Cetylpyridinium chloride

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1993-1994

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Valid experimental study under GLP. Study preceeds establishment of EU and OECD guideline methods.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1994

Report date:

1994

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

Limited or absent examination of plasma/blood kinetics and metabolites.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Cetylpyridinium chloride

EC Number:

204-593-9

EC Name:

Cetylpyridinium chloride

Cas Number:

123-03-5

Molecular formula:

C21H38N.Cl

IUPAC Name:

cetylpyridinium chloride

Constituent 2

Reference substance name:

CPC

IUPAC Name:

CPC

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Label Identification: D1470.01. Cetylpyridinium chloride. HPCR0563. White powder. 99.2% Purity. Storage: ambient conditions. Radiolabelled Article Label Identification: RC93244-01 Cetylpyridinium chloride. 6.06 mCi C14 6/93. Off-white powder. >98% Purity. Storage: ambient conditions.

Radiolabelling:

yes

Remarks:

C14

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS: CD BR VAF/Plus substrain
- Source:Charles River Laboratories, Portage, MI
- Age at study initiation: 6-7 weeks
- Weight at study initiation: 173-208 g. Upon start of the experiment, males weighed 252-265 g and females weighed 202-218 g.
- Fasting period before study: no
- Housing: stainless steel wire mesh cages. After dosing, animals remained in glass metabolism cages for the duration of the study.
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Certified Rodent Chow #5002. Purina Mills, Inc. Ad libitum. Not fasted prior to dosing.
- Water (e.g. ad libitum): ad libitum.
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 65-78 degrees F
- Humidity (%): 40-70%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12 h

Administration / exposure

Route of administration:

other: Oral gavage and intravenous

Vehicle:

other: 0.9% sodium chloride (USP)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): Saline was used as a vehicle for both routes of administration.

HOMOGENEITY AND STABILITY OF TEST MATERIAL: Not relevant for single dose administration.
PREPARATION OF DOSING SOLUTIONS:

Animals were observed for moribundity, mortality and overt toxicity at least twice daily throughout the study. Individual body weights were recorded just prior to test substance administration and at scheduled necropsy.

Duration and frequency of treatment / exposure:

72 hours after a single administration

Doses / concentrations

Remarks:

Doses / Concentrations:
25 mg/kg bw for oral administration, and 2.5 mg/kg bw for IV.

No. of animals per sex per dose / concentration:

5/sex/dose

Control animals:

no

Details on study design:

Glass metabolism chambers were fitted with a diaphragm pump (Gest D0A-P104-AA) used to draw air through the cages. A manifold system channeled the air into the cages. The air exited the cage at the urine/feces separator. The exhausted air was directed through individual flow meters to the CO2 absorption towers containing approximately 250 ml of 1M sodium hydroxide. It was then passed through a second manifold to a single dry ice trap and on to the pump. The last trap prevented any carry-over of CO2 absoprtion solution to the pump. The CO2 absorption solutions were drained at 12-24 h intervals throughout the radiological portion of the study. Fresh trapping solvent was immediately poured into the tower after each draining.
Urine was collected in a tared container and removed at 12 or 24 h intervals from the metabolism cages. Similarly, feces were removed at the same intervals.
Cages were rinsed at the 24 and 48 h fecal collection interval and after the animal necropsy with water, and the rinses were collected for radioassay.
Prior to euthanasia with CO2, blood samples for determination of radiocarbon in whole blood were obtained via cardiac puncture.

Details on dosing and sampling:

For the orally administered sample: doses were 25 mg/kg bw, 5 ml/kg, and aimed to be 300 microCuries per dose. For the iv administered sample: each dose formulation for males contained 5.07 mg of test material per g and 44.3 microCuries of radioactivity per gram. The dosage formulation for females contained 5.11 mg of test material and 56.9 microCuries of radiolabel per gram.
At necropsy, organs were removed separtely and place in preweighed glass containers. These were then reweighed and the net sample weights were determined. The samples were stored forzen until digestion. They were thawed at room temperature then, for larger tissues, divided into equal aliquots and placed into preweighed scintillation vials. The vials were reweighed and the actual aliquot weights were determined. 2 ml of Soluene 350 was added to each sample and gently shaken. Digestion proceeded until complete. 0.1 ml of 70% perchloric acid and 0.3 ml of 30% hydroden peroxide were added to each sample. The samples were mixed gently and allowed to stand at rt for 2 hours with the caps placed lightly on top of the vials. After the samples had been decolored, 15 ml of scintillation fluid was placed on top. The vials were capped, shaken and placed in the counter for at least 3 hours prior to counting for 10 min. The counts of all the samples were summed for determination of the activity of the entire sample.

