Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Near-guideline study acceptable for assessment.
Justification for type of information:
Further information on the applicability of the read-across from various diamines to C12/14-diamine can be obtained from the document "Category polyamines - 20170314.pdf" added to IUCLID Ch. 13.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report Date:
2009

Materials and methods

Objective of study:
distribution
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Principles of method if other than guideline:
The rats were subjected for whole body autoradiography and sectioned sagittaly according to the standard method, (Ullberg 1977 and Ullberg et al 1982).
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: pellets
Details on test material:
Test item: 14C-Octadecyl diamine
Source: SELCIA LTD United Kingdom
Batch: 3 025AJL003 -1
Molar mass: 328.39
Radiochemical purity: 94.7% (Jan 30, 2009, as measured at Active Biotech) Specific radioactivity: 39.9 MBq/mL (1.08 mCi/mL)
To be stored under -15°

Cold test item
Product name: Duomeen HT, Chemical name: N-(Hydrogenated tallow)-1,3-diaminopropane
Source: Akzo Nobel Surfactants, Europe AB
Chemical name: N-(Hydrogenated tallow)-1,3-diaminopropane
CAS.No.: 68603-64-5
Batch: S000905
Colour: light Yellow
Melting Point: 45-50 °C
pH: basic
Purity: N-Alkyl -1 ,3 -diaminopropanes :90%
N-Alkyl-amines: 10%* 1
C-Chain-distribution (R=alkyl):
Expiry date: September 30, 2010
Storage :at room temperature (RT)
Safety Precautions: Routine hygienic procedures will be sufficient to assure personnel health and safety.

Radiolabelling:
yes
Remarks:
14C-Octadecyl diamine

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
Species: Rat
Strains: Sprague-Dawley
Supplier: Taconic, Denmark
Weight 150 g on arrival

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Dosing Sex Route
of adm. Dose Survival time
after admin.
µCi/kg
mg/kg
Period 1,
Rep, (6xcold,1 hot) low dose M p.o. 250/6.25 1h
Rep, (6xcold,1 hot) low dose M p.o. 250/6.25 4h
Rep, (6xcold,1 hot) low dose M p.o. 250/6.25 24h
Rep, (6xcold,1 hot) high dose M p.o. 250/62.5 1h
Rep, (6xcold,1 hot) high dose M p.o. 250/62.5 4h
Rep, (6xcold,1 hot) high dose M p.o. 250/62.5 24h

Period 2,
Rep, (2xcold,1 hot) high dose M p.o. 250/62.5 1h
Rep, (2xcold,1 hot) high dose M p.o. 250/62.5 4h
Rep, (2xcold,1 hot) high dose M p.o 250/62.5 24h

Period 3,
Single, low dose M p.o. 250/6.25 1 h
Single, low dose M p.o. 250/6.25 4 h
Single, low dose M p.o. 250/6.25 24 h
Single, high dose M p.o. 250/62.5 1 h
Single, high dose M p.o. 250/62.5 4 h
Single, high dose M p.o. 250/62.5 24 h
Duration and frequency of treatment / exposure:
Single application in two dose levels and with 3 survival time points.
Two daily repeated applications in the high dose level with "cold" test item followed by one application of radiolabeled test item on 3rd day and with 3 survival time points.
Six daily repeated applications in two dose levels with "cold" test item followed by one application of radiolabeled test item on 7th day and with 3 survival time points.
Doses / concentrations
Remarks:
Doses / Concentrations:
low dose: 6.25 mg/kg bw
high dose: 62.5 mg/kg bw
No. of animals per sex per dose:
6 for low dose
9 for high dose
Control animals:
no
Positive control:
no
Details on dosing and sampling:
The rats were anaesthetized by Sevoflurane, and then immediately immersed in heptane, cooled with dry ice to -70°C, according to ABR-SOP-0130. The frozen carcasses were embedded in a gel of aqueous carboxymethyl cellulose (CMC), frozen in ethanol, cooled with dry ice (-70° C) and sectioned sagittaly for whole body autoradiography, according to the standard method, (Ullberg et al 1982 and Ullberg 1977). From each animal 20 p.m sections were cut at different levels with a cryomicrotome (Leica CM 3600) at a temperature of about -20°C. The obtained sections were caught on tape (Minnesota Mining and Manufacturing Co., No. 810) and numbered consecutively with radioactive ink. After being freeze-dried at -20°C for about 24 hours, the sections were put on 14C-imaging plates (Fuji, Japan).

