Reaction mass of 7-azatridecane-1,13-diamine and hexamethylenediamine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

No data

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Only short study summary available (lots of data missing: number of animals, precise dose administered, precise data (mean ± SD) on urine analysis, data on test material (purity...), metabolites not fully identified).

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1983

Materials and methods

Objective of study:

distribution

excretion

metabolism

Principles of method if other than guideline:

Analysis of distribution of radiolabelled test material by radioactivity quantification in selected organs after a single oral administration (after 72 h).
Analysis of distribution of radiolabelled test material by autoradiography after a single intravenous injection (after 1 h and 24 h).
Analysis of urine metabolites after a single oral administration or radiolabelled test material.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Hexamethylenediammonium dichloride

EC Number:

227-977-8

EC Name:

Hexamethylenediammonium dichloride

Cas Number:

6055-52-3

IUPAC Name:

hexane-1,6-diamine dihydrochloride

Details on test material:

- Name of test material (as cited in study report): 1,6-diaminohexane; hexamethylenediamine; 1,6-hexamethylenediamine-1,6-[14C]dihydrochloride (radiolabelled substrance)
- Specific activity: 30 mCi/mmol
- Source: Midwest Research Institute (Kansas City, MO)

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Kingston, NY
- Weight at study initiation: 200-250 g
- Housing: hanging wire cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): NIH-07 rodent diet (Zeigler Bros., Gardners, PA), ad libitum
- Water (e.g. ad libitum): tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 1 °C
- Humidity (%): 50
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

No data

Duration and frequency of treatment / exposure:

single dose

Doses / concentrations

Remarks:

Doses / Concentrations:
Experiment 1: 0.4 mg/kg corresponding to 25 µCi/250 g body weight (oral administration)
Experiment 2: 100 µCi/animal (intravenous injection)
Experiment 3: 100-200 µCi

No. of animals per sex per dose / concentration:

Experiment 1: 4 males for oral exposure
Experiment 2: 2 males and 2 females for intravenous injection
Experiment 3: male rats, No. not specified

Control animals:

no

Positive control reference chemical:

No

Details on study design:

No data

Details on dosing and sampling:

+ Oral exposure:
- Dispositions testing - the animals were placed in metabolism cages, and excreta, including expired air, were collected for 72 h. Then, the animals were killed and selected tissues, as well as the carcass, were analyzed for residual radioactivity (tissues were homogenized and after further treatment radioactivity was determined using a scintillation counter).
- Analysis of urine - urine was collected on dry ice for approx. 24 hours and analysed by HPLC and TLC. Samples were injected into a column, chromatography was run using a 45-65% methanol gradient containing 25ml/l PIC-B7 (Waters) over a 7 minute period. Fractions were collected every 0.2 minutes and counted in a scintillation counter. Urine samples were also spotted on TLC plates, after further processing radioactivity was determined using a TLC scanner.

+ Intravenous injection: Male and female rats were administered 100 µCi of test material, and one animal of each sex was killed at 1 h and at 24 h post-injection. Sections were prepared as described by Irons and Gross and analyzed by whole-body autoradiography (exposed for either 1 week (1-h animals) or for 10 days (24-h animals)).

Statistics:

None

Results and discussion

Preliminary studies:

No data

Toxicokinetic / pharmacokinetic studies

Details on absorption:

no data

Details on distribution in tissues:

The prostate contained the highest concentration of radioactivity 72 h after oral administration (table 1). Whole-body autoradiography showed that 1 h after injection, the intestine contained the greatest amount of radioactivity in a male rat followed by liver and kidney. The prostate gland was well below the liver in intensity of radiolabel. There was little radioactivity in the brain or testes. At 24 h post injection, the prostate gland contained the greatest concentration of radioactivity followed by intestine and liver. Thus, radiolabelled material either accumulates slowly in the prostate or persists in that gland for a relatively long time.
The uterus of the female rat was found to have a high concentration of radiolabel 1 h after injection but not 24 h afterwards. The accumulation of radiolabel in the uterus may be dependent on the estrous cycle. Little radioactivity was found in the ovary at either time period.

Details on excretion:

The principal route of elimination of radioactivity following oral administration was the urine (47% of the dose). About 20% of the administered radioactivity was excreted as C02 over a 72-h period while the feces contained 27%. Very little radioactivity was retained by the animals 72 h after treatment (<1.5%).

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Urine samples from treated animals were analyzed by HPLC and TLC and were observed to contain two major peaks of radioactivity. One of these, comprising 30% of the total radioactivity in the urine, comigrated with authentic 1,6-diaminohexane in both chromatographic systems.

Any other information on results incl. tables

Tissue distribution of residual radioactivity 72 h after oral administration of radiolabelled 1,6-diaminohexanedihydrochloride

Tissue or fluid	Concentration of radiolabel (mean ± SD of 4 male rats in nmol equiv./g tissue or fluid)
Prostate	250 ± 30
Intestine	113 ± 8
Kidney	194 ± 27
Liver	171 ± 26
Spleen	82 ± 13
Testes	64 ± 8
Lungs	77 ± 11
Head	51 ± 8
Brain	25 ± 6
Blood	31 ± 5

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Following oral administration of 1,6-Hexamethylenediamine-1,6-[14C]dihydrochloride to male Fischer-344 rats, about 20% of the administered dose was recovered as CO2 after 72 h. Urinary and fecal excretion accounted for 47% and 27% of the administered radioactivity, respectively.

Executive summary:

Following oral administration of 1,6-Hexamethylenediamine-1,6-[14C]dihydrochloride (HDDC) as salt of HMD, to male Fischer-344 rats, about 20% of the administered dose was recovered as CO2 after 72 h. Urinary and fecal excretion accounted for 47% and 27% of the administered radioactivity, respectively. Two peaks were found in urine with one of them, corresponding to 30 % of total radioactivity in urine and comigrating with 1,6-diaminohexane.