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Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

The results of sensitisation studies with chlorhexidine using the salt chlorhexidine digluconate in animals are summarised in the following Table (all concentrations stated in terms of chlorhexidine digluconate).

In a guinea pig maximisation test (GPMT) with a multiple dose regime, no sensitizing effects of chlorhexidine digluconate were observed. In a Buehler test conducted by the same working group, a positive response was observed in 2 of 25 animals of the test group but also in 2 of 5 control animals which showed confluent erythema regarded as an irritant reaction, even at the lowest challenge reaction (1 %). Thus, the positive response may be the result of an irritation rather than a sensitisation and the result is considered equivocal. In a further GPMT, 2 of 10 animals showed a positive response in the challenge and rechallenge reaction. There were no data for the response of the control group. This study used a lower concentration for induction but a much higher concentration (12.5 %chlorhexidine digluconate) for the challenge than in the study mentioned above (0.3 %chlorhexidine digluconate). The authors of the study suggest a weak sensitising reaction. However, because of the high challenge concentration and the lack of reporting for the control group the result should also be considered as equivocal. In the same study, a further protocol using a single injection adjuvant test (SIAT) produced a reaction in 1 of 10 animals, again, there are no data regarding the response of controls. The authors of the study suggest a very weak sensitising reaction. However, for the reasons mentioned above, the result should also be considered as equivocal. A third protocol using a modified Draize procedure gave no evidence of a sensitisation reaction.

The popliteal lymph node assay (PLNA) has been proposed for immunotoxicological tests to predict allergenic and autoimmunogenic chemicals. A PLNA was conducted with 20 %chlorhexidine digluconate in mice. The test substance or vehicle was subcutaneously injected into the right hind footpad, the contralateral footpad receiving saline vehicle only. As an index of effect (indication of a sensitisation potential), the cellularity index (CI) in the popliteal lymph nodes (PLN) was calculated from the cell count of the treated vs. the control PLN on day 7.Chlorhexidine digluconate caused a significant increase in the CI (3.8 vs. 1.0 in the control). The effect was much lower than for the positive control substance 2,4,6-trinitrobenzenesulfonate (TNBS) (dose-dependent increase in CI from 4.3-10.8). The authors of the study conclude that the PLNA in mice may be useful as a short-term test to detect drugs possibly exhibiting allergenicity potential, but also stress that further investigations on cell subset analysis are necessary and more substances need to be evaluated. Chlorhexidine digluconate is known to cause a reactive histiocytosis but no further effects in the mesenteric lymph nodes of rats after oral administration. It should be clarified whether a similar reaction – leading to a false positive response – could be involved in the observed response in the PLNA in mice.

Skin sensitisation of chlorhexidine digluconate

Species

Method

Number of animals sensitized/total number of animals

Result

Guinea pig

GPMT1, comparable to OECD guideline 406

0/25

Not sensitising

Guinea pig

Buehler-Test

2/25

Equivocal (positive reactions also in untreated control, possibly due to irritation)

Guinea pig

GPMT

2/10

Weakly sensitising (no data on controls)

Guinea pig

SIAT2

1/10

Very weakly sensitising (no data on controls)

Guinea pig

Modified Draize

0/10

Not sensitising

Mouse

PLNA2

6 animals treated

PLN cellularity index
control: 1.0 ± 0.16
treated: 3.8 ± 1.44 (p <=0.01)

1: GPMT Guinea pig maximization test;
2: SIAT: Single injection adjuvant test
3: PLN Popliteal lymph node assay.


Migrated from Short description of key information:
Chlorhexidine (tested in all studies as chlorhexidine digluconate) was not sensitising in a GPMT using a multiple dose design. This test is considered the most relevant because it used several doses of the test substances, increasing the sensitivity of the assay, and was performed in accordance with current guideline. The weakly positive responses in a Buehler test in the same study and of a GMPT and a SIAT in another study may have been due to an irritant effect rather than a sensitisation and therefore do not provide reliable evidence for a sensitisation. The same holds true for the PLNA in mice. Regarding related substances, chlorhexidine diacetate was not sensitising in a modified Buehler test and also shows a very high level of structural similarity to chlorhexidine base.
In humans, allergic reactions to chlorhexidine have been described. Allergic contact dermatitis to chlorhexidine is known but is rare (1 % or lower). In view of the widespread and worldwide use of chlorhexidine digluconate (and other chlorhexidine salts) over several decades, allergic reactions to chlorhexidine are considered an uncommon event.
In summary, it is concluded that chlorhexidine digluconate is not a skin sensitizer in standard animal tests. Allergic reactions in humans are rare.

Respiratory sensitisation

Endpoint conclusion
Additional information:
Migrated from Short description of key information:
There are no data available.

Justification for classification or non-classification

Chlorhexidine tested using chlorhexidine digluconate was not sensitising in a GPMT using a multiple dose design. This test is considered the most relevant because it used several doses of the test substances, increasing the sensitivity of the assay, and was performed in accordance with current guideline. The weakly positive responses in a Buehler test in the same study and of a GMPT and a SIAT in another study may have been due to an irritant effect rather than a sensitisation and therefore do not provide reliable evidence for a sensitisation. The same holds true for the PLNA in mice. Regarding related substances, chlorhexidine diacetate was not sensitising in a modified Buehler test.

In humans, allergic reactions to chlorhexidine have been described. Allergic contact dermatitis to chlorhexidine is known but is rare (1 % or lower). In view of the widespread and worldwide use of chlorhexidine digluconate (and other chlorhexidine salts) over several decades, allergic reactions to chlorhexidine are considered an uncommon event.

In summary, it is concluded that chlorhexidine digluconate is not a skin sensitizer in standard animal tests. Allergic reactions in humans are rare.