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REACH

N,N-dimethyldecylamine N-oxide

EC number: 220-020-5 | CAS number: 2605-79-0

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Currently viewing:

Administrative data

Link to relevant study record(s)

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

1973-01-15 to 1975-08-08

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Methods and results were adequately documented and scientifically defensible. Pre-GLP

Justification for type of information:

1. HYPOTHESIS FOR THE CATEGORY APPROACH (ENDPOINT LEVEL)
Please refer to the Amine Oxide Category justification attached in Section 13

2. CATEGORY APPROACH JUSTIFICATION (ENDPOINT LEVEL
Please refer to the Amine Oxide Category justification attached in Section 13

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

reference to same study

Objective of study:

absorption

excretion

Qualifier:

no guideline followed

Principles of method if other than guideline:

N/A

GLP compliance:

Remarks:

Pre-GLP

Radiolabelling:

yes

Species:

human

Strain:

other: N/A

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: N/A
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: 12 hours
- Housing: t he subjects employed were volunteers who remained at the test facility throughout the course of the study
- Individual metabolism cages: N/A
- Diet (e.g. ad libitum): N/A
- Water (e.g. ad libitum): N/A
- Acclimation period: N/A
- Other: two human subjects participated in this study

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

Route of administration:

dermal

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:N/A

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: N/A

Duration and frequency of treatment / exposure:

- Single dose

Remarks:

Doses / Concentrations:
- The dose was 10 mg (100 µCi 14C) per subject

No. of animals per sex per dose / concentration:

- Two human subjects

Control animals:

Positive control reference chemical:

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 (Distribution)
- Tissues and body fluids sampled: blood
- Time and frequency of sampling: N/A
- Other: hN/A

PHARMACOKINETIC STUDY (Excretion)
- Tissues and body fluids sampled: urine, feces and carbon dioxide
- Time and frequency of sampling: urine was collected at 0-6, 6-24, 24-48, 48-72 and 72-144 hours; carbon dioxide was collected at 0, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours (no data is presented regarding the sampling time of feces)
- Other: N/A

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: N/A
- Time and frequency of sampling: N/A
- From how many animals: (samples pooled or not): N/A
- Method type(s) for identification (e.g. GC-FID, GC-MS, HPLC-DAD, HPLC-MS-MS, HPLC-UV, Liquid scintillation counting, NMR, TLC): N/A
- Limits of detection and quantification: N/A
- Other: N/A

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): N/A

Statistics:

N/A

Preliminary studies:

N/A

Details on absorption:

A small percentage of cutaneously applied [1-14C-dodecyl]-test substance was absorbed by humans as indicated by the appearance of 0.01 and 0.23% of the administered radioactivity in the excretion products of the two human subjects. The percent absorption in the two human subjects was determined to be < 0.2% based on assumption of maximum non-detectable amounts in all urine collections falling in the non-detectable range. More than 92% of the applied dose could be recovered from the site by swabbing with moist gauze eight hours after dose application. The tape strippings of the application site showed that the stratum corneum contained less than two-tenths of one percent of the applied dose.

All blood samples taken contained less than 3.0E-5 percent of the dose per gram

Details on distribution in tissues:

N/A

Details on excretion:

A small percentage of cutaneously applied [1-14C-dodecyl]-test substance was absorbed by humans as indicated by the appearance of 0.01% and 0.23% of the administered radioactivity in the excretion products of the two human subjects.

Toxicokinetic parameters:

other: no parameters identified

Metabolites identified:

not specified

Details on metabolites:

N/A

Conclusions:

Only a small percentage of cutaneously applied [1-14C-dodecyl]-test substance was absorbed by humans as indicated by the appearance of 0.01 and 0.23% of the administered radioactivity in the excretion products of the two human subjects. The percent absorption in the two human subjects was determined to be 0.2% based on assumption of maximum non-detectable amounts in all urine collections falling in the non-detectable range. More than 92% of the applied dose could be recovered from the site by swabbing with moist gauze eight hours after dose application. The tape strippings of the application site showed that the stratum corneum contained less than two-tenths of one percent of the applied dose.

Executive summary:

The absorption and excretion pattern of [1-¹⁴C-dodecyl]-C10-16 alkyl dimethyl amine oxide administered dermally to two human subjects was examined. The subjects employed were volunteers who remained at the test facility throughout the course of the study. Each subject was given a complete physical examination before and after the study. The physical examination included clinical chemistries, ophthalmoscopic eye examination, EKG, hematology and blood pressure. Recommended procedures for informed consent and experimental review were followed. Before dosing, subjects were food fasted for twelve hours. Zero time blood samples were taken immediately before dosing .

An area 15 cm x 4 cm was marked off on the outer surface of the subjects’ forearms which had been clipped free of hair and inspected for breaks. One-half mL of an aqueous solution containing 10 mg of [1-¹⁴C-dodecyl]-C10-16 alkyl dimethyl amine oxide (100 µCi¹⁴C) was applied evenly over the site with a plastic syringe. The site was allowed to dry by evaporation and was covered with a non-occlusive, plastic shield. After eight hours, the C10-16 alkyl dimethyl amine oxide remaining at the application site was removed by repeatedly (10 x) swabbing the skin with water moistened gauze pads. The portion of the radioactive dose retained in the stratum corneum was assayed by repeatedly (10 x) stripping a 7.2 squared centimeter area within the area of application with tape. Normal handling and exposure of the application site was permitted after these procedures. Urine was collected in polyethylene bottles over the intervals 0-6 hours and 6-24 hours, and subsequently over 24-hour intervals through 144 hours. During the collection period, samples were stored at 0° C; upon completion of a collection interval, the urine samples were frozen on dry ice. Feces samples were collected individually as available in plastic bags and were stored frozen. Expired CO₂was collected in a modified Hanks apparatus. The air flow rate through the collection box was 12 L/min. Carbon dioxide collections on the orally dosed subjects were performed at 0, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours after dosing. The collection period was 15 minutes. Total expired radioactivity was computed from these samples of expired gases.

A small percentage of cutaneously applied [1-¹⁴C-dodecyl]-C10-16 alkyl dimethyl amine oxide was absorbed by humans as indicated by the appearance of 0.01 and 0.23% of the administered radioactivity in the excretion products of the two human subjects. The percent absorption in the two human subjects was determined to be 0.2% based on assumption of maximum non-detectable amounts in all urine collections falling in the non-detectable range. More than 92% of the applied dose could be recovered from the site by swabbing with moist gauze eight hours after dose application. The tape strippings of the application site showed that the stratum corneum contained less than two-tenths of one percent of the applied dose.

Reference 2

Endpoint:

basic toxicokinetics

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

1973-01-15 to 1975-08-08

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Methods comparable to OECD 417 (Toxicokinetics). However, only one dose level was used for each animal species in these single-dose studies; two dose levels are specified in the test guideline. No details provided on age of animals used or whether animals were acclimated and fasted. Incomplete details on housing conditions; temperature, humidity, lighting not described.

