Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.

Data source

Reference
Reference Type:
publication
Title:
Metabolism of alpha-olefin sulfonate (AOS) in rats.
Author:
Inoue, S. et al.
Year:
1982
Bibliographic source:
Fundamental and applied toxicology 2(3): 130-138

Materials and methods

Objective of study:
distribution
excretion
metabolism
Test guideline
Qualifier:
no guideline followed
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): Sodium tetradecene-1-14C-sulfonate (14C-AOS)
- Molecular weight: mean 308
- Substance type: surfactant
- Analytical purity: not specified
- Composition of test material, percentage of components: 55 % sodium 3-hydroxy alkane sulfonate, 45 % sodium alkenyl-2-sulfonate
- Radiochemical purity (if radiolabelling): 98 %
- Specific activity (if radiolabelling): 1.95 mCi/mmol
- Locations of the label (if radiolabelling): C1
- Other: Source: Daiichi Pure Chemicals Co., Tokyo, Japan
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Japan Rat Co., Tokyo, Japan
- Weight at study initiation: 200-250 g
- Fasting period before study: overnight prior to dosing
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Prior to use, radioactive AOS was diluted with the appropriate amounts of the non-radioactive AOSof the same 55:45 proportion of materials. The dose of 14C-AOS was administered by single oral and intravenous injection of 100 mg (50 µCi)/kg and 10 mg (5 µCi)/kg, respectively, in distilled water as a vehicle.
Duration and frequency of treatment / exposure:
single exposure
Doses / concentrations
Remarks:
Doses / Concentrations:
100 mg (50 µCi)/kg oral; 10 mg/ (5 µCi)/kg i.v.
No. of animals per sex per dose:
3 males
Control animals:
other: not applicable
Details on study design:
- Dose selection rationale: based on toxicity estimations established in previously published literature on mammalian toxicity
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, bile, blood, plasma, serum, other tissues: blood, brain, submaxillary gland, thymus, heart, lung, liver, spleen, kidney, adrenal, testes, seminal vesicle, fat, skin, urinary bladder, prostate, sciatic nerve, femur, femoral muscle, stomach (tissue and content), small intestine (tissues and content), cecum (tissue and content), large intestine (tissue and content)
- Time and frequency of sampling: oral: 1, 4, 12, 24 h; iv: 5, 30 min, 1, 3, 6 h
- Other: radioactivity was determined by liquid scintillation counting

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, tissues, cage washes, bile
- Time and frequency of sampling: 0-24 h urine samples from each rat were pooled
- From how many animals: (samples pooled or not) individual animals
- Method type(s) for identification HPLC, TLC, Liquid scintillation counting
- Other: formation of derivatives from urine metabolites

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
After oral administration about 80 % of the 14C-dose was rapidly absorbed from the gastrointestinal tract.
Details on distribution in tissues:
Oral administration:
The radioactive level of blood reached its peak at 3 hours after dosing and then rapidly declined. Its peak was 0.08 % of dose/mL, but little radioactivity was detected at 24 hours after administration.

At 4 hours after administration, 0.45 % dose/g tissue was detected in liver, 0.65 % dose/g was found in kidney, but other tissues except gastrointestinal tract were less than 0.1 % dose/g tissue. The radioactivity in organs and tissues was rapidly eliminated after 4 hours. At 24 hours after the administration, about 0.8 % dose/g was detected in cecum contents, in other tissues the radioactivity was below 0.02 % dose/g.

Intravenous administration:
The concentrations of intact 14C-AOS in liver and kidney were comparable with that in blood at each time point. The radioactivity present as metabolites in liver and kidney was 10-20 times higher than that in blood. After injection of metabolites the radioactivity in blood, tissues and urine was comparable.
The volume of distribution of AOS was 8 L/kg and that of the metabolites was 0.5 L/kg. Since the distribution volume of AOS was remarkably larger than body weight, the binding of AOS to protein had to be considered. In vitro binding studies of AOS and its metabolites demonstrated the binding of intact AOS, but not the metabolites to proteins.
Details on excretion:
Oral administration:
About 4 hours after administration urinary excretion reached its peak and thereafter rapidly decreased. Cumulative excretion in the urine within 12 hours after dosing was about 55 % of the dose administered. The bile level reached its peak about 3 hours after dosing and thereafter rapidly declined. Cumulative expression in the bile within 12 hours after dosing was about 4.3 % of the radioactivity administered.

Within 24 hours after oral administration, 72 % of the dose was excreted in the urine and 22 % in the feces. At the end of the 4 day sampling period, no 14C-residue (< 0.1 % of the dose) could be detected in the urine and feces.

Intravenous administration:
Urinary excretion of 14C-activity was shown to be associated with metabolites of 14C-AOS. Approximately one-half of the administered dose of radioactivity was excreted within 1 hour. During 6 hours, 90 % of the dose was excreted in the urine. A linear relationship was observed for urinary excretion, the excretion rate constant was 0.5.

