Registration Dossier

Administrative data

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Comparable to guideline study with acceptable restrictions No data are provided regarding the nature of the radiochemical impurities in the 14C-labelled chlorhexidine. Therefore, it must be considered that impurities, e.g. breakdown products of lower molecular weight, may have penetrated through the skin at a higher amount than chlorhexidine itself and contributed to the 14C-activity which was found in urine and faeces. This would have led to an overestimation of the percutaneous absorption of chlorhexidine. After the 24 h application of the test substance, excess material was wiped off but the animals were not washed. Since the animals were housed in the metabolism cages in pairs, it must also be considered that some remaining radioactivity at the site of application could have been licked up by the other animal leading to oral uptake and contributing to the excretion of radioactivity with the faeces. This would also contribute to an overestimation of the percutaneous absorption of chlorhexidine. Furthermore, the distribution of 14C-labelled chlorhexidine in blood and organs was not measured. However, the data on excretion and residual 14C-contents at the application site and in the skin patch clearly indicate that the overall amount of chlorhexidine in the body will be very small.

Data source

Reference
Reference Type:
publication
Title:
Percutaneous absorption and tissue distribution of 1-(3,4-dichlorobenzyl)-5-octylbiguanide (OPB-2045) in rats
Author:
Kudo S, Furukawa M, Okumura H, Umehara K, Odomi M & Miyamoto G
Year:
1998
Bibliographic source:
Xenobiotic Metabolism and Disposition 13, 13-20

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 427 (Skin Absorption: In Vivo Method)
Deviations:
not applicable
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Non-radioactive chlorhexidine:
Source: Sigma-Aldrich, Japan
Purity: no data

14C-labelled chlorhexidine:
Source: Amersham, Japan
Radiochemical purity: >= 97.2 %
Specific activity: 655 kBq/mg
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Kanagawa, Japan
- Age at study initiation: 5-6 w
- Weight at study initiation: 188-245 g
- Individual metabolism cages: no (in pairs)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: ca. 1 w

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 2
- Humidity (%): 60 +/- 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Type of coverage:
occlusive
Vehicle:
water
Duration of exposure:
24 hrs
Doses:
The test solution was prepared by mixing of gluconic acid with a 14C-labelled chlorhexidine solution at a 2:1 molar ratio and diluting to a final concentration of 0.04 (w/v) % a 14C-chlorhexidine (pH 4.74). 0.3 ml of the test solution was applied to a 2.5 cm-square patch, placed on the shaved back skin of the animals, covered with cloth tape, and held by elastic adhesive bandage.
No. of animals per group:
3 m
Control animals:
no
Details on study design:
In the same study, the percutaneous absorption, distribution, and excretion of 14C-labelled 1-(3,4-dichlorobenzyl)-5-octylbiguanide (OPB), a related biguanide biocide, was also studied.

Results and discussion

Signs and symptoms of toxicity:
not examined
Dermal irritation:
not specified
Percutaneous absorption
Remarks on result:
other: see table below

Any other information on results incl. tables

No differences in percutaneous absorption were observed between animals with intact or damaged skin.

Results of percutaneous absorption study in rats following single dermal application of14C‑(biguanide labelled)-chlorhexidine digluconate

Percentage of total14C-dose*

Intact skin

Damaged skin

Urinary excretion (0-168 h)

0.1+.0.1

0.3±.0.1

Faecal excretion (0-168 h)

4.2±1.8

3.5±1.7

Urine + faeces (0-168 h)

4.2±2.0

3.8±1.8

Application site (after 168 h)

1.5±0.5

2.7±1.6

Skin patch (after 24 h)

97.7±5.5

97.2±7.7

Total recovery

103.4

103.7

*: Mean ± SE of 3 animals.

Applicant's summary and conclusion

Conclusions:
Under the conditions of the assay, the percutaneous absorption of chlorhexidine is low.
Executive summary:

In this study the percutaneous absorption of 14C-labelled chlorhexidine after 24 h occlusive application to undamaged and damaged skin of rats was studied. Measurements of recovery for chlorhexidine in skin patches, skin area, urine, and faeces was done.

Under the conditions of the assay, the percutaneous absorption of chlorhexidine is quite low. More than 97 % of the applied radioactivity was removed with the skin patch and there were no significant differences in toxicokinetics between undamaged and damaged skin.