Justification for type of information:

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

reference to same study

Objective of study:

absorption

distribution

excretion

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

only one dose level was used for each animal species in these single-dose studies; two dose levels are specified in the test guideline. No details provided on age of animals used or whether animals were acclimated and fasted. Incomplete details on housi

Principles of method if other than guideline:

N/A

GLP compliance:

Remarks:

Pre-GLP

Radiolabelling:

yes

Species:

mouse

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: N/A
- Weight at study initiation: N/A
- Fasting period before study: N/A
- Housing: N/A
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): N/A
- 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

Route of administration:

other: cutaneous application, the dose was administered from a syringe fitted with a blunt needle with lateral openings

Vehicle:

water

Details on exposure:

TEST SITE
- Area of exposure: 6 cm^2
- % coverage: no data
- Type of wrap if used: N/A
- Time intervals for shavings or clippings: prior to exposure
- Other: The test site was located on back of the animal. Dosed animals were restrained in small animal resistance restrainers.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): N/A
- Time after start of exposure: N/A

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): N/A
- Concentration (if solution): 10 mg/mL
- Preparation of test solutions: N/A

VEHICLE
- Justification for use and choice of vehicle (if other than water): N/A
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): N/A
- Lot/batch no. (if required): N/A
- Purity: N/A

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes

Duration and frequency of treatment / exposure:

- Single dose

Remarks:

Doses / Concentrations:
- The applied dose was 1 mg [14C-methyl]-test substance (4.2 µmoles)

No. of animals per sex per dose / concentration:

- Three males received the [14C-methyl]-test substance dose

Control animals:

Positive control reference chemical:

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 (Distribution)
- Tissues and body fluids sampled: liver, kidney, testes, blood, carcass, total tissues and application site
- Time and frequency of sampling: no data
- Other: N/A

PHARMACOKINETIC STUDY (Excretion)
- Tissues and body fluids sampled: urine, CO2, feces and cage wash
- Time and frequency of sampling: N/A
- Other: N/A

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: N/A
- Time and frequency of sampling: N/A
- From how many animals: (samples pooled or not): N/A
- Method type(s) for identification (e.g. GC-FID, GC-MS, HPLC-DAD, HPLC-MS-MS, HPLC-UV, Liquid scintillation counting, NMR, TLC): N/A
- Limits of detection and quantification: N/A
- Other: N/A

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): N/A

Statistics:

N/A

Preliminary studies:

N/A

Details on absorption:

- Cutaneously administered [14C-methyl]-test substance was absorbed by male mice
- Following a continuous 72-hour cutaneous exposure to [14C-methyl]-test substance, 36% of the administered radioactivity was found in the excrement and body tissues (excluding the application site) of mice.

Details on distribution in tissues:

- Total percent (of administered 14C) recovery (± SD): liver (0.42 ± 0.08); kidney (0.08 ± 0.0); testes (0.02 ± 0.01); carcass (17.1 ± 3.2) and tissue total was 17.62%.
- Total recovery in the blood (± SD) was 1.10 ± 0.56 µg/g.

Details on excretion:

- Total percent (of administered 14C) recovery (± SD): urine (11.6 ± 6.0); feces (1.4 ± 0.3) and carbon dioxide (5.0 ± 1.0)
- Total percent (of administered 14C) excreted (± SD): 18.0% (10.6 ± 3.5% in the total cage wash)

Toxicokinetic parameters:

other: no parameters identified

Metabolites identified:

not specified

Details on metabolites:

N/A

Conclusions:

The test substance was absorbed by the male mouse when administered cutaneously as a single dose of 1 mg (10 mg/mL water).

Executive summary:

The absorption, tissue distribution and excretion pattern of [¹⁴C-methyl]-C10-16 alkyl dimethyl amine oxide administered in water via cutaneous application to three male mice was investigated in this study. Mice were prepared for dermal dosing by clipping an area of the back free of hair with a small animal clipper. The area of the test site was approx. 6 squared centimeters. The clipped area was inspected for breaks in the skin, and the application site was delineated by marking with a felt-tipped pen. The dermal dose was administered from a syringe fitted with a blunt needle with lateral openings. The concentration of the C10-16 alkyl dimethyl amine oxide in the test solution was 10 mg/mL and the total dose was 1 mg, resulting in a dosing volume of 0.1 mL. The specific activity of the dosing solution was 1.3 mc/g. Dermally dosed mice were restrained in small animal restrainers. Immediately after dosing, animals were placed in individual, stainless steel metabolism cages equipped for collection of expired carbon dioxide and separate collection of urine and feces. Except as otherwise noted, the duration of all experiments was 72 hours .

The distribution in specific tissues, presented as the percent of administered¹⁴C was determined. The tissues examined were liver, kidney, testes, carcass, the total percent recovery in the tissues and the percent remaining at the application site. Percent recovery in excreta (urine, feces and carbon dioxide) was examined for all animals (total carbon dioxide includes the radioactivity in the carbon dioxide safety trap). Total percent recovery in the cage wash (includes a thorough wash of the restrainer) and the percent recovery in the blood was also determined. The time intervals for these samples were not specified in the report.

When administered alone in an aqueous solution, the C10-16 alkyl dimethyl amine oxide is absorbed through the intact skin of mice. The total percent (of administered¹⁴C) recovery at the application site (± SD) was 48.9 ± 9.5%. The total percent (of administered¹⁴C) recovery in the examined tissues (± SD) was: liver (0.42 ±0.08); kidney (0.08 ± 0.0), testes (0.02 ± 0.01) carcass (17.1 ± 3.2) and tissue total (17.62%). The total recovery in the blood was 1.10 ± 0.56 µg/g. In the excreta, the total percent (of administered¹⁴C) recoveries (± SD) were: urine (11.6 ± 6.0); feces (1.4 ± 0.3); carbon dioxide (5.0 ± 1.0) and total percent (of administered¹⁴C) excreted was 18.0%. The final percent in the cage wash (± SD) was 10.6 ± 3.5% of the administered¹⁴C dose. The conclusion was that cutaneously administered C10-16 alkyl dimethyl amine oxide is absorbed by the male mouse.

Reference 3

Endpoint:

basic toxicokinetics

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

1973-01-15 to 1975-08-08

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Justification for type of information:

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

reference to same study

Objective of study:

absorption

distribution

excretion

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

Principles of method if other than guideline:

N/A

GLP compliance:

Remarks:

Pre-GLP

Radiolabelling:

yes

Species:

rabbit

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: N/A
- Age at study initiation: N/A
- Average weight at study initiation: N/A
- Fasting period before study: N/A
- Housing: N/A
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): N/A
- 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

Route of administration:

other: cutaneous application, the dose was administered from a syringe fitted with a blunt needle with lateral openings

Vehicle:

water

Details on exposure:

TEST SITE
- Area of exposure: 40 cm^2
- % coverage: no data
- Type of wrap if used: N/A
- Time intervals for shavings or clippings: prior to exposure
- Other: The test site was located on back of the animal. Rabbits were fitted with collars to prevent oral ingestion.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): N/A
- Time after start of exposure: N/A

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
- Concentration (if solution): N/A
- Preparation of test solutions:

VEHICLE
- Justification for use and choice of vehicle (if other than water): N/A
- Amount(s) applied (volume or weight with unit): 0.5 mL
- Concentration (if solution): N/A
- Lot/batch no. (if required): N/A
- Purity: N/A

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes

Duration and frequency of treatment / exposure:

- Single dose

Remarks:

Doses / Concentrations:
- The applied dose was 10 mg [14C-methyl]-test substance (42 µmoles)

No. of animals per sex per dose / concentration:

- Four males received the [14C-methyl]-test substance dose

Control animals:

Positive control reference chemical:

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 (Distribution)
- Tissues and body fluids sampled: liver, kidney, testes, blood, carcass, total tissues and application site
- Time and frequency of sampling: N/A
- Other: N/A

PHARMACOKINETIC STUDY (Excretion)
- Tissues and body fluids sampled: urine, CO2, feces and cage wash
- Time and frequency of sampling: N/A
- Other: N/A

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: N/A
- Time and frequency of sampling: N/A
- From how many animals: (samples pooled or not): N/A
- Method type(s) for identification (e.g. GC-FID, GC-MS, HPLC-DAD, HPLC-MS-MS, HPLC-UV, Liquid scintillation counting, NMR, TLC): N/A
- Limits of detection and quantification: N/A
- Other: N/A

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): N/A

Statistics:

N/A

Preliminary studies:

N/A

Details on absorption:

- Cutaneously administered [14C-methyl]-test substance was absorbed by male rabbits
- Following a continuous 72-hour cutaneous exposure to [14C-methyl]-test substance 51% of the administered radioactivity was found in the excrement and body tissues (excluding the application site) of rabbits

Details on distribution in tissues:

- Total percent (of administered 14C) recovery (± SD): liver (0.44 ± 0.12); kidney (0.1 ± 0.01); testes (0.001 ± 0.001); carcass (4.61 ± 1.1) and tissue total was 5.1%
- Total recovery in the blood was 0.03 µg/g

Details on excretion:

- Total percent (of administered 14C) recovery (± SD) in excreta were: urine (42.1 ± 6.3); feces (2.22 ± 0.66) and carbon dioxide (1.4 ± 0.7)
- Total percent (of administered 14C) excreted (± SD) was: 45.7% (3.9 ± 2.2% in the total cage wash)

Toxicokinetic parameters:

other: no parameters identified

Metabolites identified:

not specified

Details on metabolites:

N/A

Conclusions:

The test substance was absorbed by the male rabbit when administered cutaneously as a single dose of 10 mg (20 mg/mL water).

