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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Justification for type of information:
Refer to the Quaternary ammonium salts (QAS) category or section 13 of IUCLID for details on the category justification. The study with the read across substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.

Data source

Reference
Reference Type:
publication
Title:
Absorption, distribution and excretion of [14C] CTAB, a quaternary ammonium surfactant, in the rat
Author:
Isomaa B
Year:
1975
Bibliographic source:
Food Cosmet Toxicol. 1975 Apr;13(2):231-7

Materials and methods

Objective of study:
absorption
distribution
excretion
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The absorption, distribution and excretion of test substance was determined by performing in vivo study in rats. Female Sprague-Dawley rats were starved for 24 h and then given [14C] test substance (0.8 mg/kg) as an aqueous solution by gastric intubation. The distribution of the 14C-labelled test substance was studied using collected samples of blood, organs and tissues by radioassay. The excretion of 14C-labelled test substance was studied using collected samples of urine, faeces and bile by thin layer chromatography and radioassay. [14C] toluene was used as internal standard. The results were reported as radioactivity (% of administered dose of test substance).
GLP compliance:
no
Remarks:
Study from Pre-GLP period

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female

Administration / exposure

Route of administration:
other: Oral - Gastric intubation
Vehicle:
water
Doses / concentrations
Dose / conc.:
0.8 other: mg/kg of [14C] C16 TMAB in 4.0 mL/kg bw
No. of animals per sex per dose:
Distribution study: 6 groups of 3-5 animals
Excretion study: 4 animals
Bile collection: 3 animals
Control animals:
no
Details on dosing and sampling:
- Specific activity of test substance: 17.6 µCi/mg
- Volume applied: 4.0 mL/kg bw
- Exposure period: Up to 96 h
- Sampling time
Distribution study: 2, 4, 8, 24, 72, and 96 h
Excretion study: Urine and faeces were collected at 4 h intervals for 3 d.
Bile: 2 h intervals for 12 h
- Samples: Blood, urine, faeces, bile, organs (liver, kidney, spleen, skeletal muscle, hart, lungs)

Details:
Distribution studies
Female Sprague-Dawley rats (210-240 g) were starved for 24 h and then given [14C] CTAB (0.8 mg/kg) as an aqueous solution by gastric intubation. The administered volume was 4 mL/kg body weight. Blood samples were taken from the tail under mild ether anesthesia. The animals were killed 2, 4, 8, 24, 48, 72 and 96 h after intubation. In experiments lasting for more than 24 h the animals were provided with food and water ad lib. 8 h after intubation. Tissue samples weighing 100—200 mg were cut in duplicate from the liver, kidneys, spleen, heart, lungs and hind leg (gastrocnemius muscle) for radioassay. In animals killed 8 h after gastric intubation, the gastro-intestinal tract was removed and divided into four parts, namely the stomach, the proximal and distal halves of the small intestine and the caecum together with the colon. The contents of the different parts of the gastro-intestinal tract were collected by rinsing with saline.
 
Excretion studies
For the study of the excretion of 14C-labelled compounds, similarly treated animals were kept in metabolism cages permitting the separate collection of urine and faeces, which were removed at 4 h intervals for a period of 3 days and kept refrigerated until examined. Faeces were homogenized in ethanol and aliquots were taken for radioassay. Expired CO2 was trapped in 10% NaOH at 4 h intervals during day 1 after intubation. Saturated BaCl2 was added and the precipitated BaC03 was filtered off and dried, aliquots being taken for radioactivity determinations.
 
Bile collections
Biliary excretion was studied by means of a polyethylene cannula inserted into the common bile duct of rats anaesthetized with sodium pentobarbitone (40 mg/kg, ip). When bile flowed freely, the abdominal incision was closed and an aqueous solution of (0.8 mg/kg) was administered by gastric intubation. The bile was collected for 12 h at 2 h intervals and the samples were refrigerated until examined.

Results and discussion

Main ADME resultsopen allclose all
Type:
distribution
Results:
80% in GIT; 2% found in bile, 1.2% in urine, organs < 0.1%
Type:
excretion
Results:
92% excreted in faeces and 1% in urine; no radioactivity was detected in expired CO2
Type:
absorption
Results:
Based on the radioactivity found in excreta, total approx. absorption could be considered to be 3.3% (poor absorption)

