Propiononitrile

Genetic toxicity: in vivo

Administrative data

Endpoint:

genetic toxicity in vivo, other

Remarks:

aneuplody in Drosophila

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1991

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:

Aneuploidy in Drosophila, IV. Inhalation studies on the induction of aneuploidy by nitriles

Author:

Osgood, C.
Bloomfield, M.
Zimmering, S.

Year:

1991

Bibliographic source:

Osgood, C., Bloomfield, M. & Zimmering, S., 1991. Aneuploidy in Drosophila, IV. Inhalation studies on the induction of aneuploidy by nitriles. Mutation Research/Genetic Toxicology, 259(2), pp.165–176.

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The Drosophila ZESTE system was used to monitor the induction of sex chromosome aneuploidy following inhalation exposure of adult females to proplonitrile

GLP compliance:

not specified

Type of assay:

other: Drosophila aneuplody test

Test material

Test material information

Constituent 1

Reference substance name:

Propiononitrile

EC Number:

203-464-4

EC Name:

Propiononitrile

Cas Number:

107-12-0

Molecular formula:

C3H5N

IUPAC Name:

propanenitrile

Specific details on test material used for the study:

Test chemicals were supplied by Radian Corpo- ration (Dallas, TX).

Test animals

Species:

Drosophila melanogaster

Strain:

not specified

Details on species / strain selection:

test females are of the genotype y z/y2 z f YL; spa(pol)
Adult females are mated with males of the genotype attached-X-Y, w; net.

Sex:

male/female

Details on test animals or test system and environmental conditions:

The standard chemical-treatment protocol em-
ployed adult females aged 2-3 days at the time of exposure (departures from tins protocol are de- scribed m Results). The females were lightly etherized and then transferred into 30-ml serum bottles capped with a rubber septum, 20 animals per bottle. When these fhes had fully recovered from etherlzation, 5 ~1 of appropriately diluted chemacal were spotted onto 0.5-cm diameter glass fiber filters which were lmmedmtely dropped into the serum bottles and the bottles capped with a septum and sealed with an aluminum collar. At the indicated time points, the bottles were un- capped and the flies shaken into empty glass vials for recovery.

Administration / exposure

Route of administration:

inhalation: vapour

Details on exposure:

It should be noted that the reported test concentrations may over- estimate the presented dose. In calculations of dose, we assumed that all the applied chemical volatilized w~thin the treatment period. To the extent that we could assess tins wsually, tins seemed to be the case as the treatment filters appeared completely dry within nunutes of their introduction into the treatment bottles. We as- sumed that the chermcals dispersed evenly within the air volume of the bottle (30 ml) and calculated the dose accordingly. Attempts to quantify the concentrations using gas chromatography were unsuccessful, because the chromatograph was not sufficiently sensitive to detect the low concentra-
tions used in these experiments.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

10 ppm (nominal)

Doses / concentrations 2

Dose / conc.:

30 ppm (nominal)

Doses / concentrations 3

Dose / conc.:

50 ppm (nominal)

Doses / concentrations 4

Dose / conc.:

70 ppm (nominal)

No. of animals per sex per dose:

20

Control animals:

yes, concurrent no treatment

Positive control(s):

none

Examinations

Evaluation criteria:

At the indicated time points, the bottles were un- capped and the flies shaken into empty glass vials for recovery. The paralyzing effects and time for recovery varied between chemicals and treatment times. The recovered females were then shaken into bottles with w; net males (20 of each sex per bottle) and permitted to deposit eggs for two days (Brood A), transferred to fresh bottles for a second two-day sampling (Brood B) and then discarded. F1 offspring were counted and scored for exceptions on days 10 through 17 following the establishment of a brood.

Statistics:

Statistical analyses of the data were carried out as described previously (Margohn et al., 1983; Zimmering et al., 1990).

Results and discussion

Test results

Sex:

male/female

Genotoxicity:

positive

Toxicity:

yes

Vehicle controls validity:

valid

Positive controls validity:

not examined

Additional information on results:

Propionltrlle was tested at 51 ppm and was found to induce aneuploidy after 50- and 70-mm exposures. Approximately equal numbers of chro- mosome gain and chromosome loss were re- covered when one examines the data pooled over time points. As was the case with acetonitnle, toxicity (45%) and sterility were induced by the 70-mm exposure, and the majority of exceptional offspring were recovered in Brood A. Proptonltrlle similarly induced a "knock-out" effect; approxi- mately 10 min were required to paralyze all animals at the presented dose of 51 ppm.

Any other information on results incl. tables

Virtually all exceptional offspring induced by acetonitrile and propionitnle were recovered in the first sampled eggs, corresponding to treated mature oocytes. Additionally, the time interval between treatment and sampling was shown to be important, suggesting rap~d loss or detoxifica- tion of the nltriles. Genetic analysis demonstrated that most aneuploids resulted from induced segregation errors during the first division of meiosis.

Whatever the cellular target(s) for the nitrlles may be in VlVO, it is clear that Drosophila is remarkably sensitive to this class of chemicals. In part this may reflect the fact that files freely inhale chemicals in the air through their spiracles, which In turn branch into extensive networks of trachea and trachioles that reach all cells, including those of the germline (Nikam and Khole, 1989). The extremely low doses that are effective in this orgamsm suggest an easily saturated cellular target the nature of which is unknown. Nxtriles are gen- erally weakly active in conventional genotoxlclty assays (Lambotte-Vandepaer and Duverger-van Bogaert, 1984; Galloway and Ivett, 1986). Thus, the ability to detect aneuploldy Induction by this class of chemicals underscores the importance of aneuploidy test systems.

Applicant's summary and conclusion

Conclusions:

The Drosophila ZESTE system was used to monitor the induction of sex chromosome aneuploidy following inhalation exposure of adult females to four nitriles: acetonltrile, proplonitrile, acrylomtrde and fumaromtnle. Propionitrlle was a highly effective aneuploidogen, inducing both chromosome loss and chromosome gain following brief exposures to low concentrations of these chemicals, and this nitrile also induced rapid paralysis.