Didecyldimethylammonium chloride

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

GLP study, fully complying to OECD 417. No deviations. Criteria radiochemical purity and total radiation recovery were generally met. Recovery rates for dermal dose groups were slightly low. Some deviations from study plan occurred which are not considered to have compromised the validity or integrity of the study. Due to subsequent oral uptake of dermal applied dose, no information can be derived on quantitative dermal uptake from this study.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2005

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Didecyldimethylammonium chloride

EC Number:

230-525-2

EC Name:

Didecyldimethylammonium chloride

Cas Number:

7173-51-5

Molecular formula:

C22H48N Cl

IUPAC Name:

didecyldimethylammonium chloride

Details on test material:

Unlabelled: Composition similar as described in section 1.2 as typical marketed substance (act:40%, water 60%)
Composition: contains 40% Didecyldimethylammonium chloride (CAS no 7173-51-5) in 60% water. batchnumber; WIR03048
Labelled: [Methyl-14C]DDAC, purity: 98% in solution of IPA:water (2:3) batchnumber: CFQ13640

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

-Source: Charles River Laboratories France, L’Arbresle, France. Caesarean Obtained, Barrier Sustained-Virus Antibody Free (COBS-VAF®).
-Sex: 60 males and 60 females.
-Age/weight at study initiation: Young adults approx. 7 weeks old; for the bile collection group, animals were around 10 weeks old.
-Number of animals per group: Kinetics (5 groups): 9 males & 9 females (3 /group/time/sex)
-Excretion balance: (3 groups): 5 males & 5 females
-Bile collection (1 group): 4 males & 4 females
-Control animals: Yes: For the purposes of pre-dose sample analysis, plasma, blood and tissues will be collected from at least one untreated supplementary animal/sex using the above mentioned procedures.

Administration / exposure

Route of administration:

other: Gavage and topical

Vehicle:

water

Details on exposure:

Refer to study design

Duration and frequency of treatment / exposure:

6 hour(s)

Doses / concentrations

Remarks:

Doses / Concentrations:
Males: oral 50 or 200; dermal 1.5 or 15 mg/kg bw/day
Females: oral 50 or 200; dermal 1.5 or 15 mg/kg bw/day

No. of animals per sex per dose / concentration:

Males: 64; Females: 64

Control animals:

no

Positive control reference chemical:

Not applicable

Details on study design:

The blood and plasma pharmacokinetics, tissue distribution and mass balance of total radioactivity of [14C] DDAC were evaluated following single dermal administration (at 1.5 and 15 mg/kg, as 6-hour exposure over 10% of the body surface) and single (at 50 and 200 mg/kg) and repeated (at 50 mg/kg/day) oral gavage administrations to male and female Sprague-Dawley rats. In addition, the elimination of radioactivity in bile after single oral administration at 50 mg/kg was investigated. Investigations included blood and plasma pharmacokinetics, tissue distribution and mass balance of total radioactivity.

The animals were divided into 9 groups; groups 1 to 5 (each of 9 animals/sex) for plasma/blood pharmacokinetics of radioactivity and tissue distribution, groups 6 to 8 (each of 5 animals/sex) principally for excretion balance and group 9 (4 animals/sex) for bile collection. 

 The animals wore an Elizabethan collar to prevent ingestion of the test item. At the end of the exposure period, the collar was removed and kept with the swabs for analysis. After 6 hours, the treated areas were washed using dampened cotton swabs with diluted hand soap followed by two dry swabs to remove all traces of the test item.

Details on dosing and sampling:

Animals of groups 1 to 4 and 6 and 7 were treated once with the radiolabelled test item. Animals of groups 5 and 8 were treated once per day for 6 days with the unlabelled test item, followed by a single administration of the radiolabelled test item on the seventh day. All oral dosages applied 2.2 MBq/kg for radioactive dose-levels, and 3.7 MBq/kg for dermal applications. Dermal dosages were applied on clipped skin approx. 10% of the total body surface area, over the interscapular/upper back region.

Blood and plasma sampling:
Oral group: 0.5, 1, 2, 4, 8, 24, 48, 72 and 96 hours  
Dermal group: 3 and 6 (i.e. during the exposure period), 7, 8, 10, 16, 24, 48 and 72 hours.

Following the final blood sampling/animal (i.e. at 24, 48 and 72/96 hours), each sampled animal was sacrificed by cervical dislocation, under isoflurane anesthesia. The carcass were weighed and the following tissues dissected out and weighed: Adrenals, Gastro intestinal tract (complete), Lymph nodes (mesenteric and mandibular), Brain, Heart, Muscle (right leg adductor), Eyes, Kidneys, Pancreas, Fat (abdominal), Liver, Skin (lower back), Femur (right with marrow), Lungs, Spleen. In addition, for the dermal treated animals, the application site will be dissected out and weighed. Thereafter, the application site and the skin from the lower back will be each stripped completely (using tape) 13 times. No macroscopic examination was performed on the prematurely sacrificed animals or those found dead. 

