Registration Dossier

Administrative data

Description of key information

Based on expert judgement and a weight of evidence approach, diarsenic trioxide is not considered to be sensitising to skin.

Limited data is available on the sensitising properties of (inorganic) arsenic compounds. This was summarised in the ATSDR Toxicological Profile on Arsenic (ATSDR, 2007) as follows:

In a maximization test conducted according to a protocol similar to OECD TG 406, the sensitizing effects of disodium hydrogen arsenate and sodium arsenite were tested in Dunkin-Hartley guinea pigs. For intradermal induction, 4% disodium hydrogen arsenate and 0.2% sodium arsenite, and for topical induction 20% disodium hydrogen arsenate (after previous non-occlusive treatment for 24 h with 10% sodium dodecyl sulfate in petrolatum) and 0.5% sodium arsenite were used, each in water. After challenge on Day 21, 2 of 19 treated animals and 1 of 20 control animals reacted only after 24 h to 1% disodium hydrogen arsenate in physiological saline. At the 48 h reading and on testing with 0.5 and 0.1% of the test substance, none of the animals produced a reaction. After 24 h, 4 of 20 treated animals and 4 of 20 controls reacted to 0.1% sodium arsenite in physiological saline, and after 48 h only 1 of 20 control animals. None of the animals reacted to 0.05 and 0.01% sodium arsenite. Under the study conditions, sodium dioxoarsenate and disodium hydrogenarsenate were therefore not considered to be sensitizing (Wahlberg and Boman, 1986).

Examination of workers exposed to arsenic trioxide dusts in a Swedish copper smelter led Holmqvist (1951) to suspect that repeated dermal contact could cause sensitization. In support of this, the researcher obtained positive patch test results in 80% of exposed workers compared to 30% in a control population. These data suggested that workers may have been sensitized to arsenic, although the response rate in controls seemed unusually high. A much lower response rate (0.5%) was noted in a patch test conducted by Wahlberg and Boman (1986) with sodium arsenate and sodium arsenite in 379 dermatitis patients. The few positive responses seemed to be due to a cross-reactivity with nickel.

Mohamed (1998) evaluated 11 male workers at a tin smelting factory in Malaysia where arsenic trioxide levels ranged from 5.2 to 14.4 mg/m3. The workers experienced symptoms of generalized itching, dry and hyperpigmented skin, folliculitis and superficial ulcerations. The authors concluded that arsenic-containing dust collected on the sweat of the worker’s skin, causing contact dermatitis.

The few case reports mentioned above do not relate to a substantial number of people and are quite outdated. Further, the observations appear, at least in part, to be linked more to localised irritating/corrosive effects than to sensitisation (i.e. systemic allergic reaction).

The existing information is considered sufficient to conclude that diarsenic trioxide is not a skin sensitizer. Because diarsenic trioxide is a classified as Skin Corr 1B, new in vivo testing for this endpoint is not proposed. Indeed, the results of an in vivo test would likely be difficult to interpret and should also not be conducted for animal welfare reasons. In addition, 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.

References

Holmquist I (1951). Occupational arsenical dermatitis: as study among employees at a copper ore smelting work using investigations of skin reaction to contact with arsenic compounds. Acta Derm. Venereol. 31:1-214.

Mohamed KB (1998). Occupational contact dermatitis from arsenic in a tin-smelting factory. Contact Dermatitis 38:224–225.