Executive summary:

The absorption, tissue distribution and excretion pattern of [¹⁴C-methyl]-C10-16 alkyl dimethyl amine oxide administered in water via cutaneous application to four male rabbits was investigated in this study. Rabbits were prepared for dermal dosing by clipping an area of the back free of hair with a small animal clipper. The area of the test site was approx. 40 squared centimeters. The clipped area was inspected for breaks in the skin, and the application site was delineated by marking with a felt-tipped pen. The dermal dose was administered from a syringe fitted with a blunt needle with lateral openings. The concentration of the C10-16 alkyl dimethyl amine oxide in the test solution was 20 mg /mL and the total dose was 10 mg. The specific activity of the dosing solution was 1.3 mc/g. Dermally dosed rabbits were fitted with collars to prevent oral ingestion. Immediately after dosing, animals were placed in individual, stainless steel metabolism cages equipped for collection of expired carbon dioxide and separate collection of urine and feces. Except as otherwise noted, the duration of all experiments was 72 hours .

When administered alone in an aqueous solution, the C10-16 alkyl dimethyl amine oxide is absorbed through the intact skin of rabbits. The total percent (of administered¹⁴C) recovery at the application site (± SD) was39.4 ±8.2%. The total percent (of administered¹⁴C) recovery in the examined tissues (± SD) was: liver (0.44 ±0.12); kidney (0.1 ± 0.01), testes (0.001 ± 0.001) carcass (4.61 ± 1.1) and tissue total (5.1%). The total recovery in the blood was 0.03 µg/g. In the excreta, the total percent (of administered¹⁴C) recoveries (± SD) were: urine (42.1 ± 6.3); feces (2.22 ± 0.66); carbon dioxide (1.4 ± 0.7) and total percent (of administered¹⁴C) excreted was 45.7%. The final percent in the cage wash (± SD) was 3.9 ± 2.2% of the administered¹⁴C dose. The conclusion was that cutaneously administered C10-16 alkyl dimethyl amine oxide is absorbed by the male rabbit.

Reference 4

Endpoint:

basic toxicokinetics

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

1973-01-15 to 1975-08-08

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Justification for type of information:

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

reference to same study

Objective of study:

absorption

distribution

excretion

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

Principles of method if other than guideline:

N/A

GLP compliance:

Remarks:

Pre-GLP

Radiolabelling:

yes

Remarks:

[14C-methyl]-DDAO

Species:

rat

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: N/A
- Age at study initiation: N/A
- Average weight at study initiation: For the 4 male rats receiving [14C-methyl]-DDAO in water: 188 ± 8 g, For the 4 male rats receiving [14C-methyl]-DDAO in combination with the anionic surfactant AE3S-: 202 ± 6 g
- Fasting period before study: N/A
- Housing: N/A
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): N/A
- 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: 1/15/73 To: 6/1/75

Route of administration:

other: cutaneous application, the dose was administered from a syringe fitted with a blunt needle with lateral openings

Vehicle:

water

Details on exposure:

TEST SITE
- Area of exposure: 18 cm^2
- % coverage: N/A
- Type of wrap if used: N/A
- Time intervals for shavings or clippings: prior to exposure
- Other: The test site was located on back of the animal. Dosed animals were restrained in small animal resistance restrainers.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): N/A
- Time after start of exposure: N/A

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 mg
- Concentration (if solution): 20 mg DDAO/mL
- Preparation of test solutions: N/A

VEHICLE
- Justification for use and choice of vehicle (if other than water): N/A
- Amount(s) applied (volume or weight with unit): 0.5 mL
- Concentration (if solution): N/A
- Lot/batch no. (if required): N/A
- Purity: N/A

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes

Duration and frequency of treatment / exposure:

- Single dose

Remarks:

Doses / Concentrations:
- For the [14C-methyl]-test substance dose in water the applied dose was 10 mg DDAO (42 µmoles)
- For the [14C-methyl]-test substance dose in combination with the anionic surfactant AE3S- the applied dose was (10 mg DDAO + 50 mg AE3S)/application site

No. of animals per sex per dose / concentration:

- Four males received the [14C-methyl]-test substance dose in water
- Four males received [14C-methyl]-test substance in combination with the anionic surfactant AE3S-

Control animals:

Positive control reference chemical:

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 (Distribution - 14C in water)
- Tissues and body fluids sampled: liver, kidney, testes, blood, carcass, total tissues and application site
- Time and frequency of sampling: collected during the 0-72 hour time interval after administration of [14C-methyl]-test substance
- Other: N/A

PHARMACOKINETIC STUDY (Distribution - 14C in combination with the anionic surfactant AE3S-)
- Tissues and body fluids sampled: liver, kidney, testes, blood, carcass, total tissues and application site
- Time and frequency of sampling: collected during the 0-72 hour time interval after administration of [14C-methyl]-test substance
- Other: N/A

PHARMACOKINETIC STUDY (Excretion – 14C in water)
- Tissues and body fluids sampled: urine, CO2, feces and cage wash
- Time and frequency of sampling: collected in the following time intervals: 0-24 hours, 24-28 hours and 48-72 hours (cage wash determined only as total cage wash 0-72 hours)
- Other: Total carbon dioxide includes the radioactivity in the carbon dioxide safety trap. Cage wash includes thorough wash of the restrainer.

PHARMACOKINETIC STUDY (Excretion – 14C in combination with the anionic surfactant AE3S-)
- Tissues and body fluids sampled: urine, CO2 and feces
- Time and frequency of sampling: collected in the following time intervals: 0-24 hours, 24-28 hours and 48-72 hours (cage wash determined only as total cage wash 0-72 hours)
- Other: Cage wash includes thorough wash of the restrainer.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: N/A
- Time and frequency of sampling: N/A
- From how many animals: (samples pooled or not): N/A
- Method type(s) for identification (e.g. GC-FID, GC-MS, HPLC-DAD, HPLC-MS-MS, HPLC-UV, Liquid scintillation counting, NMR, TLC): N/A
- Limits of detection and quantification: N/A
- Other: N/A

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): N/A

Statistics:

N/A

Preliminary studies:

N/A

Details on absorption:

- When administered alone in an aqueous solution, the test substance was absorbed through the intact skin of rats. Cutaneous administrations of the test substance in combination with the anionic surfactant resulted in a slight enhancement of the absorption of the test substance over a 72-hour observation period
- Total percent (of administered 14C) recovery at the application site was 48.0 ± 6.5%

Details on distribution in tissues:

- Total percent (of administered 14C) recovery (± SD) of test substance w/o surfactant: liver (0.44 ± 0.06); kidney (0.05 ± 0.0), testes (0.04 ± 0.02) carcass (15.55 ± 5.01) and tissue total (16.08%).
- Total percent (of administered 14C) recovery in tissues was 16.08%
- Total recovery in the blood (± SD) was 0.43 ± 0.15 µg/g

Details on excretion:

- Total percent (of administered 14C) recovery (± SD): urine (14.2 ± 4.0); feces (1.75 ± 0.48) and carbon dioxide (2.52 ± 0.65)
- Total percent (of administered 14C) excreted (± SD): 18.5% (6.1 ± 2.6% in the total cage wash)

Toxicokinetic parameters:

other: no parameters identified

Metabolites identified:

not specified

Details on metabolites:

N/A

Conclusions:

The test substance was absorbed by the intact skin of a male rats when administered cutaneously as a single dose of 10 mg in water and in anionic surfactant.

