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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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented, acceptable publication

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1995
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
Disposition and metabolism of Acrylic acid (AA) in Fischer 344 rats after single oral administration.
GLP compliance:
yes

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 % (unlabeled AA)
- Supplier: Union Carbide Corporation

- Radiochemical purity (if radiolabelling): >= 98.6 %
- Specific activity (if radiolabelling): 0.14 - 0.4 mCi/mmol
- Locations of the label (if radiolabelling): [1-14C]AA
- Supplier: Sigma Chemical Co. (St. Louis, Mo.)
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Kingston, NY)
- Substrain: F344/NHsd
- Age at study initiation: approx. 7 wk old
- Weight at study initiation: 210 g
- Diet (ad libitum): Agway Prolab Diet Rat, Agway Inc., Syracuse, NY
- Water (ad libitum)

- Individual metabolism cages: no

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
- Vehicle: Milli-Q filtered water at a final concentration of 4 or 15 mg/mL
- Dosing volume: 10 mL/kg bw
Duration and frequency of treatment / exposure:
once
Doses / concentrations
Remarks:
Doses / Concentrations:
40 and 150 mg/kg bw
No. of animals per sex per dose:
15
Control animals:
no
Details on study design:
- Dose selection rationale: The oral dose of 40 mg/kg bw was selected for comparison to previous work on the disposition of [2,3-14C]AA in Sprague-Dawley rats (de Bethizy et al. 1987) and the 150 mg/kg bw dose was selected since a similar oral dose induced slight, acute gastric irritation in Fischer 344 rats (Ghanayem et al. 1985).
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, plasma, stomach contents (after sacrifice)
- Time and frequency of sampling: Urine was collected under dry ice and faeces were collected at room temperature at 8, 24, 48, and 72 h. At 1 and 8 hrs, 5 animals from ech group were sacrificed and blood samples collected. Tissues were sampled at termination (liver, kidney, fat, stomach).
- Traps for volatile compounds:
Room air was drawn through the metabolism cages at a rate of approximately 500 mL/min. Expired 14CO2 was collected in traps containing a solution of 2-methoxyethanol : ethanolamine (7:3, v/v), which was replaced with fresh solution at regular intervals. Other exhaled volatile 14C-labeled organic compounds were collected onto activated charcoal traps (approximately 4 g) placed in series ahead of the 14CO2 traps.







Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
In Fischer 344 rats, AA was rapidly absorbed and eliminated after single oral doses of either 150 or 40 mg/kg bw. Exhalation of 14CO2 was the major route of elimination, accounting for approximately 80-90% of the administered dose (94% of recovered radioactivity) after either dose level. This process was rapid and nearly complete within 8 h after administration of 40 mg/kg and within 24 h after 150 mg/kg. The somewhat slower rate of 14CO2 exhalation after the latter dose appeared to reflect slower absorption of the bolus dose.
Details on distribution in tissues:
AA-derived radioactivity was rapidly eliminated from stomach tissue, plasma, liver, and kidney, while elimination of radioactivity from fat was somewhat slower. Less than 2% of the dose remained in tissues or carcass 72 h after dosing.
Details on excretion:
Urinary excretion accounted for about 3-4% of the dose, with most occurring over the first 24 h. Excretion in faeces accounted for less than 0.2% of the dose. Only trace amounts of exhaled organic volatile compounds other than 14CO2 were detected.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Urine collected from rats after the oral route was analyzed by HPLC for AA and metabolites. Several peaks of radioactivity were detected by HPLC and were designated according to their order of elution in urine samples from rats dosed orally with 40 mg/kg bw. Trace amounts of material that coeluted with AA were detected in urine of orally dosed rats. The major metabolite eluted early in the gradient and accounted for about 2-3% of the oral dose (identy unknown). A metabolite that coeluted with 3-hydroxypropionic acid was also detected. Small amounts of several other metabolites more polar than AA were detected, as well as small amounts of two metabolites that were less polar than AA.
Plasma and liver from orally dosed rats were also analyzed for AA and metabolites by HPLC. One hour after dosing, a metabolite in plasma that coeluted with 3-hydroxypropionic acid accounted for about 0.5% of the dose after 40 mg/kg. This metabolite was also detected in plasma after the high dose, but the levels were variable. The polar metabolite, which was also the major urinary metabolite, was the major metabolite found in the liver 1 h after 150 mg/kg and was the only metabolite in liver after 40 mg/kg. After the high dose, peaks corresponding to 3-hydroxypropionate and a small amount of AA were detected. Neither AA nor metabolites were detected in plasma or liver at times later than 1 h, nor were they detected in kidney at any time after administration.

Any other information on results incl. tables

Disposition of radioactivity in Fischer 344 rats after oral administration of [1 -14C]AA:

Dose

150 mg/kg bw

40 mg/kg bw

Exhaled 14CO2

81.6 ± 1.8

90.3 ± 1.0

Exhaled volatiles

0.2 ± 0.4

0.1 ± 0.2

Urine

4.2 ± 1.0

2.9 ± 0.2

Faeces

0.6 ± 0.1

0.7 ± 0.0

Cage wash

0.2 ± 0.2

0.2 ± 0.1

Tissues

0.3 ± 0.1

0.3 ± 0.2

Carcass

1.0 ± 0.2

0.8 ± 0.1

Total recovery

88.1 ± 2.0

95.2 ± 0.9

The less than complete recovery of the administered doses is probably explained by the volatile nature of acrylic acid and its propensity to bind to materials such as plastic and glass, properties that may also be shared by some of the metabolites of acrylic acid.

Applicant's summary and conclusion