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Toxicological information

Dermal absorption

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Administrative data

Endpoint:
dermal absorption in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was conducted according to OECD guideline 417 and in compliance to GLP
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report date:
2006

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD 417
Deviations:
no
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
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:
N-decyl-N,N-dimethyldecan-1-aminium chloride
Details on test material:
- Name of test material (as cited in study report): Arquad 2.10-40
- Physical state: Colourless to pale yellowish liquid
- Analytical purity: 40.5 % Didecyldimethylammonium chloride (CAS No 7173-51-5)
- Composition of test material, percentage of components: 40.2 % of DDAC, amine 0.43 %, Amine HCl 0.39 %,
- Purity test date: Oct. 20, 2004
- Lot/batch No.: WIR03048
- Storage condition of test material: At room temperature

Radiolabelled Material: [Methyl-14C]DDAC
- Physical state: Colourless liquid
- Radiochemical purity (if radiolabelling): 98 % (by HPLC), 99.2 % (by TLC)
- Specific activity (if radiolabelling): 1.11 GBq/mmol; 30.1 mCi/mmol (by gravimetric analysis): 1.22 GBq/mmol; 33 mCi/mmol
- Radioactive concentration: 148 MBq/mL, 4 mCi/mL
- Batch Number: CFQ13640
- Purity test date: Nov. 19, 2003
- Expiration date of radiochemical substance (if radiolabelling):
- Storage condition of test material: -20 °C in the absence of light and air is recommended
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories France, L’Arbresle, France. Caesarean Obtained, Barrier Sustained-Virus Antibody Free (COBS-VAF®).
- Age at study initiation: 7 wk old; for the bile collection group, animals were around 10 wk (males) 12 wk females).
- Weight at study initiation: 229 g males and 159 g females
- Fasting period before study: Overnight
- Housing: 2 or 3 animals/cage in oral groups and singly in dermal and bile collection group
- Diet (e.g. ad libitum): A04 C pelleted diet ad libitum
- Water (e.g. ad libitum): Filtered tap water ad libitum
- Acclimation period: At least 7 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22± 2 °C
- Humidity (%): 50±20%
- Air changes (per hr): 12 cycles/h of filtered, non-recycled air
- Photoperiod: 12 h light/ 12 h dark

Administration / exposure

Type of coverage:
not specified
Vehicle:
water
Duration of exposure:
6 hours
Doses:
Oral: 50 and 200 mg/kg bw /day;
Dermal: 1.5 and 15 mg/kg bw /day
No. of animals per group:
9/sex/dose - Plasma/blood pharmacokinetics (Group 1-5)
5/sex/dose - Excretion balance (Group 6-8)
5/sex/dose bile collection (Group 9)
Control animals:
yes
Remarks:
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.
Details on study design:
APPLICATION OF DOSE: oral, dermal

VEHICLE
- Justification for use and choice of vehicle (if other than water): water

SAMPLE COLLECTION
- Collection of blood: yes
- Collection of urine and faeces: yes
- Collection of expired air: no

ANALYSIS
- Method type(s) for identification: Radio-HPLC for urine samples, LSC for biological samples
Details on in vitro test system (if applicable):
n.a.

Results and discussion

Signs and symptoms of toxicity:
no effects
Dermal irritation:
no effects
Percutaneous absorption
Dose:
15 mg
Parameter:
percentage
Absorption:
ca. 1 %
Remarks on result:
other: 72 h
Remarks:
No precise quantifiable information can be derived on dermal uptake from this study. Mean plasma and blood radioactivity levels were all below quantifiable limits indicating that dermal absorption was very low

Applicant's summary and conclusion

Conclusions:
Under the test conditions, the test material (containing 40.5 % DDAC) has low dermal and oral absorption.
Executive summary:

An OECD guideline 417study was conducted to investigate the blood and plasma pharmacokinetics, tissue distribution and mass balance of total radioactivity of test material [14C-DDAC] following single dermal administration (at 1.5 and 15 mg/kg, as 6 h exposure over 10% of the body surface) and single (at 50 and 200 mg/kg) and repeated (at 50 mg/kg/d) 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. 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 d with the unlabelled test item, followed by a single administration of the radiolabelled test material on Day 7.

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. 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 h, 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 material.

Blood and plasma sampling were performed as below:

Oral group: 0.5, 1, 2, 4, 8, 24, 48, 72 and 96 h
Dermal group: 3 and 6 (i.e. during the exposure period), 7, 8, 10, 16, 24, 48 and 72 h.
Following the final blood sampling/animal (i.e. at 24, 48 and 72/96 h), 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. 

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 h 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 h  after  the  radioactive gavage/dermal application
After each collection of faeces, the cages and trays will be carefully rinsed with  not  more  than  20 mL  of  water (cage wash)  (except for last collection; approximately 100 mL will be used).

Following single and/or repeated oral gavage at 50 and 200 m g/kg/d, 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-h period. The vast majority of the oral dose was excreted rapidly in the faeces. At the high oral dose-level only, quantifiable levels of radioactivity were found in some central organs at 24 h post- dosing (intestines, liver. kidney) ; otherwise, the vast majority of the dose was  confined  to the intestines  and levels decreased over time.  Only 2.57/1.14% (males/females) of the oral dose was eliminated in the bile in a 24-h period.  No metabolites or parent drug were found in urine.

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 h period.
At 24 h 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 h, 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. 

Under the test conditions, the test material (containing 40.5 % DDAC) has 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 h period (Appelqvist T, 2006).

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