Executive summary:

The absorption, tissue distribution and excretion pattern of [¹⁴C-methyl]-C10-16 alkyl dimethyl amine oxide administered in water or in combination with an anionic surfactant via cutaneous application to male rats was investigated in this study. Four rats received the C10-16 alkyl dimethyl amine oxide in water and 4 received the C10-16 alkyl dimethyl amine oxide in the surfactant. Rats were prepared for dermal dosing by clipping an area of the back free of hair with a small animal clipper. The area of the test site was approx. 18 squared centimeters. The clipped area was inspected for breaks in the skin, and the application site was delineated by marking with a felt-tipped pen. The dermal dose was administered from a syringe fitted with a blunt needle with lateral openings. The concentration of the C10-16 alkyl dimethyl amine oxide in the test solution was 20 mg/mL and the total dose was 10 mg, resulting in a dosing volume of 0.5 mL. The specific activity of the dosing solution was 1.3 mc/g. Dermally dosed rats were restrained in small animal restrainers, and rabbits were fitted with collars to restrict oral ingestion. Immediately after dosing, animals were placed in individual, stainless steel metabolism cages equipped for collection of expired carbon dioxide and separate collection of urine and feces. Except as otherwise noted, the duration of all experiments was seventy-two hours.

The distribution in specific tissues, presented as the percent of administered¹⁴C was determined for the 0- 72 hour period for all test animals. The tissues examined were liver, kidney, testes, carcass, the total percent recovery in the tissues and the percent remaining at the application site. Percent recovery in excreta (urine, feces and carbon dioxide) was examined for all animals at the 0-24 hours, 24-48 hours and 48-72 hour time intervals (total carbon dioxide includes the radioactivity in the carbon dioxide safety trap). Total percent recovery in the cage wash (includes a thorough wash of the restrainer) was determined for the 0-72 hour interval. The percent recovery in the blood was also determined (time interval(s) unspecified).

When administered alone in an aqueous solution, the C10-16 alkyl dimethyl amine oxide was absorbed through the intact skin of rats. Cutaneous administrations of the C10-16 alkyl dimethyl amine oxide in combination with the anionic surfactant resulted in a slight enhancement of the absorption of the C10-16 alkyl dimethyl amine oxide over a 72-hour observation period. The total percent (of administered¹⁴C) recovery at the application site (± SD) was 48.0 ± 6.5%. The total percent (of administered¹⁴C in water) recovery in the examined tissues were (±SD): liver (0.44 ± 0.06); kidney (0.05 ± 0.0), testes (0.04 ± 0.02) carcass (15.55 ± 5.01) and tissue total (16.08%). The total recovery in the blood was 0.43 ± 0.15 µg/g. In the excreta, the total percent (of administered¹⁴C) recoveries (± SD) were: urine (14.2 ±4.0); feces (1.75 ± 0.48); carbon dioxide (2.52 ± 0.65) and total percent (of administered¹⁴C) excreted: 18.5%. The percent recovery in the final cage wash (± SD) was 6.1 ± 2.6% of the administered¹⁴C dose. The conclusion was that cutaneously administered C10-16 alkyl dimethyl amine oxide is absorbed by the male rat.

Reference 5

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

1973-01-15 to 1975-08-08

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Methods and results adequately documented and scientifically defensible. Pre- GLP

Justification for type of information:

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

reference to same study

Objective of study:

absorption

excretion

Qualifier:

no guideline followed

Principles of method if other than guideline:

N/A

GLP compliance:

Remarks:

Pre-GLP

Radiolabelling:

yes

Remarks:

[1-14C-dodecyl]-test substance

Species:

human

Strain:

other: N/A

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: N/A
- Age at study initiation: N/A
- Weight at study initiation: N/A
- Fasting period before study: 12 hours
- Housing: The subjects employed were volunteers who remained at the test facility throughout the course of the study
- Individual metabolism cages: N/A
- Diet (e.g. ad libitum): N/A
- Water (e.g. ad libitum): N/A
- Acclimation period: N/A
- Other: Two human subjects participated in this study.

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

Route of administration:

other: an aqueous solution containing 0.25 mg [1-14C-dodecyl]-test substance per mL was drunk from a plastic cup

Vehicle:

water

Details on exposure:

Duration and frequency of treatment / exposure:

- Single dose

Remarks:

Doses / Concentrations:
- The total dose was 50 mg DDAO (100 µCi 14C) per subject

No. of animals per sex per dose / concentration:

2 human subjects were used in the study

Control animals:

Positive control reference chemical:

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 (Distribution)
- Tissues and body fluids sampled: blood
- Time and frequency of sampling: N/A
- Other: N/A

PHARMACOKINETIC STUDY (Excretion)
- Tissues and body fluids sampled: urine, feces and carbon dioxide
- Time and frequency of sampling: urine was collected at 0-6, 6-24, 24-48, 48-72 and 72-144 hours; carbon dioxide was collected at 0, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours (no data is presented regarding the sampling time of feces)
- Other: N/A

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: N/A
- Time and frequency of sampling: N/A
- From how many animals: (samples pooled or not): N/A
- Method type(s) for identification (e.g. GC-FID, GC-MS, HPLC-DAD, HPLC-MS-MS, HPLC-UV, Liquid scintillation counting, NMR, TLC): N/A
- Limits of detection and quantification: N/A
- Other: N/A

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): N/A

Statistics:

- No data

Preliminary studies:

N/A

Details on absorption:

Details on distribution in tissues:

N/A

Details on excretion:

- Excretion of radioactivity from a single oral dose of [1-14C-dodecyl]-test substance was rapid
- In the two human subjects investigated, 50 and 37% of the administered radioactivity appeared in the urine within 24 hours after dose administration
- Expired carbon dioxide collected during the 24-hour interval contained 18 and 22% of the dosed radioactivity in the two human subjects
- In the feces 2.7 and 2.5% of the dosed radioactivity was recovered
- Total excretion (percent of dosed radioactivity) was 79.8 and 69.3%

Toxicokinetic parameters:

other: no parameters identified

Metabolites identified:

not specified

Details on metabolites:

N/A

No ready explanation of the low recovery of radioactivity from the orally dosed humans is apparent. Possible explanations include loss of urine or fecal samples or retention of radioactivity in the body for periods exceeding the length of the collection period.

Conclusions:

A single oral dose of DDAO administered orally to two human volunteers was rapidly and extensively absorbed and excreted.

Executive summary:

The absorption and excretion pattern of [1-¹⁴C-dodecyl] C10-16 alkyl dimethyl amine oxide administered orally to two human subjects was examined. The subjects employed were volunteers who remained at the test facility throughout the course of the study. Each subject was given a complete physical examination before and after the study. The physical examination included clinical chemistries, ophthalmoscopic eye examination, EKG, hematology and blood pressure. Recommended procedures for informed consent and experimental review were followed. Before dosing, subjects were food fasted for twelve hours. Zero time blood samples were taken immediately before dosing. An aqueous solution containing 0.25 mg [1-¹⁴C-dodecyl] C10-16 alkyl dimethyl amine oxide per mL was drunk from a plastic cup. The total dose was 50 mg test substance (100 µCi¹⁴C) per subject. The dosing cup was immediately rinsed twice with 200 mL of tap water, and the rinsings were ingested by the subject. Urine was collected in polyethylene bottles over the intervals 0-6, 6-24, 48, 72, 96, 120 and 144 hours. A total fecal sample was also collected. During the collection period, samples were stored at 0° C; upon completion of a collection interval, the urine samples were frozen on dry ice. Feces samples were collected individually as available in plastic bags and were stored frozen. Expired CO₂was collected in a modified Hanks apparatus. The air flow rate through the collection box was 12 L/min. Carbon dioxide collections on the orally dosed subjects were performed at 0, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours after dosing. The collection period was 15 minutes. Total expired radioactivity was computed from these samples of expired gases.

The absorption of radioactivity was rapid. In both subjects, the highest concentration of radioactivity was observed in blood samples taken 1 hour after dose administration; these levels for the two subjects were 5 x 10^-4 and 1.2 x 10^-3% of the dose per gram whole blood (0.25 and 0.6 µg equivalents of DDAO per gram). Excretion of radioactivity from a single oral dose of [¹⁴C-methyl] C10-16 alkyl dimethyl amine oxide was rapid. In the two human subjects investigated, 50 and 37% of the administered radioactivity appeared in the urine within 24 hours after dose administration. Expired carbon dioxide collected during the 24-hour interval contained 18 and 22% of the dosed radioactivity in the two human subjects. In the feces 2.7 and 2.5% of the dosed radioactivity was recovered. Total excretion (percent of dosed radioactivity) was 79.8 and 69.3%

A single oral dose of C10 -16 alkyl dimethyl amine oxide administered orally to two human volunteers was rapidly and extensively absorbed and excreted.

