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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication which meets basic scientific principles (no data on test material (purity) and vehicle).
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1990

Materials and methods

Objective of study:
excretion
metabolism
Principles of method if other than guideline:
Identification of 1,6-hexamethylene diamine metabolites in urine after oral administration in 6 volunteers.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name of test material (as cited in study report): 1,6-hexamethylene diamine
Source: Janssen (Beerse, Belgium)
Radiolabelling:
no

Test animals

Species:
human
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
Healthy, non smoking males aged from 25 to 50 years with normal biochemical tests of liver and kidney.

Administration / exposure

Route of administration:
other: oral route
Vehicle:
other: slightly acidic liquid
Details on exposure:
8.2 mg of 1,6-hexamethylene diamine was given on 2 separate occasions 3 months apart, each time after an overnight fast (> 10 h)
Duration and frequency of treatment / exposure:
2 separate administrations 3 months apart, each time after an overnight fast (> 10 h)
Doses / concentrations
Remarks:
Doses / Concentrations:
About 0.1 mg/kg bw
No. of animals per sex per dose:
6
Control animals:
no
Positive control:
No
Details on study design:
No data
Details on dosing and sampling:
All urine was repeatedly sampled (every second hour during the first 15 h) during the following 24 h. Pre-exposure sampling was done in the morning in all experiments in order to analyse background and sample contamination, as well as for recovery studies. The urine samples were made acidic by the addition of 5 mL of 6M HCl/100 mL of urine and were stored at 4 °C..
Statistics:
Spearman rank correlation method was applied to determine a possible relationship between the HMD respectively 6-aminohexanoic acid excretion and the acetylator status.

Results and discussion

Preliminary studies:
No data

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Not examined
Details on distribution in tissues:
Not examined
Details on excretion:
1,6-hexamethylene diamine in hydrolysed urine:
The peak amounts of compounds determined as free 1,6-hexamethylene diamine in single urine samples were 0.080 to 0.19 mg, and were measured in the different subjects 2 to 5 h after the intake of the substance. In four of the six subjects no 1,6-hexamethylene diamine could be detected after 10 h. In two subjects there was a prolonged elimination process, and there were low amounts still traceable at 15 and 20 hours respectively. The eliminary half-time was 1.5 h. The cumulated amounts of excreted 1,6-hexamethylene diamine varied between 0.090 and 0.48 mg in the different subjects, which corresponds to 1 to 6% of the administered dose .

6-aminohexanoic acid in hydrolysed urine:
The peak amounts of 6-aminohexanoic acid, 0.2-0.9 mg, appeared in urine samples in the different subjects, collected 4 to 6 h after dosing. The principal part (> 90%) of the excretion was completed within 10 h. The cumulated amounts varied between <0.05 and 2.2 mg, which corresponds to <1 to 27% of the administered dose. There was a considerable intra- and inter-individual variation in the excretion of 6-aminohexanoic acid.

The amounts of excreted 1,6-hexamethylene diamine were mean 2% and mean 5% of given dose in the subjects classified as slow and rapid acetylators, respectively. Using the Spearman rank correlation method it could be concluded that these two parameters corelate positively. No such coincidence was found with the excretion of 6-aminohexanoic acid.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
6-aminohexanoic acid: quantified in hydrolysed uriine
N-acetyl-1,6-hexamethylene diamine (monoacetylated HDA): just verified in non-hydrolysed urine (not quantified)

Any other information on results incl. tables

Acetylation phenotype and cumulated excretion of 1,6 -hexamethylene diamine and 6 -amino-hexanoic acid in urine following oral intake of 1,6 -hexamethylene diamine

Subject

Experi-

ment n°

Excretion

Acetylation

1,6-hexamethylene diamine

6-aminohexanoic acid

Acetylation ratio

Phenotype

mg

% of dose

mg

% of

dose

1

1

0.37

5

0.6

20

0.39

rapid

 

2

0.30

4

1.0

12

 

 

2

1

0.39

5

1.3

16

0.49

rapid

 

2

0.48

6

0.2

3

 

 

3

1

0.41

5

<0.05

<1

0.41

rapid

 

2

0.45

5

0.6

7

 

 

4

1

0.24

3

0.8

10

0.18

slow

 

2

0.24

3

0.5

6

 

 

5

1

0.09

1

2.2

27

0.16

slow

 

2

0.13

2

0.8

10

 

 

6

1

0.14

2

0.5

6

0.14

slow

 

2

0.10

1

0.7

8

 

 

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no data
1,6-hexamethylene diamine orally administered is rapidly excreted (within 10 h) in urine, with the eliminary half life being approximately 1.5 hours. Two excretion products were identified in hydrolysed urine: i.e. 1,6-hexamethylene diamine and 6-aminohexanoic acid. The fast acetylators excreted more HMD than the slow acetylators.
Executive summary:

1,6-hexamethylene diamine (HMD) was orally administered to six healthy volunteers. After acid hydrolysis of the urine by hydrochloric acid, HMD and the metabolite 6-aminohexanoic acid were quantified. In hydrolysed urine, a mean of 0.28 mg (range 1 to 6%) of the administered dose (8,2 mg) was recovered as parent compound, and a mean of 0.8 mg (range <1 to 27%) as 6-aminohexanoic acid. The urinary excretion of both the determined compounds was rapid, and the principal part (>90%) of the elimination was completed within 10 h. The eliminary half life determined was approx. 1.5 hours. There was a considerable inter-individual variation in the excreted amounts, but the intra-individual variation in the exaction of HMD was limited. The subjects N-acetylator phenotype was determined by a dapsone test. Three slow acetylators excreted lower amounts (mean 2% of given dose) of 1,6-hexamethylene diamine than three rapid ones (mean 5% of given dose).