The elimination rate constant of AOS from blood was remarkably smaller than that of the metabolites, which was nearly the same as the urinary excretion rate constant of 0.5.

The biological half-life of AOS was about 15 hours, while that of the metabolites was 1 hour.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Oral administration:
In the blood 14C-activity of intact AOS was about one third of that of metabolites. Metabolites accounted for most of the 14C-activity found in the liver, kidney, urine and bile. The 14C-activity in gastrointestinal tissues was present as intact 14C-AOS. One third of the 14C-activity found in the gastrointestinal contents was present as metabolites. TLC showed that the metabolites were more polar than intact 14C-AOS. Chromagenic agents indicated the presence of hydroxylated, carboxylated and sulfonated urinary metabolites.

Digestion of 0-24 hours combined rat urine with urease resulted in no significant amount (< 0.1 %) of 14CO2 liberated. Thus, no significant amount of 14C-activity was present as urea in the urine.

Derivative formation experiments indicated that the majority of 14C-activity in urine had either a carboxylic or a sulfonic functionality or both. The combined data indicate that the majority of 14C-activity in the urine had a sulfonic acid and alcohol functionality, but less than 4 % of the 14C-activity had a carboxylic acid functionality. To summarize the oral administration experiment, about 80 % of the dose was absorbed, metabolized and then rapidly excreted in the urine.

Intravenous administration:
Intact 14C-AOS rapidly decreased after injection and reached a plateau after 1 hour. Metabolite levels reached their peak at 15 min after the injection. In the case of intact 14C-AOS, a 2-compartment model was proposed. The elimination rate of metabolites' beta-phase was about six times faster than that of intact 14C-AOS.

Blood levels of radioactivity after intravenous injection of radioactive metabolites (isolated from urine by HPLC after oral administration of 14C-AOS) rapidly decreased within 15 min after the injection, and thereafter slowly declined. The data suggests a 2-compartment system which is remarkably different from the elimination pattern of intact 14C-AOS.

Any other information on results incl. tables

Distribution of radioactivity in organs and tissues after oral administration of 100 mg (50 µCi/kg) of 14C-AOS to rats:

Organ or tissue

% of the radioactivity given (%/g tissue) (mean of 3 animals)

Time after administration (hr)

1

4

12

24

Blood

0.071

0.086

0.020

0.002

Brain

0.006

0.006

0.005

0.000

Submaxillary gland

0.031

0.019

0.018

0.001

Thymus

0.017

0.012

0.011

0.001

Heart

0.024

0.033

0.009

0.001

Lung

0.038

0.038

0.014

0.001

Liver

0.492

0.450

0.284

0.012

Spleen

0.016

0.019

0.015

0.001

Kidney

0.407

0.640

0.305

0.016

Adrenal

0.034

0.085

0.053

0.003

Testes

0.005

0.008

0.003

0.000

Seminal vesicle

0.012

0.018

0.006

0.001

Fat

0.009

0.008

0.004

0.001

Skin

0.030

0.021

0.008

0.001

Urinary bladder

0.058

0.114

0.009

0.001

Prostate

0.028

0.026

0.013

0.001

Sciatic nerve

0.014

0.032

0.009

0.001

Femur

0.007

0.010

0.010

0.001

Femoral muscle

0.009

0.008

0.004

0.000

Bone marrow

0.024

0.041

0.025

0.006

Stomach tissue

1.474

1.206

0.234

0.009

Stomach contents

39.100

21.396

3.716

0.147

Small intestine tissue

1.025

0.145

0.053

0.001

Small intestine contents

27.421

6.948

0.356

0.038

Small intestine mucosa

0.205

0.360

0.087

0.004

Cecum tissue

0.034

0.914

0.815

0.023

Cecum contents

0.005

9.425

7.603

0.795

Large intestine tissue

0.027

0.066

0.073

0.009

Large intestine contents

0.021

0.459

4.527

0.028

Urinary and fecal excretions of the radioactivity after oral administration of 100 mg (50 µCi/kg) of 14C-AOS to rats:

Day

% of radioactivity given (mean of 3 animals)

Urine

Feces

Total

1

72.04

22.27

94.31

2

0.76

1.15

1.91

3

0.15

0.07

0.22

4

0.06

0.07

0.13

5

0.04

0.06

0.10

Total

73.05

23.62

96.67

Conclusion:

In this study it was established that single oral and intravenous doses of 14C-AOS administered to rats were readily absorbed, metabolized and excreted in the urine.

The fact that about 80 % of the AOS dose was rapidly absorbed from the GI-tract is a point of particular interest in view of the widely accepted principle that compounds which are ionized at the pH of the gastrointestinal lumen are generally poorly absorbed.

Applicant's summary and conclusion