Acrylonitrile

Basic toxicokinetics

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:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

publication

Title:

Urinary excretion of mercapturic acids and thiocyanate in rats exposed to acrylonitrile

Author:

Tardif R, Talbot D, Grin M & Brodeur J

Year:

1987

Bibliographic source:

Toxicology Letters, 39: 255-261

Materials and methods

Objective of study:

excretion

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The study investigated the urinary excretion of acrylonitrile metabolites following inhalation, i.v. or i.p. exposure

GLP compliance:

not specified

Remarks:

: published study

Test material

Test material information

Constituent 1

Reference substance name:

Acrylonitrile

EC Number:

203-466-5

EC Name:

Acrylonitrile

Cas Number:

107-13-1

Molecular formula:

C3H3N

IUPAC Name:

prop-2-enenitrile

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

Male adult Sprague-Dawley rats

Administration / exposure

Route of administration:

other: inhalation (vapour), intravenous and intraperitoneal

Vehicle:

not specified

Details on exposure:

Rats were exposed to acrylonitrile vapour, or acrylonitrile was administered in a single dose i.v. or i.p.

Duration and frequency of treatment / exposure:

6 hours - inhalation

Doses / concentrations

Remarks:

Doses / Concentrations:
Inhalation: 0, 4, 20 or 100 ppm. i.v. or i.p.: 0.6-15 mg/kg bw

No. of animals per sex per dose / concentration:

5 males per group

Control animals:

yes, concurrent no treatment

Positive control reference chemical:

Not examined.

Details on study design:

The formation of urinary metabolites following exposure to acrylonitrile administered via 3 routes was determined

Details on dosing and sampling:

No further information

Statistics:

No information available

Results and discussion

Preliminary studies:

Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Not investigated in this study.

Details on distribution in tissues:

Not investigated in this study.

Details on excretion:

Following inhalation exposure:

Thiocyanate was the major metabolite identified in urine, with levels of excreted HMA being higher than levels of CMA. CMA represented only 8% of total urinary metabolites. As exposure levels of acrylonitrile increased, excretion of thiocyanate became relatively more important, as shown by the ratio of excreted thiocyanate to the sum of CMA and HMA, rising from 0.47 at 4 ppm to 0.89 at 20 ppm, and 2.93 at 100 ppm.

Following i.v. or i.p. administration:

CMA represented 74-78% of metabolites excreted in the urine. Levels of thiocyanate excreted were low.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Thiocyanate was the major metabolite following inhalation exposure, with levels of excreted HMA being higher than levels of CMA. In contrast, CMA represented 74-78% urinary metabolites following i.v. or i.p. administration.

Any other information on results incl. tables

Inhalation exposure

Following inhalation exposure, 15% of the inhaled acrylonitrile was excreted as thiocyanate - this was identified as the major urinary metabolite. Levels of excreted 2-hydroxyethylmercapturic acid (HMA) were higher than levels of 2-cyanoethylmercapturic acid (CMA; 8% of total urinary radioactivity). As exposure levels increased, the excretion of thiocyanate became relatively more important as shown by the ratio of excreted thiocyanate to the sum of CMA and HMA at 4 ppm (0.47), 20 ppm (0.89) and 100 ppm (2.93).

Intravenous / intraperitoneal dosing

CMA represented 74-78% of total urinary metabolites follwoing iv and ip dosing; in contrast the urinary levels of excreted thiocyanate were low.

Applicant's summary and conclusion

Conclusions:

The results of this study indicate that the metabolic profile of acrylonitrile in the rat is different following inhalation exposure or parenteral administration. Findings indicate that the metabolism of acrylonitrile via conjugation with glutathione is the predominant pathway following parenteral administration, whereas cytochrome P450- oxidation (via CEO and generating thiocyanate) is the predominant pathway following inhalation exposure.

Executive summary:

The authors investigated the urinary metabolism of acrylonitrile in the rat, following exposure by different routes. Adult male Sprague-Dawley rats were exposed acutely to acrylonitrile using different routes of administration: inhalation (6 hour exposure), intravevous or intraperitoneal injection. Urinary metabolites measured at 24 hours after administration were identified as 2-cyanoethylmercapturic acid (CMA), 2 -hydroxyethylmercapturic acid (HMA) and thiocyanate. In all experiments the relationship between excretion of total urinary metabolites and the degree of exposure was reasonably linear. However, there was a marked influence of the route of administration on the pattern excretion. Following i.p. and i.v. injection, CMA was the most important metabolite while after inhalation it was thiocyanate. The results of the study indicate an important effect of the dose on the metabolism and excretion of acrylonitrile.