Reference 6

Endpoint:

basic toxicokinetics

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

1975-10-27 to 1978-10-02

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Methods comparable to OECD 417 (Toxicokinetics). However, only dose level was used for each animal species in these signle-dose studies. No details provided on age of animals used or whether animals were acclimated. Incomplete details on housing conditions; temperature, humidity, lighting not described.

Justification for type of information:

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

only dose level was used for each animal species in these signle-dose studies. No details provided on age of animals used or whether animals were acclimated. Incomplete details on housing conditions; temperature, humidity, lighting not described.

GLP compliance:

Radiolabelling:

yes

Remarks:

[14C-1-dodecyl]

Species:

rabbit

Strain:

other: New Zealand

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: N/A
- Age at study initiation: N/A
- Weight at study initiation: ca. 2 kg
- Fasting period before study: overnight
- Housing: after dosing rats were housed individually in stainless steel metabolism cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): provided ad libitum 24 hours after dosing
- 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

Route of administration:

oral: unspecified

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- No data

DIET PREPARATION
- Rate of preparation of diet (frequency): no data
- Mixing appropriate amounts with (Type of food): no data
- Storage temperature of food: no data

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

HOMOGENEITY AND STABILITY OF TEST MATERIAL:
- No data

Duration and frequency of treatment / exposure:

- Single oral dose

Remarks:

Doses / Concentrations:
- Oral doses of 8.0 mL of a 0.25 mg [14C]-DDAO/mL aqueous solution dosed to each approximately 8 kg rabbit, so that each animal received 1 mg/kg bw

No. of animals per sex per dose / concentration:

- Two male and two female rabbits

Control animals:

not specified

Positive control reference chemical:

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
- Tissues and body fluids sampled: N/A
- Time and frequency of sampling: N/A
- Other: N/A

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: N/A
- Time and frequency of sampling: N/A
- From how many animals: N/A
- Method type(s) for identification: N/A
- Limits of detection and quantification: N/A
- Other: N/A

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): N/A

Statistics:

N/A

Preliminary studies:

N/A

Details on absorption:

N/A

Details on distribution in tissues:

The concentration of 14C in the blood was determined at various times after oral dosing of [14C]-test substance. The maximum blood concentrations of 14C occurred at approx. 1.5 hours. In a separate experiment, plasma samples were isolated from the blood at 1.5 hours after dosing. The radioactivity content of the plasma samples was low, which limited the chromatographic resolution of individual metabolite peaks. Virtually all of the metabolite peaks observed in urine samples were also observed in plasma.

Details on excretion:

Most of the dosed radioactivity was eliminated in the urine and about 30% of it was eliminated as [14C]CO2. Less than 10% was found in the feces. A large fraction of the CO2 summation value for rabbits had to be estimated; however, the estimates appear to be correct as judged by the material balance and by comparing them to the rat data. No sex-related differences in the excretion patterns were evident.

Toxicokinetic parameters:

other: no parameters identified

Metabolites identified:

yes

Details on metabolites:

Ten urinary metabolites (identified as metabolites A-J) were isolated in cation exchange chromatography. The primary metabolites were D (N,N-dimethyl-N-oxide-4-aminobutyric acid) and E (N,N-dimethyl-4-aminobutyric acid), 33 and 24%, respectively.

N/A

Conclusions:

The maximum blood concentrations of 14C occurred at approx. 1.5 hours. Most of the dosed radioactivity was eliminated in the urine and about 30% of it was eliminated as [14C]CO2. Less than 10% was found in the feces. No sex-related differences in the excretion patterns were evident. Ten urinary metabolites (identified as metabolites A-J) were isolated in cation exchange chromatography. The primary metabolites were D (N,N-dimethyl-N-oxide-4-aminobutyric acid) and E (N,N-dimethyl-4-aminobutyric acid), 33 and 24%, respectively.

Executive summary:

One New Zealand rabbit of approx. 2 kg body weight was fasted for 48 hrs and then orally dosed with 1 ml of an aqueous [¹⁴C] DDAO solution of 2 mg/ml, to acheive a dose of 1 mg [¹⁴C]DDAO/kg BW.After dose administration, the time of maximum plasma¹⁴C concentration was determined by measuring the¹⁴C content of plasma samples taken at 0.5, 1.0, 1.5, 2.0, 3.0, 3.5 and 4.0 hours.

For plasma for metabolite separation, one male and one female rabbit were anesthetized with ether 1.0 h after dosing (as above with 1 mg/kg BW) and the largest possible volume of blood was taken by cardiac puncture. The blood was centrifuged and the plasma was removed and frozen.

Two male and two female New Zealand rabbits of approx. 2 kg body weight were fasted overnight and then orally dosed with 8.0 mL of an aqueous [¹⁴C]DDAO solution of a concentration of 0.25 mg/mL, such that each rabbit was dosed with 1 mg [¹⁴C]DDAO/kg BW. Animals were placed in metabolism cages for collection of CO2 for the first 7 hours of each 24 hr period for 72 hours. Urine and feces were collected each 24 hr period for 72 hours.

Before metabolite separation, samples of urine were treated by anion exchange chromatography, followed by lyophilization and extraction with alcohol.

The maximum blood concentrations of ¹⁴C occurred at approx. 1.5 hours. In a separate experiment, plasma samples were isolated from the blood at 1.5 hours after dosing. The radioactivity content of the plasma samples was low, which limited the chromatographic resolution of individual metabolite peaks. Virtually all of the metabolite peaks observed in urine samples were also observed in plasma. Most of the dosed radioactivity was eliminated in the urine and about 30% of it was eliminated as [¹⁴C]CO₂. Less than 10% was found in the feces. A large fraction of the CO₂summation value for rabbits had to be estimated; however, the estimates appear to be correct as judged by the material balance and by comparing them to the rat data. No sex-related differences in the excretion patterns were evident. Ten urinary metabolites (identified as metabolites A-J) were isolated in cation exchange chromatography.

Reference 7

Endpoint:

basic toxicokinetics

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

1975-10-27 to 1978-10-02

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Methods comparable to OECD 417 (Toxicokinetics). However, only dose level was used for each animal species in these single-dose studies. No details provided on age of animals used or whether animals were acclimated. Incomplete details on housing conditions; temperature, humidity, lighting not described.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

GLP compliance:

Radiolabelling:

yes

Remarks:

[14C-1-dodecyl]-DDAO

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: N/A
- Age at study initiation: N/A
- Weight at study initiation: ca. 250 g
- Fasting period before study: overnight
- Housing: after dosing rats were housed individually in stainless steel metabolism cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): provided ad libitum 24 hours after dosing
- 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

Route of administration:

oral: unspecified

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- N/A

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:
- N/A

Duration and frequency of treatment / exposure:

- Single oral dose

Remarks:

Doses / Concentrations:
- Oral doses of 1 mL of 0.25 mg/mL administered, so that each animal received approximately 1 mg DDAO/kg bw

No. of animals per sex per dose / concentration:

- Two male and three female rats

Control animals:

not specified

Positive control reference chemical:

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
- Tissues and body fluids sampled: N/A
- Time and frequency of sampling: N/A
- Other: N/A

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: blood, urine, feces and urine
- Time and frequency of sampling: 0, 24, 48 and 72 hours
- From how many animals: all animals
- Method type(s) for identification: N/A
- Limits of detection and quantification: N/A
- Other: N/A

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): N/A

Statistics:

N/A

Preliminary studies:

N/A

Details on absorption:

N/A

Details on distribution in tissues:

Details on excretion:

Most of the dosed radioactivity was eliminated in the urine (60%) and about 30% of it was eliminated as [14C]CO2. Less than 10% was found in the feces. No sex-related differences in the excretion patterns were evident.

