Chromium trioxide

Endpoint summary

Description of key information

Skin sensitisation potential of Cr(VI) was shown in guinea pigs testing potassium dichromate. There is also evidence of cross-reactivity between Cr(VI and Cr(III) compounds.

No in vitro data or animal data on respriatory sensitisation are avaialble for Cr(VI) compounds. However it was conculded that Cr(VI) compounds have the potential to cause respiratory sensitisation in exposed humans (please refer to 7.10.4)

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Principles of method if other than guideline:

The sensitization was done in the following manner: 5 injections of 0.2 ml each of emulsion containing either 1 mg/ ml of potassium dichromate (Merck, Darmstadt, FRG) in Freund's complete adjuvant (FCA) (DIFCO Laboratories, Detroit, Michigan) or 2 mg/ml of chromium chloride (Merck, Darmstadt, FRG) in FCA were given into the footpad and nape of the neck. Animals were restimulated once a week by an intradermal injection of 25 µg either of potassium dichromate or chromium chloride in 0.1 ml 0.15 M NaCl solution into the skin of the right flank. Simultaneously 0.02 ml of either 0.5% potassium dichromate or chromium chloride solution in 1 % Triton X-100 were applied epicutaneously on the skin of the left flank. The boosting was continued weekly until a positive reaction to the hapten was observed. The animals were then challenged epicutaneously with both haptens and the skin inflammation evaluated 24 hr later according to an arbitrary scale: red, swollen = 2, red, contluent = 1, red spots = 0.5.

GLP compliance:

not specified

Remarks:

published study

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

available data, published before LLNA declared as gold standard

Specific details on test material used for the study:

potassium dichromate (Merck, Darmstadt, FRG)

Species:

guinea pig

Strain:

other: Rockefeller

Sex:

male/female

Details on test animals and environmental conditions:

Inbred strain 2 and partially inbred strain Rockefeller guinea pigs of either sex were used. They weighed about 350- 400 g when sensitization was begun. The animals were bred at the Institute for Biochemical Research, Füllinsdorf, Switzerland. They were fed on pellet diet supplemented ad libitum with water containing vitamin C.

Route:

intradermal

Vehicle:

other: Freund's adjuvant (FCA)

Concentration / amount:

5 injections of 0.2 ml each of emulsion containing either 1 mg/ ml of potassium dichromate in Freund's complete adjuvant (FCA)

Day(s)/duration:

not specified

Adequacy of induction:

not specified

Route:

intradermal and epicutaneous

Vehicle:

other: intradermal: 0.1 ml 0.15 M NaCl solution; epicutaneously: 1% Tritox X-100

Concentration / amount:

intradermal: 25 µg potassium dichromate in NaCl solution; epicutaneously: 0.02 ml of 0.5% potassium dichromate in Triton X-100

Day(s)/duration:

once a week for 4-6 weeks until positive reaction occured

Adequacy of induction:

not specified

No.:

#1

Route:

other: epicutaneously

Vehicle:

not specified

Concentration / amount:

not specified

Day(s)/duration:

24h

Adequacy of challenge:

not specified

No. of animals per dose:

11 animals

Details on study design:

see above

Challenge controls:

not specified

Positive control substance(s):

no

Positive control results:

none

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

not specified

No. with + reactions:

11

Total no. in group:

11

Remarks on result:

positive indication of skin sensitisation

All guinea pigs sensitized with potassium dichromate in FCA and boosted several times epicutaneously and intradermaliy with the same hapten responded after 4-6 weeks to an epicutaneous challenge with this hexavalent chromium salt.

Conclusions:

Guinea pigs sensitized with either the trivalent chromium chloride or the hexavalent potassium dichromate are capable of reacting in vivo and in vitro to challenges with both chromium salts. This double reactivity is retained also after repeated restimulations with only 1 of these chromium compounds.

Executive summary:

The results of this study show that Cr (VI) tested as potassium dichromate is able to induce skin sensitisation in guinea pigs. Also, there is evidence of cross-reactivity between Cr(VI) and Cr(III) compounds. The experiments in guinea pigs showed that animals which were sensitised to Cr(VI) compounds produced a positive skin response when challenged with Cr(III) compounds, and that animals sensitised to Cr(III) give a positive skin response when challenged with Cr(VI).

Reference 2

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

GLP compliance:

no

Remarks:

study predates GLP

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

available data, published before LLNA declared as gold standard

Species:

guinea pig

Strain:

Hartley

Sex:

female

Details on test animals and environmental conditions:

Albino guinea pigs weighing 300-500 grams are used. While susceptibility is not influenced by sex, we prefer females because of their greater tractability. The combativeness of males often damages the test sites. Pregnant animals are entirely unsuitable because of decreased capacity to manifest an inflammatory reaction.

