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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication based on scientific principles, part of a comprehensive test programme (Rohm & Haas)

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1995

Materials and methods

Objective of study:
metabolism
Principles of method if other than guideline:
Metabolic in-vitro studies on tissue slices and homogenates from rats (F344 and Sprague Dawley), using 1-14C-labelled AA. The rate of oxidation [expressed as nmol CO2/h per g tissue or mg protein and kinetic parameters (pseudo-Km and Vmax) were determined.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Acrylic acid
- Analytical purity: 98 %
- Supplier: Rohm and Haas Company

- Radiochemical purity (if radiolabelling): > 98 % and 95 %, respectively
- Specific activity (if radiolabelling): 0.1-0.5 mCi/mmol and 1.44 mCi/mmol, respectively
- Locations of the label (if radiolabelling): [1-14C]Acrylic acid
- Supplier: Sigma Chemical Co. (St. Louis, MO) and Chemsyn Science Laboratories (Lenexa, KS), respectively
Specific details on test material used for the study:
- Name of test material (as cited in study report): Acrylic acid
- Analytical purity: 98 %
- Supplier: Rohm and Haas Company

- Radiochemical purity (if radiolabelling): > 98 % and 95 %, respectively
- Specific activity (if radiolabelling): 0.1-0.5 mCi/mmol and 1.44 mCi/mmol, respectively
- Locations of the label (if radiolabelling): [1-14C]Acrylic acid
- Supplier: Sigma Chemical Co. (St. Louis, MO) and Chemsyn Science Laboratories (Lenexa, KS), respectively
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
other: Fischer 344 and Sprague Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Wilmington, MA)
- Weight at study initiation: 249 ± 50 g (Fischer 344); 386 ± 120 g (Sprague-Dawley)
- Housing: 1-2 per cage
- Diet (ad libitum): Purina Certified Lab Chow Checkers (Purina, St. Louis, MO)
- Water: ad libitum

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
other: The kidney and liver were the organs showing the highest oxidation rates. All tissues were able to oxidize AA to a certain extent. Lung, glandular stomach, heart, spleen, small and large intestine oxidized AA at rates that were between 10 and 40 %.
Toxicokinetic parameters:
other: Oxidation of AA in Fischer 344 rat kidney and liver slices were described by pseudo MIchaelis-Menten kinetics. The pseudo Km value did not vary between kidney and liver: ca. 0.5 mM. However, the pseudo Vmax in kidney was approx. twice the value in liver.

Any other information on results incl. tables

The kidney and liver were the organs showing the highest oxidation rates, with maximal velocities of 4 and 2 µmol/h/g, respectively. The metabolic conversion rate was similar in both strains with no difference between slice model and homogenate. All tissues were able to oxidize AA to a certain extent, but with considerable variation. Lung, glandular stomach, heart, spleen, small intestine and large intestine oxidized AA at rates that were between 10 and 40 % of the rate measured in liver. The remaining tissues (forestomach, brain, skin, fat, and muscle) oxidized AA at less than 10 % of the rate observed in the liver.

Compared to the mouse (see Black et al., 1993), the absolute rates per g tissue in the rat are 2 - 3 x higher than in the mouse.

Oxidation of AA in Fischer 344 rat kidney and liver slices were described by pseudo MIchaelis-Menten kinetics. The pseudo Km value did not vary between kidney and liver: approx. 0.5 mM. However, the pseudo Vmax in kidney was approx. twice the value in liver. At relatively low concentrations, i.e. well below km, AA oxidation would follow apparent first-order kinetics, and the half-life of AA in liver and kidney would be approx. 10 min or less.

AA tissue-to-blood partition coefficients were measured in homogenates by micropartitioning. Relatively little variation between tissues in the partition coefficient was observed, with values ranging between 0.9 (fat) and 2.1 (brain).

Applicant's summary and conclusion