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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-documented publication which meets basic scientific principles.

Data source

Reference Type:
Comparative Toxicities of Aliphatic Nitriles
Bibliographic source:
Toxicol. Letters, 12: 157-163

Materials and methods

Objective of study:
other: tissue markers of nitrile exposure
Principles of method if other than guideline:
Comparison of aliphatic nitrile and potassium cyanide as related to cyanide release, cytochrome c oxidase inhibition and extent of glutathione depletion.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
- Name of test material (as cited in study report): Acetonitrile
- Analytical purity: Purity was established using a gas chromatograph equipped with FID and chromosorb 102 column (80-100 mesh) using the temperature gradient of 80 degree -150 degree C.
- Supplier: Aldrich Chemical Co. (Milwaukee, WI).

Test animals

Details on test animals or test system and environmental conditions:
- Source: Charles River, Wilmington, MA
- Weight at study initiation: 150-200 g
- Fasting period before study: Overnight
- Diet: Purina Rat Chow ad libitum
- Water: ad libitum
- Acclimation period: one week prior to dosing

Administration / exposure

Route of administration:
oral: gavage
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Dosing solutions of aliphatic nitriles or potassium cyanide were prepared in 0.9070 sodium chloride immediately before treatment.

Duration and frequency of treatment / exposure:
Single dose
Doses / concentrations
Doses / Concentrations:
LD50 dose (2460 mg/kg) of acetonitrile administered.
No. of animals per sex per dose / concentration:
Control animals:
yes, concurrent vehicle
Details on study design:
- Observation period: 1 hour post-dose
- Sacrifice: Yes, decapitation after 1 hour observation period.
- Tissues: Liver, kidney, brain and gastric content were collected, frozen immediately in liquid nitrogen, and stored at 30 °c until the time of analysis.
- Blood: blood was collected by completely draining the decapitated animals into heparinized tubes.
- Behavioral Observations: external animal behavior was closely observed and the physiological changes were graded on a scale of 1<2<3<4.

Tissue and blood cyanide (CN-) levels were determined according to the conway diffusion method described by Pettigrew and Fell [13]. Activities of cytochrome c oxidase in tissue homogenates were determined according to the method described by Cooperstein and Lazarow [14] by following the decrease in absorbance at 550 nm due to oxidation of ferrocytochrome c by cytochrome c oxidase. Levels of soluble sulfhydryl in tissue homogenates were determined colorimetrically using Ellman's reagent [15].
Statistical analysis was carried out using Student's-test as a test of null hypothesis with P < 0.05 considered significant.

Results and discussion

Main ADME results
Cytochrome c oxidase activity and GSH levels of brain, liver and kidney of rats were not remarkably affected 1 hour after administration of an oral LD50 dose of acetonitrile, although cyanide levels were increased in these tissues.

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
Cyanide levels 1 hour after oral LD50 administered (means +/- S.D. of 6 animals)
Brain: 28 ± 5 ug/g
Liver: 16 ± 6 ug/g
Kidney: 102 ± 39 ug/g
Details on excretion:
Gastric secretion was 0.24 (+/-) 0.05 ml

Any other information on results incl. tables

The LD50 of acetonitrile, 2460 mg/kg, was provided by Union Carbide.

Cytochrome c Oxidase Activities 1 h After Oral LD50 of Acetonitrile:

Liver: Activity(a) 0.97 ± 0.046 / %Control 96

Kidney: Activity(a) 1.6 ± 0.22 / %Control 102

Brain: Activity(a) 1.64 ± 0.21 / %Control 92

(a(delta) log [ferrocytochrome c] per min for a 1: 100 tissue dilution. Values are means ± S.D. of 6 animals.)

GSH Levels in Liver, Kidney, and Brain 1 h after Oral LD50 of Acetonitrile:

Liver: 1.19 ± 0.17 / %Control 96

Kidney: 708 ± 64 / %Control 102

Brain: 336 ± 20 / %Control 97

Applicant's summary and conclusion

It appears from our results that in the rat the toxic expressions of aliphatic nitriles depend not only upon cyanide liberation but also on their chemical structure. Substantial concentrations of CN were found in the livers, kidneys and brains of all the animals treated with all the aliphatic nitriles and KCN. Concentrations of CN- in livers were consistently higher than those in kidneys and brains, but considerable variation was noted among nitriles.
Executive summary:

Ahmed et al (1982) reported that cytochrome c oxidase activity and GSH levels of brain, liver and kidney of rats were not remarkably affected 1 hour after administration of an oral LD50 dose of acetonitrile, although cyanide levels were increased in these tissues.