Route:

intradermal and epicutaneous

Vehicle:

other: adjuvant or petrolatum

Remarks:

see 'any other information on materials and methods' for further details on induction procedure

Concentration / amount:

1 %

Day(s)/duration:

21

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

water

Concentration / amount:

0.1 %

Day(s)/duration:

1

Adequacy of challenge:

highest non-irritant concentration

No. of animals per dose:

24

Details on study design:

see 'any other information on materials and methods'

Positive control substance(s):

yes

Remarks:

eleven known allergens were tested, including Mercaptobenzothiazole

Positive control results:

Eleven known allergens (Benzocaine, Malathion, Mercaptobenzothiazole, mercuric chloride, monobenzyl ether of hydroquinone, neomycin, nickel sulfate, strepromycin, sulfathiazole, turpentine, and Vioform) were used. The Maximization testing readily identified these, a majority of animals usually becoming sensitized.

Reading:

other: final result from readings after 24 and 48h

Group:

test chemical

Dose level:

0.5 %

No. with + reactions:

18

Total no. in group:

24

Clinical observations:

not specified

Remarks on result:

positive indication of skin sensitisation

Reading:

other: final result from reading after 24 and 48h

Group:

negative control

Dose level:

0.5 % SLS

No. with + reactions:

0

Total no. in group:

25

Clinical observations:

not specified

Remarks on result:

no indication of skin sensitisation

Reading:

other: final result from reading after 24 and 48h

Group:

positive control

Dose level:

15 % Mercaptobenzothiazole

No. with + reactions:

8

Total no. in group:

20

Clinical observations:

not specified

Remarks on result:

positive indication of skin sensitisation

Conclusions:

Potassium dichromate was shown to be sensitising in the guinea pig maximization test

Executive summary:

The results of this study show that Cr (VI) tested as potassium dichromate is able to induce skin sensitisation in the guinea pig maximization test.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

The following information is taken from the EU RAR:

'Skin sensitisation resulting from occupational contact with Cr(VI) compounds is relatively common in humans. This has also been demonstrated in patch testing of contact dermatitis patients and in investigations of various occupational groups. In addition, the skin sensitisation potential of Cr (VI) compounds has been clearly demonstrated in standard and modified guinea pig maximisation tests and in the mouse ear swelling test. The current understanding of the mechanism involved in the sensitisation indicates that Cr (III) is the ultimate hapten. Skin contact with Cr (VI) leads to penetration of Cr (VI) into the skin where it is reduced to Cr (III). There is some evidence for cross-reactivity between Cr (III) and Cr (VI); Cr(VI)-sensitised subjects may also react to Cr (III). Overall, it is not possible to reliably determine a threshold for either induction or challenge in an exposed population using the available data, however it is assumed that all water soluble Cr (VI) compounds are human skin sensitisers.'

Conclusively, skin sensitisation potential of Cr(VI) was shown in animals testing Cr(VI) compounds, e.g. potassium dichromate. There is also evidence of cross-reactivity between Cr(VI and Cr(III) compounds.

Besides several positive animal studies available data from human exposure indicate that water-soluble Cr(VI) compounds are skin sensitisers. Therefore, further testing of this group of compounds for skin sensitisation is not proposed, also based on the low pH and classification as corrosive.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

No suitable animal tests are available for the detection of respiratory sensitisation. The EU RAR discusses reports of occupational asthma in workers exposed to Cr(VI) compounds:

'Asthma arising from exposure to Cr(VI) was first suggested in the 19th century. A number of case reports, mainly within the chrome plating industry, provide evidence that inhaled Cr (VI) can cause asthma, although the total number of reported cases is small in relation to the number of workers potentially exposed. Positive findings are available from several well-conducted bronchial challenge tests. No information is available on the dose-response relationships for induction of the hypersensitive state or elicitation of an asthmatic response in hypersensitive individuals. The available case reports and evidence from well-conducted bronchial challenge tests, show that inhalation of Cr (VI) compounds can cause occupational asthma. As with skin, Cr (VI)- sensitised subjects may react to Cr (III). It is not possible to determine a no-effect level or exposure-response relationship for induction or elicitation of occupational asthma.'

It is therefore concluded that chromic acid (as other Cr(VI) compounds) has the potential to cause respiratory sensitisation in exposed humans and should be classified.

Justification for classification or non-classification

Chromium (VI) trioxide, sodium chromate, sodium dichromate and potassium dichromate are classified under Annex I to directive 67/548/EEC. Chromium (VI) trioxide is listed in Annex VI to Regulation (EC) No 1272/2008 under Index No 024-001-00-0 with the following harmonised classification:

Skin Sens. 1, H317 ‘May cause an allergic skin reaction’ and Resp. Sens. 1, H334 ‘May cause allergy or asthma symptoms or breathing difficulties if inhaled’

No change to this classification is proposed.