for their evaluations (Tseng et al., 1968 & 1977), EPA (2007), UBA (1999) and ATSDR (2005) all derived the same tolerable dose for the chronic oral exposure of arsenic, based on a NOAEL of 0.8 ug/kg bw/d to derive their RfD (EPA), TRD (UBA) and MRL (ATSDR) values.

 

Oral (chronic) DNEL =1.7µgAs/kg bw/d, corresponding to 2.2µg As2O3/kg bw/d

 

Since this systemic DNEL is derived directly from a substantial human epidemiological data base on ingestion also involving detailed biomonitoring, no modification for aspects such as bioavailability, route of administration or physiological factors is required. It is not considered to derive a different oral DNEL for the general population than for workers.

 

 

Dermal DNEL:

 

In consideration of the systemic nature of arsenic carcinogenicity, route-to-route extrapolation from the data obtained from drinking water studies as above to the dermal route is considered justified. For this purpose, modification of the oral DNEL derived above by considering a dermal absorption factor of 2% (refer to toxicokinetics section, reference Wester et al., 1993) is appropriate. The chronic dermal DNEL can therefore be derived as follows:

 

Dermal (chronic) DNEL = 1.7µg As/kg bw/d (oral) / 2% = 85µg As/kg bw/d, corresponding to 112µg As2O3/kg/day.

Similar to the above, this DNEL is applicable to workers and the general population.

 

 

 

Inhalation DNEL:

 

Several studies exist that document the association between inhalation exposure to arsenic and lung cancer, mores specifically to arsenic trioxide dust in air at copper smelters (Enterline et al., 1987; Lee-Feldstein et al., 1983 & 1986; 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) mine. 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, some inherent imprecision of such retrospective exposure estimates cannot be excluded.

 

Overall, all of the above studies have many shortcomings and therefore do not allow the precise definition of a reliable NOAEL for diarsenic trioxide and consequently of a reliable DNEL. For this reason, two alternative approaches for a DNEL (inhalation, chronic) derivation were pursued:

 

 

Approach I (oral-inhalation route-to-route extrapolation)

 

Since arsenic-associated carcinogenicity is systemic and not essentially related to the route of entry into the body, the NOAEL value derived from epidemiological data on drinking of arsenic containing drinking water is selected as a starting point. Thus, using the most recent study by Ahsan et al. (2006) from which an oral NOAEL of 1.7µgAs/kg/day was derived as a starting point, plus a body weight of 70 kg for a European adult and a breathing volume of 10m3(workers, 8-h shift), the following “uncorrected” DNEL can be derived:

 

Inhalation (chronic) DNEL (uncorrected) = 1.7 µg As/kg bw/d x 70 kg ÷ 10 m3/d = 11.9 µg As/m3, corresponding to 15µg As2O3/kg/day.

 

This DNEL does not require modification for bioavailability, since the oral bioavailability of the soluble diarsenic trioxide may be considered similarly complete as for inorganic arsenical contained in drinking water; inhalation bioavailability is also considered to be close to 100% for material deposited in the lungs, as well the percentage that is translocated to the GI tract, for which an oral absorption of 100% is assumed.

 

Apart from the consideration of the breathing volume (10m3/shift), there is no requirement for the introduction of assessment factors for allometric scaling. However, for the general population, a different breathing volume needs to be considered, which is 20m³/day, resulting in an uncorrected DNEL for the general population of 6 µg As/m³.

 

Assessment factors for interspecies differences, intraspecies differences, differences in duration of exposure and quality of the data base are not considered to be required. However, in consideration of the oral-to-inhalation read-across, in order to cover any remaining uncertainties with respect to local effects, an assessment factor of 3 is applied to the above derived “uncorrected” DNEL, finally yielding:

 

Inhalation (chronic) DNEL, workers: = 4µg As/m3, corresponding to 5µg As2O3/kg/day.

Inhalation (chronic) DNEL, general population: = 2µg As/m3, corresponding to 2.5 µg As2O3/kg/day.

 

 

 

Approach II (linear extrapolation from epidemiological data)

 

The German AGS (2011) has recently derived an “ERB” (Exposure Risk Relationship) for arsenic exposure in the workplace. They used the study by Lubin et al. (2008) as the basis, with a point of departure associating a workplace concentration of 135 ug/m3with an added risk of cancer at a level of 6.5%. In the absence of a documented threshold or mechanistic data suggesting otherwise, a linear calculation procedure (AGS, 2008) was applied acknowledging the uncertainties and inherent conservatism of this approach, leading to the following values:

 

- tolerance risk (4:1,000) = 8.3 ug As/m3

- acceptance risk (4:10,000) = 0.8 ug As/m3.

 

In comparison to the uncertainties associated with the exposure assessment of the data from Lubin et al (2008) and the conservatism of the linear extrapolation method used for the ERB derivation, the value derived from the Ahsan et al (2006) appears to be more reliable.

 


 

Overall summary, DNEL derivation for diarsenic trioxide

 

The major health concern for exposure to diarsenic trioxide is carcinogenicity, and the derived DNELs are correspondingly low. Other effects form repeated exposure including reproduction toxicity are expected to occur only at considerably higher exposure levels, which is why DNELs for these endpoints are not considered to be required.

 

Similarly, because of the resulting need for very tight exposure controls, DNELs for acute exposures are also not considered to be required, since acute health effects are only observed at exposures exceeding those associated with chronic effects by several orders of magnitude.

 

Consumer exposure to diarsenic trioxide is ruled out, since the substance is not made available to the general public as such, or in any preparation or article etc. However, since members of the general population may theoretically be exposure indirectly via the environment due to arsenic from industrial emission from the production and use of diarsenic trioxide, DNEL for the general population have also been established.

 

 

 

Summary of DNELs for systemic effects derived for diarsenic trioxide. DNELs for local effects are not considered to be required (qualitative assessment because of corrosive nature, or covered by high protection levels required due to long term effects).

 

Oral

Dermal

Inhalation

Workers

Long term, systemic

2.2 µg/kg bw/d (formally not required)

112 µg/kg bw/d

5 µg/m3

General population

Long term, systemic

2.2 µg/kg bw/d

112 µg/kg bw/d

2.5 µg/m3

 

For the sake of comparison, we note that humans are also exposed to arsenic due to its natural occurrence. Ambient background data (non-exhaustive) is presented in an appendix to the exposure scenario document for As2O3. Typical arsenic intake data for the EU population is estimated as follows:

-      via food = 50-100 µg As/d (0.7-1.4 µg As/kg bw/d); corresponding to up to 1.8 µg As2O3/kgbw/day

-      via drinking water = 0.4-0.6 µg As/d (0.006-0.009 µg As/kg bw/d)

-      via air = 0.004 µg As/d

In other words, the oral DNEL derived above is close to the total background daily intake of arsenic via food, water and air.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 µg/m³
Most sensitive endpoint:
carcinogenicity
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
112 µg/kg bw/day
Most sensitive endpoint:
carcinogenicity
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.2 µg/kg bw/day
Most sensitive endpoint:
carcinogenicity
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Please refer to extensive discussion in the section on workers.