Excreta: Urine and faeces were collected from the groups 6 to 8 animals for the radioactive treatments at the following times:
- during a period of 24 hours before radioactive dosing on day 1 (groups 6 and 7), or day 7 (group 8),
- and then during the periods 0-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 hours after the radioactive gavage/dermal application.

After each collection of faeces, the cages and trays were carefully rinsed with not more than 20 mL of water (cage wash) (except for last collection; approximately 100 mL were used). Expired CO2 was not collected as earlier studies with DDAC showed no radioactivity in the expired air. Any measurement of radioactivity lower then two times the blank was reported as BLQ (below the limit of quantification).

Statistics:

Not reported

Results and discussion

Main ADME results

Type:

other: Absorption, distribution and excretion

Results:

Low dermal and oral absorption. The actual minimal fraction of the oral dose absorbed was 0.93 to 3.16%; this was eliminated rapidly, essentially within a 48 hour period.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral:
Following single and/or repeated oral gavage at 50 and 200 mg/kg/day, the plasma and blood radioactivity levels were non-quantifiable indicating a low oral bioavailability. The actual minimal fraction of the oral dose absorbed was 0.93 to 3.16%; this was eliminated rapidly, essentially within a 48-hour period. The vast majority of the oral dose was excreted rapidly in the faeces.

Dermal:
Following single dermal application at 1.5 and 15 mg/kg, the plasma and blood radioactivity levels were non-quantifiable at all time-points. For the 1.5 mg/kg group, around 1% and 50% of the dose was eliminated in the urine and faeces, respectively, mostly within a 48-hour period, suggesting that the dermal dose was highly absorbed via the skin. However, as the test site was not protected with an Elizabethan collar during the main part of the collection period (the collar was worn during the exposure period only), this may have been due to the animal licking the test site. This is also supported with the finding that after oral dosing only 1-2.5% was excreted via bile back to intestines, and 2-3% excreted via urine. If similar routes of excretion are expected for dermal absorbed doses, it would not be possible to find levels of 50% of applied doses in intestines with only 1% excreted via urine. This indicates that about 50% of the dermal applied dose was taken up orally after all.

Details on distribution in tissues:

Oral:
At the high oral dose-level only, quantifiable levels of radioactivity were found in some central organs at 24 hours post-dosing (intestines, liver., kidney) ; otherwise, the vast majority of the dose was confined to the intestines and levels decreased over time. 

Dermal:
At 24 hours post-dosing, most of the radioactivity was in the "stripped" skin (dermis and epidermis) application site (6.07 to 21.6% of the dose) and intestines for both dose-levels, though some radioactivity was in the skin adjacent to the application site (most likely from cross-contamination due to grooming) and minor traces were in the eyes and other organs. At 72/168 hours, levels in the application site were 1.06 to 2.82% of the radioactive dose, suggesting the skin acted as a drug reservoir. In the stratum corneum of the application site, the levels of radioactivity were of similar magnitude in the different layers at each time point. For all tissues/organs, the radioactivity levels essentially decreased over time. All data showed generally a low inter-animal variability. In addition, there was no evidence of gender differences.

Details on excretion:

Oral:
Only 2.57/1.14% (males/females) of the oral dose was eliminated in the bile in a 24-hour period.  No metabolites or parent drug were found in urine.

Dermal:
For the 1.5 mg/kg group, around 1% and 50% of the dose was eliminated in the urine and faeces, respectively, mostly within a 48-hour period.

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Conclusion: 

Low dermal and oral absorption. The actual minimal fraction of the oral dose absorbed was 0.93 to 3.16%; this was eliminated rapidly, essentially within a 48 -hour period.

Applicant's summary and conclusion

Conclusions:

Low oral and probably negligible dermal absorption. The total oral absorption value was roughly in the range around 3-7%, based on urinary (0.93 - 3.16%) and bile (1.8-4.0%) excretion; elimination was rapidly, essentially within a 48 hour period.

Executive summary:

The blood and plasma pharmacokinetics, tissue distribution and mass balance of total radioactivity of [14C] DDAC were evaluated following single dermal administration (at 1.5 and 15 mg/kg, as 6-hour exposure over 10% of the body surface) and single (at 50 and 200 mg/kg) and repeated (at 50 mg/kg/day) oral gavage administrations to male and female Sprague-Dawley rats. In addition, the elimination of radioactivity in bile after single oral administration at 50 mg/kg was investigated. Investigations included blood and plasma pharmacokinetics, tissue distribution and mass balance of total radioactivity.

Conclusion

Low oral and probably negligible dermal absorption. The total oral absorption value was roughly in the range around 3-7%, based on urinary (0.93 - 3.16%) and bile (1.8-4.0%) excretion; elimination was rapidly, essentially within a 48 hour period.