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Toxicological information

Basic toxicokinetics

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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: Meets generally accepted scientifical standards, well documented and acceptable for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

Objective of study:
distribution
excretion
Principles of method if other than guideline:
9 male Fischer rats were exposed intravenously to 2 mg/kg labeled 14C-MDA. Excreta and urine was collected after 6, 12, 24, 48, 72, and 96 h. After various time points rats were sacrificed and tissue distributon was determined.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- unlabeled MDA (Aldrich Chemical Company)
- Ring-labeled 14C-methylenedianiline was prepared by the radiochemical synthesis section of MRI. The compound was received as the free base (3.2 mCi) in 100% ethanol or as the hydrochloride (8.18 mCi) with a specific activity of 14.8 mCi/mmol.
Radiochemical purity: >99% (analysed by HPLC and TLC)
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
- Adult rats were purchased from Charles River Laboratories, North Wilmington, Massachusetts.
- Housing: 10-15 air changes per hour in polycarbonate cages
- Temperature/humidity: 72°C ±2/50% ±10
- 12h-Light/dark cycle
- Acclimatisation time: 7 days
- Diet: Purina Certified Rodent Chow (Ralston Purina Company)
- Drinking water ad libitum
- Weight: 149-218 g

Administration / exposure

Route of administration:
intravenous
Vehicle:
other: ethanol/water (1:4)
Duration and frequency of treatment / exposure:
single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
2 mg/kg bw (0.4 ml per animal)
No. of animals per sex per dose:
9 male rats
Control animals:
no
Details on study design:
Rats were treated and placed in individual metabolism cages.
Details on dosing and sampling:
Dosing was performed through the saphenous vein.
Excreta was collected after 6, 12, 24, 48, 72, and 96 h following administration. Three animals were sacrificed at 6, 24, and 96 h for tissue sampling. Urine was collected in containers kept on dry ice. After collection cages were rinsed and cage washings were analyzed. The animals were sacrificed and blood, tissue and organs were removed. Tissue and organs were washed with saline, blotted with absorbing paper, weighed and prepared for radiochemical analysis. All samples were kept on dry ice during necropsy.

Results and discussion

Preliminary studies:
In a preliminary study (data not shown) the appropriate sampling times were selected and the methods of treatment and sampling determined.
In 3 rats most (approx. 95%) of the i.v. dose was eliminated in urine and feces during a 96-h period following dosing.

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
Significant amounts of radioactivity (24% at 6h) were recovered in the GI tract, probably through the bile. Blood and tissue contained 19% of the doses at 6h, but their 14C contents declined to 2% of the doses at 96h. The highest 14C-concentrations were demonstrated in the liver (9.5%, 4-9 times the blood level).
Details on excretion:
Total recoveries in excreta and tissue averaged 98.3, 98.1, and 99.3% at 6, 24, and 96 h after dosing.
During 96 h following i.v. dosing, 67.0 and 30.7% of doses were eliminated in urine and feces, respectively.

Metabolite characterisation studies

Metabolites identified:
not specified
Details on metabolites:
No data

Any other information on results incl. tables

Table 1: Recovery of radioactivity in rats treated i.v. with 4,4´-MDA.

recovery

Percent of dose

dose

0.4 mg/rat, i.v

time

6h

24h

96h

 blood

 2.8

0.44 

0.22 

 tissue

 16.6

4.33 

1.31 

 GI tract

 23.94

4.14 

0.11 

 urine

 54.65

67.35 

66.96 

 feces

 0.28

21.79 

30.66 

 total absorbed

 98.27

98.06 

99.25 

 dose wash

 -

 application area

 -

 recovery

 98.27

98.06 

99.25 

Table 2: Radioactivity in blood, tissue, and excreta of rats at 6 and 96 h following intravenous dose (0.4 mg) of 14C-MDA.

 n=3  % of dose (6h) % of dose (96h)
 Blood 2.8  0.22 
 Plasma 1.97  0.10 
 RBCs 0.55  0.09 
 Liver 9.47  0.86 
 Kidney 0.48  0.03 
 Lungs 0.26  0.02 
 Brain 0.08  0.00 
 Spleen 0.09  0.02 
 Testes 0.26  0.00 
 Adrenals 0.01  0.00 
 Bladder 0.00  0.00 
 Muscle 2.77  0.21 
Fat -
GI tract 23.94  0.11 
 Nontreated skin 3.19  0.16 
 Urine 54.65 66.96 
 Feces 0.28 30.66 
 Dose wash
 Application area
 Recovery 98.27  99.25 
 

Applicant's summary and conclusion