Wahlberg JE and Boman A (1986). Contact sensitivity to arsenical compounds—clinical and experimental studies. Dermatosen Beruf Umwelt 34: 10–12.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
, adopted 12-05-1981
GLP compliance:
not specified
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
This study, published in 1986, has been conducted at a time when the guinea pig maximisation test (GPMT) was also an accepted method. It provides adequate information for the assessment of the skin sensitisation potential of the test item(s).
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
not specified
Details on test animals and environmental conditions:
no data
Route:
intradermal and epicutaneous
Vehicle:
other: distilled water (induction) and saline (challenge)
Concentration / amount:
Induction:
Na2HAsO4
- intradermal injection: 4% (w/w)
- topical application: 20% (w/w)
NaAsO2
- intradermal injection: 0.2% (w/w)
- topical application: 0.5% (w/w)
Challenge:
Na2HAsO4: 1.0, 0.5 and 0.1% solutions in saline
NaAsO2: 0.1, 0.05 and 0.01% solutions in saline
Route:
epicutaneous, occlusive
Vehicle:
other: distilled water (induction) and saline (challenge)
Concentration / amount:
Induction:
Na2HAsO4
- intradermal injection: 4% (w/w)
- topical application: 20% (w/w)
NaAsO2
- intradermal injection: 0.2% (w/w)
- topical application: 0.5% (w/w)
Challenge:
Na2HAsO4: 1.0, 0.5 and 0.1% solutions in saline
NaAsO2: 0.1, 0.05 and 0.01% solutions in saline
No. of animals per dose:
20 animals
Details on study design:
Guinea pigs were exposed in groups of 20 animals to Na2HAsO4 and NaAsO2 according to the GPMT method under conditions previously reported (J.E. Wahlberg & A. Boman (1978)*; J.E. Wahlberg & A. Boman (1985)**).

MAIN STUDY
A. INDUCTION EXPOSURE
At induction 4% Na2HAsO4 (w/w) was used for intradermal injection and 20% (w/w) - after treatment for 24 h with 10% sodium lauryl sulphate in petrolatum - for topical application. For NaAsO2 0.2% (w/w) was used for intradermal injection and 0.5% (w/w) for topical application. Distilled water was used as vehicle.

B. CHALLENGE EXPOSURE
Challenge testing was performed on day 21 using 1.0, 0.5 and 0.1% solutions of Na2HAsO4 in saline and 0.1, 0.05 and 0.01% solutions of NaAsO2 in saline. Testing for cross reactivity was performed simultaneously.

ATOMIC ABSORPTION SPECTROPHOTOMETRY: the arsenic compounds used for the guinea pig maximisation test (GPMT) were analysed with a Perkin Elmer 303 atomic absorption spectrophotometer in order to identify impurities of other metals (i.e. nickel or cobalt) contributing to the test reactions.

References:
* Wahlberg, J.E., Boman, A. (1978) Sensitization and testing of guinea pigs with cobalt chloride, Contact Dermatitis 4, 128 - 132.
** Wahlberg, J.E., Boman, A. (1985) Guinea pig maximization test in Curr. Probl. Derm. 14, Anderson, K.E., Maibach, H.I. (Eds.), S. Karger, Basel (1985) (in press).
Challenge controls:
Sham-treated control groups (20 animals per group) were run in each experiment.
Positive control substance(s):
not specified
Positive control results:
no data
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
1.0% (w/w) of Na2HAsO4 * 7 H2O
No. with + reactions:
0
Total no. in group:
19
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 1.0% (w/w) of Na2HAsO4 * 7 H2O. No with. + reactions: 0.0. Total no. in groups: 19.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.5% (w/w) of Na2HAsO4 * 7 H2O
No. with + reactions:
0
Total no. in group:
19
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 0.5% (w/w) of Na2HAsO4 * 7 H2O. No with. + reactions: 0.0. Total no. in groups: 19.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.1% (w/w) of Na2HAsO4 * 7 H2O
No. with + reactions:
0
Total no. in group:
19
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 0.1% (w/w) of Na2HAsO4 * 7 H2O. No with. + reactions: 0.0. Total no. in groups: 19.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
1.0% (w/w) of Na2HAsO4 * 7 H2O
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 1.0% (w/w) of Na2HAsO4 * 7 H2O. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0.5% (w/w) of Na2HAsO4 * 7 H2O
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 0.5% (w/w) of Na2HAsO4 * 7 H2O. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0.1% (w/w) of Na2HAsO4 * 7 H2O
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 0.1% (w/w) of Na2HAsO4 * 7 H2O. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.1% (w/w) of NaAsO2
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 0.1% (w/w) of NaAsO2. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.05% (w/w) of NaAsO2
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 0.05% (w/w) of NaAsO2. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.01% (w/w) of NaAsO2
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 0.01% (w/w) of NaAsO2. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0.1% (w/w) of NaAsO2
No. with + reactions:
1
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 0.1% (w/w) of NaAsO2. No with. + reactions: 1.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0.05% (w/w) of NaAsO2
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 0.05% (w/w) of NaAsO2. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0.01% (w/w) of NaAsO2
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 0.01% (w/w) of NaAsO2. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
other: no positive control used in study
Hours after challenge:
0
Group:
positive control
Dose level:
0
No. with + reactions:
0
Total no. in group:
0
Remarks on result:
other: no positive control used in study

