Diarsenic trioxide

Endpoint summary

Description of key information

Read across approach

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 acute toxicity, of diarsenic trioxide.

The acute toxicity of arsenic compounds has been studied to great extent in animal studies and there are also many case reports of acute effects in humans. The focus of such investigations has been on oral exposure. Because of the enormous amount of data, reference is made to available reviews, such as the "Toxicological Profile for Arsenic (ATSDR, 2007), or to peer-reviewed factual databases, such as the Hazardous Substance Databank (HSDB) and the Registry of Toxic Effects of Chemical Substances (RTECS).

Oral

For diarsenic trioxide, reported oral LD50s in animals are in the range from ca. 10-214 mg/kg, which is in agreement with the existing harmonized classification as Acute Tox 2 - H300 according to Regulation (EC) No 1272/2008. Human case reports of accidental or deliberate poisoning support the conclusion that diarsenic trioxide is acutely toxic via the oral route.

Inhalation

Acute inhalation exposure of humans to diarsenic trioxide usually does not take place to a significant extent and does not usually lead to lethality, but irritation of skin and mucous membranes has been observed (in agreement with the existing harmonised classification as Skin Corr. 1B). After evaluation of all available data (existing reviews, literature searches in factual and bibliographic databases) a reliable standard toxicity descriptor value, such as a LC50(4h), cannot be established for diarsenic trioxide. A standard acute inhalation toxicity study (e.g. OECD TG 403 or comparable guideline) is not available. Some animal studies are available which used intratracheal injection as the route of exposure, but are not focused on lethality as an endpoint, but rather on local lung effects, lung clearance issues or carcinogenicity. Due to the well-known toxicological profile of arsenic compounds, including diarsenic trioxide, and specifically because of the carcinogenic potential, strict measures are already in place to exclude or minimise as far as possible any exposure of humans to such compounds.

Dermal

Adverse effects from dermal exposure to inorganic or organic arsenicals have not been extensively investigated. No studies were located regarding death in humans after dermal exposure to inorganic arsenicals. In rats, no deaths resulted from dermal exposure to arsenate or arsenite at doses up to 1000 mg As/kg (e.g. Gaines, 1960). These data indicate that dermal exposure to inorganic arsenic compounds is very unlikely to result in lethality. According to reliable reviews, the dermal absorption of inorganic arsenic compounds is considered to be low (<10%), rendering this route of exposure to be of limited relevance. The chemical nature of arsenic metal, together with its poor solubility, renders its potential for uptake through skin low. This is also the case for any expected transformation/dissolution products, i.e. dissolved arsenic in ionic form. Uptake of arsenic through the skin has been determined to occur at rates below 2%, when applied in dissolved form as radiolabelled arsenic acid to human skin in vitro (Wester et al., 1993).With regards to this low dermal absorption, we can consider this route of exposure to be of limited relevance.

Due to the well-known toxicological profile of arsenic compounds, including diarsenic trioxide, and specifically because of the carcinogenic potential, strict measures are already in place to exclude or minimise as far as possible any exposure of humans to such compounds. Therefore, and for animal welfare reasons, it is not justified to conduct further toxicological studies in experimental animals.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

other: cited in secondary literature

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Cited in peer reviewed factual database (RTECS). Primary bibliographic source unavailable.

Principles of method if other than guideline:

Not available. Cited in peer reviewed factual database (RTECS). Primary bibliographic source unavailable.

Species:

mouse

Route of administration:

oral: unspecified

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

145 mg/kg bw

Based on:

not specified

Clinical signs:

other: Behavioral: Ataxia; Gastrointestinal: Hypermotility, diarrhea

Interpretation of results:

Toxicity Category III

Remarks:

Migrated information Criteria used for interpretation of results: EU

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

other: cited in secondary literature

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Cited in peer reviewed factual database (RTECS). Primary bibliographic source unavailable.

Principles of method if other than guideline:

Not available. Cited in peer reviewed factual database (RTECS). Primary bibliographic source unavailable.