Toxicokinetic parameters:

other: no parameters were identified

Metabolites identified:

yes

Details on metabolites:

To ensure that the metabolites found in the urine were actually excreted in the urine and were not the result of fecal contamination, two male rats were fitted with anal cups to prevent contamination of the urine with fecal matter and to prevent coprophagy. The 0-24 hour urine samples from these animals showed essentially the same distribution of radioactivity among the metabolite peaks as was observed in profiles from rats without anal cups. Therefore, all of the metabolite peaks observed in the urine represent compounds that are actually excreted in the urine.

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
Most of the dosed radioactivity was eliminated in the urine (60%) and about 30% of it was eliminated as [14C]CO2. Less than 10% was found in the feces. No sex-related differences in the excretion patterns were evident. The maximum blood concentrations of 14C occurred at approx. 1.5 hours. The proportion of long-chained metabolites increased in rat urine when the test substance dose increased. Ten urinary metabolites (identified as metabolites A-J) were isolated in cation exchange chromatography. The primary metabolites were D (N,N-dimethyl-N-oxide-4-aminobutyric acid) and E (N,N-dimethyl-4-aminobutyric acid).

Executive summary:

One male Sprague Dawley rat of approx. 0.25 kg body weight was fasted overnight and then orally dosed with 1 ml of an aqueous [¹⁴C] DDAO solution of 0.25 mg/ml, to acheive a dose of 1 mg [¹⁴C]DDAO/kg BW.After dose administration, the time of maximum plasma¹⁴C concentration was determined by measuring the¹⁴C content of plasma samples taken at 0.5, 1.0, 1.5, 2.0, 3.0, 3.5 and 4.0 hours.

For plasma for metabolite separation, three male and three female rats were anesthetized with ether 1.5 h after dosing (as above with 1 mg/kg BW) and the largest possible volume of blood was taken from the vena cava. The blood was centrifuged and the plasma was removed and frozen.

Two males and three female Sprague-Dawley rat of approx. 250 g body weight were fasted overnight and then orally dosed with 1.0 mL of an aqueous [¹⁴C]-DDAO of a concentration of 0.25 mg/mL to acheive a dose of 1 mg/kg BW.

Animals were placed in metabolism cages for collection of CO2, urine, and feces each 24 hr period for 72 hours.

Before metabolite separation, samples of urine were treated by anion exchange chromatography, followed by lyophilization and extraction with alcohol.

The maximum blood concentrations of¹⁴C occurred at approx. 1.5 hours. In a separate experiment, plasma samples were isolated from the blood at 1.5 hours after dosing. The radioactivity content of the plasma samples was low, which limited the chromatographic resolution of individual metabolite peaks. Virtually all of the metabolite peaks observed in urine samples were also observed in plasma. Most of the dosed radioactivity was eliminated in the urine and about 30% of it was eliminated as [¹⁴C] CO₂. Less than 10% was found in the feces. No sex-related differences in the excretion patterns were evident. Ten urinary metabolites (identified as metabolites A-J) were isolated in cation exchange chromatography.

Reference 8

Endpoint:

basic toxicokinetics

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

1973-01-15 to 1975-08-08

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Methods similar to OECD 417 (Toxicokinetics). However, only one dose level was used for each animal species in these single-dose studies; two dose levels are specified in the test guideline. No details provided on age of animals used or whether animals were acclimated and fasted. Incomplete details on housing conditions; temperature, humidity, lighting not described.

Justification for type of information:

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

reference to same study

Objective of study:

absorption

distribution

excretion

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

Principles of method if other than guideline:

N/A

GLP compliance:

Remarks:

Pre-GLP

Radiolabelling:

yes

Remarks:

[1-14C-dodecyl]-test substance and [14C-methyl]-test substance

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: N/A
- Age at study initiation: N/A
- Weight at study initiation: For intragastric exposures: [14C-methyl]-DDAO average weight (males): 204.8 ± 4 g; [1-14C-dodecyl]-DDAO average weight (males): 184.8 ± 5 g; For oral exposures: [1-14C-dodecyl]-DDAO average weight (males): 202 ± 1.5 g; For intraperitoneal exposures: [14C-methyl]-DDAO average weight (males): 230 ± 30 g
- Fasting period before study: N/A
- Housing: N/A
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): N/A
- 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: 1/15/73 To: 6/1/75

Route of administration:

other: intragastric intubation

Vehicle:

not specified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: N/A

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: N/A

Duration and frequency of treatment / exposure:

- Single dose

Remarks:

Doses / Concentrations:
100 mg (intragastric administration experiment)
40 mg (stomach intubation for bile duct experiment)

No. of animals per sex per dose / concentration:

- Four males and 4 females received [1-14C-dodecyl]-test substance
- Four males received [14C-methyl]-test substance
- Three bile duct-cannulated males received [14C-methyl]-test substance orally

Control animals:

Positive control reference chemical:

N/A

Details on study design:

- Dose selection rationale: No data
- Rationale for animal assignment (if not random): No data

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Distribution)
- Tissues and body fluids sampled: In males: liver, intestines, stomach and esophagus, testes, kidney, lungs, spleen, heart, brain and spinal cord, pancreas, carcass, leg muscle, epidermal fat, bone marrow and whole blood; In females: liver, intestines, stomach and esophagus, ovaries and tubules, kidney, lungs, spleen, heart, brain and spinal cord, pancreas, adrenals, capsule of the eye, fluid of the eye, lens of the eye, carcass, leg muscle, subcutaneous fat, bone marrow, blood cells and blood plasma
- Time and frequency of sampling: Collected 72 hours after oral administration of [14C-methyl]-DDAO and [1-14C-dodecyl]-DDAO
- Other: N/A

PHARMACOKINETIC STUDY (Excretion – intragastric exposures)
- Tissues and body fluids sampled: urine, CO2, feces and tissue + carcass
- Time and frequency of sampling: daily (plus final cage wash for urine, contents of safety traps for CO2 and contents of GI tract at sacrifice)
- Other: N/A

PHARMACOKINETIC STUDY (Excretion – bile duct-cannulated rats)
- Tissues and body fluids sampled: urine, CO2, feces, bile and carcass
- Time and frequency of sampling: daily (plus final cage wash for urine and contents of safety traps for CO2)
- Other: The common bile ducts were cannulated 24 hours prior to dosing via stomach intubation (100 mg [14C-methyl]-DDAO/kg). Bile and other excretion products were collected for 72 hours after dosing. The bile duct cannulated rats were kept in small animal restrainers during the predose and excretion product collection period. As a consequence of the cage type restrainer employed, feces frequently accumulated within the restrainer causing cross-contamination of urine and feces.

PHARMACOKINETIC STUDY (Excretion – i.p. rats)
- Tissues and body fluids sampled: urine and cage wash, CO2, feces and carcass
- Time and frequency of sampling: 24-hour period after administration of the i.p. injection
- Other: N/A

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: N/A
- Time and frequency of sampling: N/A
- From how many animals: (samples pooled or not): N/A
- Method type(s) for identification (e.g. GC-FID, GC-MS, HPLC-DAD, HPLC-MS-MS, HPLC-UV, Liquid scintillation counting, NMR, TLC): N/A
- Limits of detection and quantification: N/A
- Other: N/A

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): N/A

Statistics:

N/A

Preliminary studies:

N/A

Details on absorption:

An oral dose of 14-C-methyl-test substance or 1-14C-dodecyl-test substance was extensively and rapidly absorbed by rats.

Details on distribution in tissues:

- The greatest accumulation and the highest concentration of radioactivity was found in the liver (1.25% of the total [14C-methyl]-test substance dose was found in the liver in males and 1.48% of the total [1-14C-dodecyl]-test substance dose in females)
- The distribution among body tissues of radioactivity from an oral dose of [1-14C-dodecyl]-DDAO was similar for male and female rats
- The fractions of dosed radioactivity appearing in the liver, kidney and blood reached a maximum within one hour after an oral dose of [14C-methyl]-test substance

Observation:

other: N/A

Details on excretion:

In male and female rats, the total excretion of radioactivity from orally administered DDAO was rapid. Within 24 hours after dosing, 73.9 and 67.4 percent of the radioactivity from orally dosed [14C-methyl]-test substance and [1-14C-dodecyl]-test substance, respectively, was excreted by male rats. More than two-thirds of the radioactivity excreted as expired 14CO2 appeared within 12 hours after oral administration of either [14C-methyl]-test substance or [1-14C-dodecyl]-test substance. Notably, the percent of administered radioactivity excreted as 14CO2 by rats dosed p.o. with [1-14C-dodecyl-test substance was consistently greater than that appearing is expired 14CO2 from rats dosed p.o. with [14C-methyl]-test substance.