Statistics:

Microgram Equivalence per gram of test substance, and specific activity, were calculated using standard methods. Net dpm/aliquot was calculated off-line by the spreadsheet program by subtraction of the gross dpm/cocktail bland from the gross sample or control matrix dpm/aliquot value.
Group results were presented as Mean +/1 standard error of the mean.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Maximum absorption of CPC after oral gavage was 13% for female and 14% for male rats.

Main ADME results 2

Type:

excretion

Results:

After oral dosing, the main route was fecal, at 85% (females) and 87% (males). Urinary was 3.3% (females) and 4.6% (males). After iv dosing, fecal was 37 and 36% in females, males, respectively. Urinary elimination was 26 and 32% (females, males).

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Maximum absorption of CPC after oral gavage was 13% for female and 14% for male rats.

Details on distribution in tissues:

Distribution of radiolabel occurred to many tissues; the heart contained the highest relative radioactive concentration in both sexes.

Transfer into organs

Transfer into organs 1

Test no.:

#1

Transfer type:

other: blood perfusion

Observation:

distinct transfer

Remarks:

via oral route

Transfer into organs 2

Test no.:

#2

Transfer type:

other: blood perfusion

Observation:

distinct transfer

Remarks:

via IV route

Details on excretion:

After oral dosing, the main route of elimination was fecal, at 85% (females) and 87% (males). Urinary excretion was low in both female and male animals (3.3% and 4.6%, respectively). Only a very small fraction of the dose was exhaled as radiolabeled CO2 by either sex, less than 0.01%. Inspection of tissues revealed residual radioactiivty in all tissues, however, the relative concentration of residual radioactivity was not uniform among tissues. Male and females showed the heart to contain the higher level, followed by the kidney and pancreas. The cage rinse was 1.6% for females and 1.2% for males. Recovery of 94% was observed for females and 99% for males after oral administration of test article.
After iv dosing, fecal elimination was 37 and 36% in females, males, respectively. Urinary elimination was 26 and 32% (females, males). CO2 exhalation of radiolabel was negligible. Less than 5% of the radioactivity remained in the tissues after 72 hours. The carcass accounted for 15% in females and 13% in males. The cage rinse was 1.8% for females and 2.6% for males. The overall recovery of the IV-administered test article was 80% in females and 84% in males.

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

No study on metabolism was undertaken

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

13-14% maximum absorption after oral gavage dosing.

Any other information on results incl. tables

Recovery of Radiolabel after Oral and Intravenous Dosing of Cetylpyridinium Chloride

	Oral - Female	Oral - Male	IV - Female	IV - Male
Recovery	94	99	80	84
Feces	85	87	37	36
Urine	3.3	4.6	26	32
CO2	-	-	-	-
Tissues	0.6	0.2
Carcass	3.3	3.1	15	13
Cage Rinse	1.6	1.2	1.8	2.6

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Cetylpyridinium chloride (CPC) is absorbed to a moderate degree (13-14%) following an oral gavage exposure, and is readily eliminated from the body. The predominant route by which both male and female rats eliminated the substance was the feces (>85% of the oral dose); urinary excretion accounted for a small portion (<5%) and respiratory elmination as CO2 was negligible. Total recovery of the radiolabel was 94 and 99% for females and males, respectively. After an IV administration of CPC, up to 37% of the radiolabel was found in the feces, indicating that CPC and/or its metabolites are elimated through the bile. Urinary excretion of IV administered material was higher, 26% and 32% for females and males, respectively. Total recovery of the radiolabel was 80% and 84% for females and males, respectively.