D-gluconic acid, compound with N,N''-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediamidine (2:1)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1979-10-19 to 1980-03-17

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

There are some deficiencies in reporting of study details such as pre-acclimatization period, initial age of animals, or preparation of the carcass. Tissue distribution was not studied. Excretion in expired air and in bile was not measured. However, this is not considered to be of major significance for the evaluation of the study. The findings are considered relevant and the present documentation is considered to present valuable information regarding the toxicokinetics of chlorhexidine digluconate.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1982

Report date:

1982

Materials and methods

Objective of study:

excretion

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

Some deficiencies in reporting of study details (e.g. tissue distribution was not studied and excretion in expired air and in bile was not measured)

GLP compliance:

yes

Remarks:

According to ICI’s policies and procedures for GLP

Test material

Test material information

Constituent 1

Reference substance name:

D-gluconic acid, compound with N,N''-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediamidine (2:1)

EC Number:

242-354-0

EC Name:

D-gluconic acid, compound with N,N''-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediamidine (2:1)

Cas Number:

18472-51-0

Molecular formula:

C22H30Cl2N10.2C6H12O7

IUPAC Name:

N',N'''''-hexane-1,6-diylbis[N-(4-chlorophenyl)(imidodicarbonimidic diamide)] - D-gluconic acid (1:2)

Radiolabelling:

yes

Remarks:

14C uniform ring-labelled

Test animals

Species:

mouse

Strain:

other: C57 B1/10J

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
-Source: ICI, Animal Breeding Unit, Alderley Park
-Weight at study initiation: 21-31 g
-Fasting period before study: no
-Housing: animals were housed in pairs in metabolism cages
-Individual metabolism cages: Urine and faeces were collected for 7 days. Cages were washed each day and washings were retained for analysis
-Diet: ad libitum
-Water: ad libitum

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Duration and frequency of treatment / exposure:

Animals were dosed once via gavage

Doses / concentrations

Remarks:

Doses / Concentrations:
25, 50, 100 or 200 mg/kg bw

No. of animals per sex per dose / concentration:

6 m / 6 f

Control animals:

no

Details on study design:

Urine and faeces were collected for 7 days. Cages were washed each day and washings were retained for analysis. Animals were sacrificed at the end of the study and carcasses were retained for analysis of radioactivity.

Details on dosing and sampling:

Group 1 and 2 (25 mg/kg bw): 4.08 mg 14C-base (preparation 17R), 2 ml water, 2.9 mg 1,5-gluconolactone, 63.6 ul chlorhexidine digluconate (20 % solution), 1.93 ml water to produce 0.5 % chlorhexidine digluconate. 266 ul of the solution were given by gavage.
Group 3 and 4 (50 mg/kg bw): 3.81 mg 14C-base (preparation 17R), 2 ml water, 2.7 mg 1,5-gluconolactone, 166 ul chlorhexidine digluconate (20 % solution), 1.83 ml water to produce 1 % chlorhexidine digluconate. 266 ul of the solution were given by gavage.
Group 5 and 6 (100 mg/kg bw): 1.3 mg 14C-base (preparation 17R) + 3.3 mg (preparation 18R), 3 ml water, 3.5 mg 1,5-gluconolactone, 359 ul chlorhexidine digluconate (20 % solution), 1.96 ml water to produce 1.5 % chlorhexidine digluconate. 355 ul of the solution were given by gavage.
Group 7 and 8 (200 mg/kg bw): 1.8 mg 14C-base (preparation 19R), 4 ml water, 1.3 mg 1,5-gluconolactone, 783 ul chlorhexidine digluconate (20 % solution), 0.54 ml water to produce 3 % chlorhexidine digluconate. 355 ul of the solution were given by gavage.

Statistics:

no data

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:

Urinary excretion at all dose levels accounted for 0.6 +/- 0.1 % of the dosed radioactivity. Urinary excretion over the dose range 25-200 mg/kg bw was 0.55 +/- 0.06 %. There was no apparent dose dependency, although the highest excretion was observed at the highest dose level, but data were derived only from two animals. Faecal excretion amounted to 77.9 +/- 2.7 % of the administered dose. Faecal excretion occurred over several days, possibly due to the loss of appetite. A mean of 94 % of the faecal excretion of radioactivity occurred within the first 3 days.
Analysis of the carcass of the animals from which the lowest recoveries of radioactivity were obtained showed that only 2.2 +/- 0.6 % of the administered dose remained in the body.

Toxicokinetic parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

half-life 1st:

Toxicokinetic parameters 2

Toxicokinetic parameters:

half-life 2nd:

Toxicokinetic parameters 3

Toxicokinetic parameters:

half-life 3rd:

Metabolite characterisation studies

Metabolites identified:

no

Any other information on results incl. tables

Death and loss of appetite for 1 or 2 days following dosing were observed in all dose groups except 50 mg/kg bw. However, the reason for the death of some animals and for the marked differences in sensitivity (ranging from death to no observable symptoms) are unknown.

Applicant's summary and conclusion

Conclusions:

The bioaccumulation potential is low based on study results
The data are indicating a low excretion in urine (0.6 %). In combination with a high recovery of chlorhexidine digluconate in faeces and a low recovery in the carcass, the data are indicating that the substance is poorly absorbed from the gastrointestinal tract.

Executive summary:

In this study equivalent to OECD Guideline 417, 14C-uniform ring-labelled chlorhexidine digluconate was administered by gavage to male and female mice at dose levels of 25 – 200 mg/kg bw. Excretion of radioactivity in urine and faeces was followed in metabolism cages for a period of seven days and radioactivity in the carcass was determined at termination of the study. A number of animals at all dose groups except at 50 mg/kg bw died after dosing. However, there was no dose response and the cause of death could not be elucidated. Urinary excretion of radioactivity was low at all dose levels (0.6 %) and most of the radioactivity was found in faeces (77.9 %). The low recovery could not be attributed to retention in the body as the analysis of the carcass of animals with the lowest recoveries of radioactivity revealed that only 2.2 % of the dose remained in the body.

It is well known from other studies that chlorhexidine is bound to the mesenteric lymph nodes in which high amounts of chlorhexidine may be found. The preparation of the carcass is not described in detail in the present report. If the gut, or part of the gut, had been removed prior to the further processing and subsequent determination of radioactivity in the carcass, it seems likely that a portion of the radioactivity that could not be accounted for was removed with the mesenteric lymph nodes.