Species:

rat

Route of administration:

oral: unspecified

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

763 mg/kg bw

Based on:

not specified

Clinical signs:

other: Behavioral: Ataxia; Gastrointestinal: Hypermotility, diarrhea

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

other: cited in secondary literature

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Cited in peer reviewed factual database (RTECS). Primary bibliographic source unavailable.

Principles of method if other than guideline:

Not available. Cited in peer reviewed factual database (RTECS). Primary bibliographic source unavailable.

Species:

mouse

Route of administration:

oral: unspecified

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

144 mg/kg bw

Based on:

not specified

Interpretation of results:

Toxicity Category III

Remarks:

Migrated information Criteria used for interpretation of results: EU

Reference 4

Endpoint:

acute toxicity: oral

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

10 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Clinical signs:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Reason / purpose for cross-reference:

data waiving: supporting information

Qualifier:

according to guideline

Guideline:

other: No guideline was followed

GLP compliance:

not specified

Test type:

other: single dermal dose

Limit test:

yes

Specific details on test material used for the study:

Calcium arsenate and lead arsenate

Species:

rat

Strain:

Sherman

Sex:

female

Details on test animals or test system and environmental conditions:

The rats used in these studies were reared in a separate building of the laboratory where the tests were made. They were at least 90 days old and had minimum body weights of 175 and 200 g for the males and females, respectively. The animals were individually caged during the study and fed Purina Laboratory Chow. None of them was fasted prior to dosage. The survivors were held for daily observation until they appeared to have recovered completely or for a minimum of 14 days.

Type of coverage:

open

Vehicle:

other: 95% ethyl alcohol

Details on dermal exposure:

In this study the test substances were suspended in 95% ethyl alcohol prior testing. The fur of the rats was clipped over the top of the shoulder and forward part of the back with an Ang-Ra No. 2 animal clipper to provide a clean area of about 3.0 X 4.5 cm for application of the test substance. The clipped area of unbroken skin was bathed with a 1:1 solution of acetone and 95% ethyl alcohol to remove dirt and excess oils.
The formulations of the test substances were applied slowly to prevent run-off, using a 1-ml pipette. The rats were observed at least once each hour during the first day after dosage, and twice a day thereafter, for symptoms of poisoning and time of death. The LD50 values were determined by the method of Litchfield and Wilcoson (1949).

Duration of exposure:

14 d

Doses:

0.0016 mL/kg bw

No. of animals per sex per dose:

20 females

Control animals:

not specified

Key result

Dose descriptor:

LD50

Effect level:

> 2 400 mg/kg bw

Based on:

test mat.

Remarks on result:

other: calcium arsenate

Key result

Dose descriptor:

LD50

Effect level:

2 400 mg/kg bw

Based on:

test mat.

Remarks on result:

other: lead arsenate

Interpretation of results:

study cannot be used for classification

Conclusions:

Under the study conditions, the LD50s of the tested substances were > 2400 mg/kg bw after single dermal application.

Executive summary:

A 14-day acute dermal toxicity study was conducted to determine the potential toxic effects of calcium arsenate and lead arsenate when applied as a single dermal dose to adult rats. 20 Sherman strain female rats were used. The substances were suspended in 95% ethyl alcohol and tested separately at the dose of 0.0016 mL/kg bw. Under the study conditions, the LD50s of the tested substances were > 2400 mg/kg bw after single dermal application (Gaines, 1960).

Reference 2

Endpoint:

acute toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Diarsenic trioxide is classified as Acute Tox 2 - H300 (Fatal if swallowed) according to Regulation (EC) No 1272/2008 based on a large database of human and animal data. LD50s (oral) reported for diarsenic trioxide in peer-reviewed factual databases are in the range from ca. 10-214 mg/kg. There are no guideline-conform studies on acute toxicity following inhalation or dermal exposure to As2O3, and the conduct of such animal studies is not justifiable for animal welfare reasons in consideration of the irritating/corrosive nature of As2O3.

Further, based on the known toxicological profile of arsenic compounds strict risk reduction measures are usually in place to protect against long term effects, specifically against carcinogenicity. In conclusion, further classifications for acute toxicity via the dermal or oral route are not justified.