Formaldehyde, oligomeric reaction products with aniline

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:

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

Test material information

Constituent 1

Reference substance name:

4,4'-methylenedianiline

EC Number:

202-974-4

EC Name:

4,4'-methylenedianiline

Cas Number:

101-77-9

Molecular formula:

C13H14N2

IUPAC Name:

4,4'-methylenedianiline

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 or test system 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 / concentration:

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.

Main ADME results

Main ADME results 1

Type:

excretion

Results:

During 96 h following i.v. dosing, 67.0 and 30.7% of doses were eliminated in urine and feces, respectively.

Main ADME results 2

Type:

distribution

Results:

At 6 h 24% of the dose was in the GI tract and 19% in the blood and tissue. The highest 14C-concentrations were demonstrated in the liver (9.5%, 4-9 times the blood level).

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