An average of 12.1 or 9.4 percent of the radioactivity administered p.o. as [14C-methyl]-test substance or [1-14C-dodecyl]-test substance was excreted in the feces. Although restraint of bile duct cannulated rats resulted in extensive cross contamination of radioactivity in urine, feces and carcass, the data indicate that biliary pathway is a minor excretory pathway for radioactivity administered p.o. as [14C-methyl] since bile excreted over the 48 hour period after dosing contained less than 4 percent of the administered dose.

Toxicokinetic parameters:

other: no parameters identified

Metabolites identified:

not specified

Details on metabolites:

N/A

Conclusions:

The oral doses of both [14C-methyl]- and [1-14C-dodecyl]-DDAO were rapidly and extensively absorbed and excreted by rats.

Executive summary:

The absorption, tissue distribution and excretion pattern of [¹⁴C-methyl]-C10-16 alkyl dimethyl amine oxide and [1-¹⁴C-dodecyl]-C10-16 alkyl dimethyl amine oxide administered via oral routes of exposure to male and female rats was investigated in this study. Four males and 4 females received [1-¹⁴C-dodecyl]-C10-16 alkyl dimethyl amine oxide via intragastric intubation at a dose of 100 mg/kg while 4 males received [¹⁴C-methyl]-C10-16 alkyl dimethyl amine oxide at the same dose. A dose of 40 mg/kg was administered to 3 bile duct-cannulated male rats and 4 additional males received 22 mg/kg via intraperitoneal injection. For bile duct-cannulated rats, the common bile ducts were cannulated and the dose was administered one day after the procedure; the bile and other excretion products were collected for 72 hours thereafter. All test substance administrations were given as a single dose. Immediately after dosing, all animals were placed in individual, stainless steel metabolism cages equipped for collection of expired carbon dioxide and separate collection of urine and feces. The bile duct cannulated rats were kept in small animal restrainers during the predose and excretion product collection period. As a consequence of the cage-type restrainer employed, feces frequently accumulated within the restrainer causing cross-contamination of urine and feces.

In the distribution studies, the following tissues and body fluids were sampled in males: liver, intestines, stomach and esophagus, testes, kidney, lungs, spleen, heart, brain and spinal cord, pancreas, carcass, leg muscle, epidermal fat, bone marrow and whole blood; in females: liver, intestines, stomach and esophagus, ovaries and tubules, kidney, lungs, spleen, heart, brain and spinal cord, pancreas, adrenals, capsule of the eye, fluid of the eye, lens of the eye, carcass, leg muscle, subcutaneous fat, bone marrow, blood cells and blood plasma. All samples were collected 72 hours after oral administration of [¹⁴C-methyl]-C10-16 alkyl dimethyl amine oxide and [1-¹⁴C-dodecyl]-C10-16 alkyl dimethyl amine oxide. Distribution was studied in the twelve rats that received a single intragastric dose; these same animals were also studied for excretion of the radiolabelled compounds. Four females were dosed with [1-¹⁴C-dodecyl]-C10-16 alkyl dimethyl amine oxide while 8 males (4 per group) were dosed with [¹⁴C-methyl]-C10-16 alkyl dimethyl amine oxide or [1-¹⁴C-dodecyl]-C10-16 alkyl dimethyl amine oxide. Urine, carbon dioxide, feces and tissue + carcass were sampled daily (in addition to a final cage wash sample of urine, contents of safety traps for carbon dioxide and the contents of the GI tract at sacrifice). For excretion examinations in the bile duct-cannulated rats urine, carbon dioxide, feces, bile and the carcass were sampled daily (in addition to a final cage wash sample for urine and the contents of the safety trap for carbon dioxide). Excretion of the test substance in the 3 rats administered intraperitoneal injections was also studied; sample of urine and cage wash, carbon dioxide and the carcass were collected during the 24-hour period after the administration.

The greatest accumulation and the highest concentration of radioactivity were found in the liver (1.25% of the total [¹⁴C-methyl]-C10-16 alkyl dimethyl amine oxide dose was found in the liver in males and 1.48% of the total [1-¹⁴C-dodecyl]-C10-16 alkyl dimethyl amine oxide dose in females). The distribution among body tissues of radioactivity from an oral dose of [1-¹⁴C-dodecyl]-C10-16 alkyl dimethyl amine oxide was similar for male and female rats. The fractions of dosed radioactivity appearing in the liver, kidney and blood reached a maximum within one hour after an oral dose of [¹⁴C-methyl]-C10-16 alkyl dimethyl amine oxide.

In male and female rats, the total excretion of radioactivity from orally administered test substance was rapid. Within 24 hours after dosing, 73.9 and 67.4 percent of the radioactivity from orally dosed [¹⁴C-methyl]-C10-16 alkyl dimethyl amine oxide and [1-¹⁴C-dodecyl]-C10-16 alkyl dimethyl amine oxide, respectively, was excreted by male rats. More than two-thirds of the radioactivity excreted as expired¹⁴CO2 appeared within 12 hours after oral administration of either [¹⁴C-methyl]-C10-16 alkyl dimethyl amine oxide or [1-¹⁴C-dodecyl]-C10-16 alkyl dimethyl amine oxide. Notably, the percent of administered radioactivity excreted as¹⁴CO2 by rats dosed p.o. with [1-¹⁴C-dodecyl-C10-16 alkyl dimethyl amine oxide was consistently greater than that appearing is expired¹⁴CO2 from rats dosed p.o. with [¹⁴C-methyl]-C10-16 alkyl dimethyl amine oxide. An average of 12.1 or 9.4 percent of the radioactivity administered p.o. as [¹⁴C-methyl]-C10-16 alkyl dimethyl amine oxide or [1-¹⁴C-dodecyl]-C10-16 alkyl dimethyl amine oxide was excreted in the feces. Although restraint of bile duct cannulated rats resulted in extensive cross contamination of radioactivity in urine, feces and carcass, the data indicate that biliary pathway is a minor excretory pathway for radioactivity administered p.o. as [¹⁴C-methyl] since bile excreted over the 48 hour period after dosing contained less than 4 percent of the administered dose.

Intraperitoneally administered [¹⁴C-methyl]-C10-16 alkyl dimethyl amine oxide was also excreted rapidly by rats. Over the first twenty-four hours after dosing 67, 8, and 6 percent of the radioactivity from an i.p. dose of [¹⁴C-methyl]-C10-16 alkyl dimethyl amine oxide was excreted in the urine, expired¹⁴CO2 and feces, respectively. The rate of¹⁴CO2 production was initially rapid, but this excretion rate declined rapidly to a low value within eight hours after dosing. No significant differences are observed between the distributions of radioactivity among the urine, feces and¹⁴CO2 when results for intragastric and intraperitoneal administration of [¹⁴C-methyl]-C10-16 alkyl dimethyl amine oxide in rats are compared. This suggests that microbial metabolism by gastrointestinal flora does not play a major role in the metabolism of DDAO in rats.

The oral doses of C10-16 alkyl dimethyl amine oxide were rapidly and extensively absorbed and excreted by rats after dosing by intragastric intubation.

Reference 9

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across based on grouping of substances (category approach)

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.

Justification for type of information:

Reason / purpose for cross-reference:

read-across: supporting information

Objective of study:

distribution

excretion

metabolism

Qualifier:

no guideline available

Principles of method if other than guideline:

N/A

GLP compliance:

Remarks:

Pre-GLP

Radiolabelling:

yes

Remarks:

1-dodecyl-14C

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system 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

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

Remarks:

Doses / Concentrations:
0.5% amine oxide

No. of animals per sex per dose / concentration:

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 reference chemical:

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.