Toxicokinetic / pharmacokinetic studies

Details on absorption:
About 80% of the dose of radioactivity was found in the gastro-intestinal tract 8 h after administration, only small amounts were found in the blood plasma and about 2% of the administered radioactivity was excreted in the bile during the first 12 h after treatment. The low levels of radioactivity in the serum and bile, together with the large amounts of radioactivity found in the gastro-intestinal tract, indicated poor intestinal absorption of C16 TMAB.
Details on distribution in tissues:
Distribution of radioactivity
The distribution of radioactivity in the gastro-intestinal tract 8 h after oral administration of [14C] C16 TMAB A total of about 80% of the administered radioactivity was found in the gastro-intestinal tract, about 87% of this amount being in the gastro-intestinal contents. About 90% of the administered dose had left the stomach within 8 h. Only small amounts of radioactivity were found in tissues other than the gastro-intestinal tract. The level of radioactivity in all the organs examined exceeded that of the blood plasma, the peak level in which occurred 2-4 h after administration of the dose. The liver and kidneys showed the highest levels of radioactivity, the peak in these two organs occurring approximately 8 h after dosing. At that time, assuming an even distribution of radioactivity in the liver tissues, the liver contained about 0.8% of the administered radioactivity, but 4 days after the administration of [14C] C16 TMAB, only traces of radioactivity remained in the liver and kidneys. The amount of radioactivity found in the skeletal muscle and spleen was 5-10% of that found in the liver. In the heart and the lungs, the levels of radioactivity were about the same as those in skeletal muscle.
Details on excretion:
Excretion of radioactivity
About 2% of the administered dose was excreted in the bile during the first 12 h after administration of [14C] CTAB. There was thus no appreciable enterohepatic circulation of radioactivity. The low levels of radioactivity in the serum and bile, together with the large amounts of radioactivity found in the gastro-intestinal tract, indicated poor intestinal absorption of CTAB. Thin- layer chromatography of bile revealed five spots of radioactivity all with an RF value smaller than that of the standard. Cationic surfactants can form ion-pairs with organic anions and it has been suggested that quaternary ammonium compounds are transferred across the gut wall as neutral complexes by virtue of their combination with endogenous anions. To test whether such a complex could explain the spots found on the chromatograms, [14C] CTAB was incubated with bile collected from the animals before treatment. However, chromatography of these incubates showed only one radioactive spot, with an RF value similar to that of the standard. After 3 days, 92% of the administered dose of radioactivity had been excreted in the faeces and only in the urine. Thin-layer chromatography of ethanolic faecal extracts revealed three radioactive spots that with the same RF value as the [14C] CTAB standard accounted for about 85% of the radioactivity in the faeces collected during day 1, while the other two spots had RF values smaller than that of the [14C] CTAB standard. In the urine, the peak levels of radioactivity were found in samples collected 4-8 h after dosing. Thin-layer chromatograms or urine samples showed four radioactive spots, the RF values of which were in one case similar to and in the others smaller than the [14C] CTAB standard. Faecal homogenates and urine incubated with showed onlv one radioactive spot, with the same RF value as the standard. No radioactivity was found in the expired CO2, collected during day 1 after administration of [14C] CTAB.

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

Table 1: Distribution radioactivity in the gastro-intestinal tract of rats 8 h after oral intubation of 0.8 mg [14C] CTAB/kg 

Region of gut

Radioactivity (% of administered dose*)

Stomach

10 ± 3.1£

Small intestine, proximal half

2.5 ± 0.3£

Small intestine, distal half

13.5 ± 1.5£

Caecum and colon

53.8 ± 2.4£

Complete gastro-intestinal tract: Total

79.9 ± 1.3£

Contents

69.8 ± 2.4

Wall

10.1 ± 2.3

Gastric emptying

90 ± 3.1

*Values represent means ± SEM for five rats

£ Wall plus contents

 

 

Table 2: Distribution of radioactivity in urine and faeces after oral intubation of 0.8 mg [14C] CTAB/kg

Radioactivity

(% of administered dose*)

Day

Faeces

Urine

Faeces + Urine

1

89.10± 2.23

1.06± 0.11

90.16±1.98

2

2.83± 1.20

0.13± 0.02

2.96±1.06

3

0.56± 0.17

0.03± 0.02

0.59±0.15

Total

92.49± 2.06

1.22± 0.10

93.71±2.15

*Values represent means SEM for four rats

Applicant's summary and conclusion

Conclusions:
Uptake C16-TMAC was at least 3.3%, based on radioactivity found in the excreta; the value could be higher since levels of radioactivity found in different organs (excluding the g.i.tract) and in the carcass were not quantified, although presumably low.
Executive summary:

A study was conducted to determine the absorption, distribution and excretion of orally administered radiolabelled read across substance, [14C] C16 TMAB, in female rats. Approximately 80% of the dose of radioactivity was found in the gastro-intestinal tract 8 h after administration, only small amounts were found in the blood plasma and about 2% of the administered radioactivity was excreted in the bile during the first 12 h after treatment. The low levels of radioactivity in the serum and bile, together with the large amounts of radioactivity found in the gastro-intestinal tract, indicated poor intestinal absorption of the test substance. Only small amounts of radioactivity were found in the liver, kidneys, spleen, heart, lungs and skeletal muscle, and the tissue radioactivity declined rapidly, only traces being found in the examined tissues 4 d after [14C] test substance administration. Within 3 d of ingestion, 92% of the administered radioactivity had been excreted in the faeces and 1% in the urine. No radioactivity was found in the expired CO2 collected during day 1 after administration of [14C] test substance, indicating that no complete oxidation of the cetyl group occurred. The results of thin-layer chromatography of bile and urine samples indicated that the test substance was metabolized to some extent in the rat. Based on the results of the study, the test substance can be assumed to have very low absorption (i.e., <10%), distributed mainly in GIT and excreted in faeces (Isomaa, 1975).