Atomic absorption spectrophotometry

NaAsO2 contained 0.3 ppm cobalt and less than 0.2 ppm nickel and NaHAsO4 less than 0.2 ppm nickel and cobalt.

GMPT Test results:

No statistically significant difference between the exposed and the control groups was seen. There was no evidence of cross-reactivity.

Reading

Hours after challenge

Group

Dose level

No. with + reactions

Total no. in group

Cliinical observations

1streading

24

test group

1.0% (w/w) of  

Na2HAsO4 * 7 H2O

2

19

2ndreading

 48

test group

1.0% (w/w)  

of 

Na2HAsO4 * 7 H2O

0

19

1streading

24

test group

0.5% (w/w)  

of 

Na2HAsO4 * 7 H2O

0

19

2ndreading

 48

test group

0.5% (w/w)  

of 

Na2HAsO4 * 7 H2O

0

19

1streading

24

test group

0.1% (w/w)  

of 

Na2HAsO4 * 7 H2O

0

19

2ndreading

 48

test group

0.1% (w/w)  

of 

Na2HAsO4 * 7 H2O

0

19

1streading

24

negative control

1.0% (w/w)  

of 

Na2HAsO4 * 7 H2O

1

20

2ndreading

 48

negative control

1.0% (w/w)  

of 

Na2HAsO4 * 7 H2O

0

20

1streading

24

negative control

0.5% (w/w)  

of 

Na2HAsO4 * 7 H2O

0

20

2ndreading

 48

negative control

0.5% (w/w)  

of 

Na2HAsO4 * 7 H2O

0

20

1streading

24

negative control

0.1% (w/w)  

of 

Na2HAsO4 * 7 H2O

0

20

2ndreading

48 

negative control

0.1% (w/w)  

of 

Na2HAsO4 * 7 H2O

0

20

1streading

24

test group

0.1% (w/w) of  

NaAsO2

4

20

2ndreading

48 

test group

0.1% (w/w)  

of 

NaAsO2

0

20

1streading

24

test group

0.05% (w/w)  

of 

NaAsO2

0

20

2ndreading

 48

test group

0.05% (w/w)  

of 

NaAsO2

0

20

1streading

24

test group

0.01% (w/w)  

of 

NaAsO2

0

20

2ndreading

48 

test group

0.01% (w/w)  

of 

NaAsO2

0

20

1streading

24

negative control

0.1% (w/w)  

of 

NaAsO2

4

20

2ndreading

 48

negative control

0.1% (w/w)  

of 

NaAsO2

1

20

1streading

24

negative control

0.05% (w/w)  

of 

NaAsO2

0

20

2ndreading

 48

negative control

0.05% (w/w)  

of 

NaAsO2

0

20

1streading

24

negative control

0.01% (w/w)  

of 

NaAsO2

0

20

2ndreading

 48

negative control

0.01% (w/w)  

of 

NaAsO2

0

20

Control groups treated with saline showed no reaction.

Interpretation of results:
GHS criteria not met
Conclusions:
The sensitive predictive test method (GMPT) does not suggest that the studied arsenicals are skin allergens.
According to Regulation (EC) No. 1272/2008 and subsequent regulations, the substance is not classified as a skin sensitiser.
Endpoint:
skin sensitisation: in vitro
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro skin sensitisation study does not need to be conducted because adequate data from an in vivo skin sensitisation study are available
Reason / purpose for cross-reference:
data waiving: supporting information
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on expert judgement and a weight of evidence approach, diarsenic trioxide is not considered to be sensitising to skin. No classification for this endpoint according to Regulation (EC) No. 1272/2008 is proposed.