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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1975-09-23 to 1979-01-16
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Toxicokinetics study to evaluate the relationship between long-term feeding of commercial amine oxide, the development of cataracts and the metabolism of DDAO. Three treatment groups and one control group were tested with 2 males and 2 females in each group. Study was well documented.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report Date:
1979

Materials and methods

Objective of study:
distribution
excretion
metabolism
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
N/A
GLP compliance:
no
Remarks:
Pre-GLP

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): dodecyl dimethyl amine oxide (DDAO)
- Molecular formula (if other than submission substance): N/A
- Molecular weight (if other than submission substance): 235.7
- Smiles notation (if other than submission substance): N/A
- InChl (if other than submission substance): N/A
- Structural formula attached as image file (if other than submission substance): see Fig. N/A
- Substance type: Active
- Physical state: N/A
- Analytical purity: N/A
- Impurities (identity and concentrations): N/A
- Composition of test material, percentage of components: N/A
- Isomers composition: N/A
- Purity test date: N/A
- Lot/batch No.: N/A
- Expiration date of the lot/batch: N/A
- Radiochemical purity (if radiolabelling): N/A
- Specific activity (if radiolabelling): 10 micro Ci/g
- Locations of the label (if radiolabelling): 14-C
- Expiration date of radiochemical substance (if radiolabelling): N/A
- Stability under test conditions: N/A
- Storage condition of test material: N/A
- Other: N/A
Radiolabelling:
yes
Remarks:
1-dodecyl-14C

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Age at study initiation: Weanling
- Weight at study initiation: N/A
- Fasting period before study: N/A
- Housing: Individual metabolism cages designed to limit contamination of the excretion products with spilled food.
- Individual metabolism cages: yes
- Diet (ad libitum): Control - Purina Laboratory Rat Chow (amine oxide naive group)
Test Group - Purina Laboratory Rat Chow with commercial amine oxide preparatoin add to give 0.5% amine oxide.
- Water (e.g. ad libitum): N/A
- Acclimation period: N/A


ENVIRONMENTAL CONDITIONS
- Temperature (°C): N/A
- Humidity (%): N/A
- Air changes (per hr): N/A
- Photoperiod (hrs dark / hrs light):N/A


IN-LIFE DATES: From: N/A To: N/A

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: aqueous commercial amine oxide preparation
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Radioactive test substance was mixed wtih the aqueous commercial amine oxide preparation to give a solution that contained 272 mg of amine oxide/mL and test substance with a specific activity of approximately 0.13 microns Ci/mg. Of this solution, 42.1 g was added to 2300 g of diet to provide an amine oxide concentration of 0.5%.

DIET PREPARATION
- Rate of preparation of diet (frequency): N/A
- Mixing appropriate amounts with (Type of food): N/A
- Storage temperature of food: N/A


VEHICLE
- Justification for use and choice of vehicle (if other than water): N/A
- Concentration in vehicle: N/A
- Amount of vehicle (if gavage): N/A
- Lot/batch no. (if required): N/A
- Purity: N/A


HOMOGENEITY AND STABILITY OF TEST MATERIAL:
Duration and frequency of treatment / exposure:
Groups I and II - 1 day
Groups III and IV - 10 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0.5% amine oxide
No. of animals per sex per dose:
2 male/2 female per dose group
Control animals:
other: control animals were administered 0.5% radioactive DDAO for one day and then given a nonradioactive diet
Positive control:
N/A
Details on study design:
- Dose selection rationale: N/A
- Rationale for animal assignment (if not random): N/A
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : urine, blood, eyes, heart, liver, kidneys, pancreas, adrenal glands, testes or ovaries and uterus, epididymal fat or fat attached to the uterus, body fat from the abdominal cavity, and a sample of muscle attached to the femur.
- Time and frequency of sampling: urine: 24 hour intervals after first dosing until sacrifice. Tissue samples were completed at sacrifice.
- Other: N/A


METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, blood, eyes, heart, liver, kidneys, pancreas, adrenal glands, testes or ovaries and uterus, epididymal fat or fat attached to the uterus, body fat from the abdominal cavity, and a sample of muscle attached to the femur.
- Time and frequency of sampling: urine: 24 hour intervals after first dosing until sacrifice. Tissue samples were dissected at sacrifice.
- From how many animals: (samples pooled or not) N/A
- Method type(s) for identification: Tissue samples were burned at 800 degree C in flowing oxygen; the resulting CO2 was trapped in a solution of monoethanolamine in 2-methoxyethanol (1/7, v/v).
Aliquots of the monethanolamine solutions, urine, plasma, blood cell washes, and the eye fluid samples were assayed for 14 C by standard liquid scintillation.
- Limits of detection and quantification: N/A
- Other: N/A
-Separation of Urinary Metabolites: Test substance urinary metabolites were separated by cation exchange chromatography. Radiochemical recoveries from the chromotography column were 100 +/- 10% and the retention volumes of the metabolites peaks were repeatable to within on collection fraction. When the recoveries from the column were not exactly 100%, they were corrected to 100% before tabulation of the results.