Preliminary studies:

N/A

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:

other: no parameters identified

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.

N/A

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.

Description of key information

Key value for chemical safety assessment

Additional information

Toxicokinetics:

There are three key toxicokinetic studies investigating the absorption, distribution, metabolism and excretion of the test substance (dodecyl dimethyl amine oxide, AO, radiolabelled with C-14) following either oral or dermal administration in animals and man (Procter & Gamble study 13708 (1975), P&G study 21376 (1978) and P&G study 21910 (1979)].

Methodology

Two C-14 radio-labelled versions of the test substance were used in the toxicokinetic studies:
[methyl-¹⁴C]-dodecyldimethylamine and [1-dodecyl-¹⁴C]-dodecyldimethylamine. The toxicokinetics of the radiolabelled test substance was studied in rats, mice and rabbits and also in human volunteers.

Rats were orally dosed with radiolabelled test substance at either 1, 40 (bile duct cannulated rats) or 100 mg/kg and at 22 mg/kg for an intraperitoneal dose. Rabbits were orally dosed with radiolabelled test substance at 1 mg/kg. Following dosing stainless steel animal metabolism cages were employed to separate and collect expired carbon dioxide, urine and faeces for up to 72 hours post dose and tissues and organs were collected for analysis at the termination of the experiment.

The radiolabelled test substance was administered topically to rats (10 mg to 18 cm²), mice (1 mg to 6 cm²) and rabbits (10 mg to 40 cm²). The animals were restrained or fitted with collars to restrict oral ingestion of the test substance. Expired carbon dioxide, urine and faeces were collected for up to 72 hours post dose and tissues and organs were collected for analysis at the termination of the experiment.

Humans orally took 50 mg of radiolabelled test substance in water and expired carbon dioxide (up to 72 hours post-dose), excreta (up to 144 hours) and blood samples were collected. For the human dermal study, 10 mg of the radiolabelled test substance in 0.5 mL of water was topically applied to a 60 cm²area of forearm skin and left on the skin for 8 hours. At 8 hours, the skin was repeatedly swabbed and subsequently tape-stripped to remove any dose remaining in the stratum corneum. Expired carbon dioxide (up to 72 hours post-dose) and excreta (up to 144 hours) were collected for analysis.

Absorption, distribution and excretion

The major conclusions on absorption, distribution and excretion that could be drawn from the oral TK studies in rats are:

· The test substance is rapidly (T_max1.5 hours) and readily absorbed following oral administration (>80%).

· Microbial metabolism by gastrointestinal flora does not play a major role in the oral absorption and excretion of the test substance.

· Biliary excretion is a minor excretory route (<5%).

· The test substance is rapidly excreted (~75% within 24 hours).

· The test substance is extensively metabolised and excreted primarily in urine, but also initially (first 12 hours) as CO₂(proportions depend upon the position of the C-14 tracer).

· There were no major differences in the route (urine vs expired CO₂) or rate of excretion of dose between the 1 and 100 mg/kg dose levels.

· The test substance (or its metabolites) is widely distributed throughout the body with the highest proportions remaining primarily in the excretory organs (liver, stomach, kidneys and lungs) at 72 hours after dosing. The reproductive organs also contained similar proportions of dose at 72 hours after dosing to the kidneys/stomach.

The absorption, distribution and excretion of the radiolabelled test substance in the rabbit after oral administration was very similar to the rat, with a blood T_maxof 1.5 hours, most of the radioactivity excreted in the urine, approximately 30% as expired carbon dioxide and less than 10% in the faeces.

The absorption, distribution and excretion of the radiolabelled test substance in humans after oral administration were also similar to the rat although an incomplete mass balance was obtained (69% and 80% recoveries). Over half of the recovered radioactivity was detected in the urine and approximately a quarter measured in the expired carbon dioxide indicating a very high (>75%) oral absorption of dose. Almost the entire recovered dose was rapidly excreted within the first 24 hours and a blood T_maxof 1 hour was seen.

The major conclusions on absorption, distribution and excretion that could be drawn from the dermal TK studies in rats, mice and rabbits are:

· The test substance is slowly absorbed following dermal application (approximately 5% per day was consistently excreted in urine up to 72 hours post dose) with approximately 50% of dose still remaining at the dose site 72 hours after dosing (rats).

· Approximately 20% of the dose was absorbed and excreted (up to 72 hours) following dermal application with a further ~20% recovered from the carcass/cage wash which may have been due to contamination of the applied dose (rats).

· The overall distribution of dose was very similar between rats and mice; however, the rabbit excreted twice as much dose (~46%).

· The rate of penetration (flux) of the test substance through rabbit, rat and mouse skin was calculated to be 12.8, 6.0 and 1.7 nmol/hour/cm²respectively.

The major conclusions on absorption, distribution and excretion that could be drawn from the dermal TK study in man are:

· More than 92% of the applied topical dose was removed from the dose site after 8 hours.

· Less than 0.2% of dose was detected in the stratum corneum.

· A very small percentage (~0.2%) of dose was estimated to have been absorbed.

· The rate of penetration (flux) of the test substance though human skin was estimated to be <0.2 nmol/hour/cm².

Whist the absorption, distribution and excretion of the radiolabelled test substance following oral administration was very similar in the test animals; rats, rabbits and mice to man, this was not the case following dermal dosing. Results from these studies indicate that the dermal absorption of the test substance is a magnitude lower in man than the test animals. Whilst it is often seen that the dermal absorption of many test substances is greater in animals than man, the magnitude of difference from these studies is greater than would be expected. It is quite likely that the extent of absorption seen from the animal studies was compromised by oral absorption (licking of the test site) and by external contamination of the animal carcasses. As such, the extent of absorption of dose following the animal dermal studies may be an over estimate. A major difference in the study design for the human dermal absorption work was that the dose was only left on the application site for 8 hours, whereby it was swabbed and tape stripped; whereas in the animal studies it was left on the application site for 72 hours. Since the animal studies showed that the dermal absorption of the dose was very slow (approximately 5% per day) this may be another explanation as to the extent of the differences seen. However, if following human dermal exposure to the test substance the skin is thoroughly washed at the end of a working day, then the assumption that only a small proportion of dose is absorbed and that 90% or more of the dose would be removed by washing would appear reasonable.

Based on the recovery of 92 % of the applied topical dose of amine oxide from the test site in humans a value of 8 % is used in the risk assessment to model worse case systemic exposure via the dermal route.

Metabolism

The test substance was extensively metabolised after oral administration as shown by at least 10 metabolites characterised in urine in addition to a substantial proportion of dose completely biotransformed to CO₂. There were several different pathways of metabolism proposed:

· Oxidative degradation of the alkyl side chain by ω-oxidation to form a carboxylic acid followed by the loss of two-carbon fragments by sequential β-oxidation. This route of metabolism is frequently observed in similar substances to the test substance.

· Hydroxylation of the alkyl side chain at a position four or five carbons from the end of the chain.

· Reduction of the amine oxide group to the parent amine.

Qualitatively, the metabolic profiles (from urine) were similar for rat, rabbit and man but quantitatively there were differences. The identity of the major human metabolite of the test substance was proposed as N-methyl-4-aminobutyric acid N-oxide (~60% of urinary profile). This metabolite was also the most abundant metabolite in rabbit urine but not for rats. The major metabolite in rats resulted from hydroxylation of the side chain. The proportion of this metabolite in rat urine doubled when the dose of the test substance was increased from 1 to 100 mg/kg. Another substantial (~30%) metabolite seen in rats, rabbits and humans was proposed to be N,N-dimethyl-4-aminobutyric acid. The presence of this metabolite would indicate that a dodecyldimethylamine (DDA) was a likely metabolic intermediate. Further examination of the urinary metabolic profiles indicated that the rat excreted >12% of the dose as long-chain compounds (at least half of these were C-hydroxylated amino-alcohols), which was in contrast to the rabbit and man. As such, it appears that the metabolism of the test substance by the rabbit is closer to that of man than the rat.

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N,N-dimethyldecylamine N-oxide

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Description of key information

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