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Basic toxicokinetics

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Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
From February 10, 2004 to March 13, 2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Read across justification is presented from the structurally analogous quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides to the quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites.

In the stomach the gastic juice is acidic, made up of acids and enzymes. In such an evironment it is highly unlikely that the quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites substance (s) will remain ionically bound to each other and thus are prone to dissociation in which case the released cation(s) will associate with other anions and the released anion will associate with cations. Thererfore, it is suggested read-across that data from the corresponding quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides is considered approriate in that such substances are likely to dissociate in a similar manner.

Furthermore, in 1988, the US EPA, Office of Pesticides and Toxic Substances issued a Notice to producers, Formulators, Distributors and Registrants regarding quaternary ammonium compounds with regard to "Clustering" of such quaternary ammonium compounds.

Prior to this, EPA had required each quat compound to be individually coded and registered as a new chemical, even when the chemical structure of individual compounds differed only slightly in alkyl distribution and chain lengths. This procedure was continued with the new generations of quats having two, three, and four chains. As a result, EPA records showed that some 211 registered technical grade active ingredient products containing varying concentrations of Quats, each coded separately on the basis of alkyl chain length and percentage carbon distribution within the chain. At this time, there are approximately eight to ten thousands (8-10,000) registered end-use formulations.

However, questions were raised regarding whether the EPA could cluster or group the quats and pick one or more representative members of each cluster to be used in toxicity studies, instead of requiring separate studies on each quat. These same questions were raised when the EPA issued its March 4, 1987 Data Call-In Notice requiring all registrants of antimicrobial active ingredients to submit subchronic and chronic toxicological data to support the continued registration of their products.

In response to these questions, EPA·solicited information from industry, the public, academia, industry cooperative work groups, the state of California, and Canada. EPA then reviewed all of the assembled information along with the chemical structure of most of the quats. Based on the results of this review, EPA developed the following four groupings of currently registered quat compounds:

Group I. The alkyl or hydroxyalkyl (straight chain) substituted Quats
Group II. The non-halogenated benzyl substituted Quats (includes hydroxybenzyl, ethylbenzyl, hydroxyethybenzyl, napthylmethyl, dodecylbenzyl, and alkyl benzyl)
Group III. The di-and tri-chlorobenzyl substituted
Group IV. Quats with unusual substituents (charged heterocyclic ammonium compounds).

Fundamental to this discussion EPA determined that "X-" in all of these structures would be attributed to "any anionic species". Therefore, this would mean in terms of toxicological evaluation the coutner anion in such quaternary ammonium compounds could be regarded as; e.g halogen (Cl-, Br-, I-,), saccharinate or cyclohexylsulphamate. It is therefore suggested here that nitrite (NO2-) could also be regarded as a pertinent anion.

Since the US EPA deem that such a clustering of structures for toxicological evaluation is well founded then it would seem that to consider read-across data from quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides to the closely structurally analogous quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites to be equally justifiable.

Furthermore, in certain organic solvents it has been reported that the exchange constants between nitrite and chloride in quaternary ammonium salts (QAS) are approximately equal. [Zhurnal Analiticheskoi Khimii, 2010, Vol. 65, No. 6, pp. 579–584. (E.M. Rakhman’ko, M.S. Markovskaya, L.S. Stanishevskii, Yu.S. Zubenko, A.R. Tsyganov)]

Cross-reference
Reason / purpose for cross-reference:
read-across: supporting information

Data source

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

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes

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:
Didecyldimethylammonium chloride
Test material form:
liquid
Specific details on test material used for the study:
- 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

Route of administration:
other: Oral gavage and dermal
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg

TEST SITE
- Area of exposure: Interscapular/upper back region
- % coverage: 10 % (25 -30 cm2 for 250-300 g rat)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Washed to remove all traces of test material by wiping with at least 3 cotton swabs dampened with water and diluted normal hand soap solution.
- Time after start of exposure: 6 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1.5 mL of dosage form/kg ( Dose: 1.5 mg/kg)

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes
Duration and frequency of treatment / exposure:
6 h
Doses / concentrationsopen allclose all
Dose / conc.:
50 mg/kg bw/day (nominal)
Remarks:
Oral
Dose / conc.:
200 mg/kg bw/day
Remarks:
Oral
Dose / conc.:
1.5 mg/kg bw/day
Remarks:
Dermal
Dose / conc.:
15 mg/kg bw/day
Remarks:
Dermal
No. of animals per sex per dose / concentration:
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:
other: 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.
Positive control reference chemical:
Not applicable
Details on study design:
- Rationale for animal assignment (if not random): Random
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : Blood, plasma, serum, urine, feces, cage washes, bile, skin-application site
- Time and frequency of sampling: Oral groups: 0.5, 1, 2, 4, 8, 24, 48, 72 and 96 h post gavage on Day 1 (Groups 1, 2 and 5)
Dermal group: 3, 6, 7, 8, 10, 16, 24, 48 and 72 h post dermal application (Groups 3 and 4)
Excreta and tissue collection: 0-24, 24-48, 48-72, 96-120, 120-144 and 144-168 h after the radioactive gavage/dermal application (Group 6-8)
Bile collection: 0-3, 3-6, 6-12 and 12-24 h post injection/gavage (Group 9)

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled : urine, faeces, tissues, cage washes, bile
- Method type(s) for identification : Radio- HPLC for urine samples and LSC for biological samples
Statistics:
None

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Low oral bioavailability (0.93 to 3.16 %); rapidly eliminated within a 48 h period
Type:
distribution
Results:
Radioactive levels generally decreased over time in all tissues
Type:
excretion
Results:
A mean 2.57±2.39 (males) and 1.14±0.69 % (females) of the radioactive dose was recovered over the 24 h period in the bile

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
Oral gavage:
50 mg/kg (single dose): The mean radioactivity levels were below quantifiable limits (Group 1) in all tissues except for intestines, kidneys and liver
200 mg/kg (single dose): The mean radioactivity levels were above quantifiable limits (Group 2) in half analysed tissues and organs at 24 h. Specifically high levels were present in adrenals, abdominal fat, eyes, heart, kidneys, liver, lungs, lymph nodes and pancreas.
50 mg/kg (repeated dose): The mean radioactivity levels were below quantifiable limits (Group 1) in all tissues except for intestines, kidneys, liver and mesenteric lymph nodes
Dermal application:
Single application (1.5 mg/kg): Radioactivity levels were below quantifiable limits in all tissues/organs at all time points except for the stripped skin from the application site and intestine (15 mg/kg)
Single application (15 mg/kg): Radioactivity levels were below quantifiable limits in all tissues/organs at all time points except for the stripped skin from the application site, adrenals, heart, kidneys, liver and lungs
Details on excretion:
Following single oral gavage at a nominal dose level of 50 mg/kg to rats, a mean 2.57±2.39 (males) and 1.14±0.69 % (females) of the radioactive dose was recovered over the 24 h period in the bile
Toxicokinetic parametersopen allclose all
Key result
Toxicokinetic parameters:
other: Oral: Mean plasma and blood radioactivity levels were all below quantifiable limits
Key result
Toxicokinetic parameters:
other: Dermal: Mean plasma and blood radioactivity levels were all below quantifiable limits

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
No metabolites nor parent drug were found in urine samples

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:
Interpretation of results (migrated information): no bioaccumulation potential based on study results.

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.
Executive summary:

The toxicokinetics of the test material was investigated in an OECD guideline 417conducted to GLP.

This study is assigned a reliability score of 1 in accordance with the criteria for assessing data quality set forth by Klimisch et al (1997).

The study 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.

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