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): N/A
Statistics:
Statistical evaluation of the data was made using Student's t test.

Results and discussion

Preliminary studies:
N/A

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
The concentration in the blood of groups I and II 72 hours after receiving the one day dose of radiolabeled test substance ranged from 3-6 ug/g. The concentration in the blood of groups III and IV 72 hours after receiving the 10 day dose of radiolabeled test substance ranged from 31-50 ug/g. The concentration of radioactivity in the tissues of the animals were about the same or less than the plasma concentration with the exception of the liver, kidneys, and adrenal glands, which were greater. The concentrations in the liver, kidneys, and adrenal glands were as follows: Group I: ranged from 19-44 ug/g, ranged from 4-13 ug/g, and 13-63 ug/g, respectively; Group II: ranged from 19-31 ug/g, ranged from 4-13 ug/g, and ranged from 25-63 ug/g, respectively; Group III: ranged from 252 to 377 ug/g, ranged from 123-188 ug/g, and ranged from 377 to 503 ug/g, respectively; Group IV: ranged from 366 to 440 ug/g, ranged from 125 to 252 ug/g, and ranged from 377 to 692 ug/g, respectively. The concentration of radioactivity in the pancreas (57 ug/g) and hearts (ranging from 38-57 ug/g) of the males rats in Group I was higher than the concentration of radioactivity in their plasma.
The distirbution of radioactive test substance in the tissues of rats in Group III was similar to that of their respective sex in Group IV, the only exception being the fat deposits in female rats. In Group IV females, the uterine fat and body fat both contained about 2-3 times the concentration of 14 C as comparable fat from the female rats in Group III. There was a greater concentration of 14 C in the pancreas of only the female rats of both groups III and IV, and lower concentrations of 14 C in the eyes of all rats. The eye capsule and fluid contained detectable radioactivity, however, the lens did not.
Details on excretion:
In groups I and II the quantity of radioactive test substance consumed per kilogram body weight and the percentage of the dose excreted in the urine were similar for both the control and the amine oxide pre-treated groups.
In groups III and IV the percentage of the dose excreted in the urine was also similar for both groups, however, female rats excreted a significantly (p<0.001) smaller portion (37.1%) in their urine than did male rats (46.8%).
Toxicokinetic parameters
Toxicokinetic parameters:
other: no parameters identified

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Within groups I, II and IV there was a sex-related difference in the urinary metabolite composition. Female rats excreted relatively more of metabolite E than D, while male rats excreted more D than E.
In groups III and IV the female rats produced relatively more of metabolite E than D, while male rats produced more of metabolite D than E. However, metabolite D and E together account for approximately 10% more of the urinary radioactivity of the males (approximately 33%) than of the females (approximately23%). Nevertheless, the relative proportions of the various metabolites in these urine samples show no cataract related differences.

Any other information on results incl. tables

N/A

Applicant's summary and conclusion

Conclusions:
There were no demonstrable differences in the tissue distribution of 14 C nor changes in the proportions of metabolites in the urine of rats consuming the test substance that can be related to commercial amine oxide-induced cataracts.
Subchronic treatment of rats with the commercial amine oxide preparation did not alter significantly the test substance biotransformation pathways.
Executive summary:

The relationship between the long-term feeding of commercial amine oxides, the development of cataracts, and the metabolism of the test substance in rats was studied. A group of rats (groups consisted of 2 male and 2 female rats) was treated with commercial amine oxide for 130 days to induce cataracts in a portion of the group, then a single dose of the radioactive test substance was administered in the diet to both the commercial amine oxide-treated rats and control rats. The metabolite in the urine from these groups of rats were similar both qualitatively and quantitatively by cation exchange chromatography. In another experiment, the urinary metabolites excreted by the commercial amine oxide-treated rats after they had been fed the test substance in diet for 10 days were similar whether or not they had developed cataracts during the commercial amine oxide treatment phase.

The tissue distribution of radioactivity in rats fed the test substance showed no differences that could be attributed to either treatment with the commercial amine oxide or to cataract development. For all groups, radioactivity was widely distributed in the body. The tissue concentrations of radioactivity were generally equal to or less than the plasma concentration. The only tissues that consistently concentrated radioactivity were the liver, the adrenal glands, and the kidneys. There was no concentration of radioactivity in the eye relative to the plasma and no radioactivity at all was detected in the lens.

It was concluded that commercial amine oxide-treated rats that did or did not develop cataracts and control rats metabolized the test substance in the same way. Therefore, even assuming that the test substance is the cataractogenic agent in the commercial amine oxide preparation, a metabolically unique subpopulation of rats that might be predisposed to cataract formation was not detected.