Sections were chosen for phosphor imaging (Amemiya Y et al 1987) to best represent the tissues and organs of interest. Together with a set of 4C calibration standards, the sections were then put on imaging plates. The imaging plates were exposed for 4-5 days enclosed in light tight cassettes at -20°C in a lead shielding box to protect from environmental radiation.
After exposure the imaging plates were scanned at a pixel size of 50 pm using BAS 2500 (Fuji Film Sverige AB, Sweden). The tissues and organs of interest were quantified using AIDA, version 4.19 (Raytest, Germany) (Ahr H.J. and Steinke W., 1994)
A water-soluble standard test solution of 14C-radioactivity was mixed with whole blood and used for the production of the calibration scale. The 14C calibration standards consisted of 10 dilutions from 289.5 to 3.559 kBq/g. For the purpose of quantification, it was assumed that all tissues had similar density and quench characteristics as that of whole blood. The tissue density was set to 1 g/mL. The limit of quantification was defined as the mean concentration value of eight measurements for background plus three times the standard deviation value of these measurements.
The various tissues and organs were identified either on the autoradiogram or on the corresponding tissue section.
Statistics:
Not applicable

Results and discussion

Main ADME resultsopen allclose all
Type:
distribution
Results:
Distribution was similar, independent of time points, doses or dose regimens. Highest tissue concentrations of radioactivity were registered in the intestinal mucosa, abdominal lymph nodes, liver, spleen, adrenal, myocardium and brown fat.
Type:
absorption
Results:
The labeled diamine seemed to be quite slowly absorbed from the gastrointestinal tract. The blood radioactivity was low and slightly above LOQ for the different doses and dose regimens.

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
Tissue distribution and tissue uptake
The test item showed quantifiable levels of radioactivity for most tissues at 4 and 24 hours but almost no radioactivity at 1hour.
The distribution pattern was similar for all animals independent of time points, doses or dose regimens.
The highest tissue concentrations of radioactivity were registered in the intestinal mucosa, abdominal lymph nodes, liver, spleen, adrenal, myocardium and brown fat.

Time dependence
The test item was slowly absorbed from the gastrointestinal tract, and blood radioactivity was low and slightly above LOQ.
The highest concentration of radioactivity was obtained at 24 hours for almost all tissues.

Dose dependence
Seven daily repeated applications of 6.25 mg/kg compared to corresponding daily applications of 62.5 mg/kg showed similar tissue to blood ratios at 4 hours.
At 24 hours the tissue to blood ratios were generally up to two times higher for the low dose compared to the high dose.
A single application of the low dose compared to the high showed similar tissue to blood ratios at 4 hours, but at 24 hours it showed two to three times higher tissue to blood ratios.

Single and repeated high dose dependence
Three daily applications of the test item compared to a single dose generally showed slightly higher tissue to blood ratios at both 4 and 24 hours.
Seven daily applications compared to a single application of the test item showed similar tissue to blood ratios at both 4 and 24 hours.
Seven daily applications of the test item compared to three, showed slightly lower tissue to blood ratios at both 4 and 24 hours.

Metabolite characterisation studies

Metabolites identified:
no

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
Distribution was similar, independent of time points, doses or dose regimens. Highest tissue concentrations of radioactivity were registered in the intestinal mucosa, abdominal lymph nodes, liver, spleen, adrenal, myocardium and brown fat.The labeled diamine seemed to be quite slowly absorbed from the gastrointestinal tract. The blood radioactivity was low and slightly above LOQ for the different doses and dose regimens.
Executive summary:

The aim of the study was to determine tissue/organ distribution of14C-Octadecyl diamineafter oral administration in the male rat using quantitative whole-body autoradiography. Specifically: the rats were given 62.5 or 6.25 mg/kg body weight of the test item by gavage, and were killed 1, 4 and 24 hours after the last administration.

Two daily repeated applications in the high dose level with "cold" test item followed by one application of radiolabeled test item on the 3rd day.

Six daily repeated applications in two dose levels with "cold" test item followed by one application of radiolabeled test item on the 7th day.

Generally, the distribution pattern was similar for all animals independent of time points, doses or dose regimens. The highest tissue concentrations of radioactivity were registered in the intestinal mucosa, abdominal lymph nodes, liver, spleen, adrenal cortex, myocardium and brown fat. All other tissues showed low or very low levels of radioactivity.

 

The labeled diamine seemed to be quite slowly absorbed from the gastrointestinal tract. The blood radioactivity was low and slightly above LOQ for the different doses and dose regimens. Furthermore, for almost all tissues the highest concentration of radioactivity was obtained at 24 hours after the administration.