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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Subacute and chronic action of acrylonitrile on adrenals and gastrointestinal tract: biochemical, functional and ultrastructural studies in the rat
Author:
Szabo S, Gallagher GT, Silver EH, Maull EA, Horner HC, Komanicky P, Melby JC, McComb DJ & Kovacs K
Year:
1984
Bibliographic source:
J Appl Toxicol. 1984, Jun; 4(3):131-40

Materials and methods

Principles of method if other than guideline:
The authors carried out a number of studies in order to elucidate the sub-acute and chronic actions of acrylonitrile on the adrenals, stomach, and duodenum of experimental animals by correlation of biochemical, functional, and morphological findings, and to gain insight into mechanisms of action.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Acrylonitrile
EC Number:
203-466-5
EC Name:
Acrylonitrile
Cas Number:
107-13-1
Molecular formula:
C3H3N
IUPAC Name:
acrylonitrile

Test animals

Species:
rat
Strain:
not specified
Sex:
female

Administration / exposure

Route of administration:
other: drinking water and gavage
Vehicle:
water
Details on oral exposure:
Rats were exposed to 0, 0.0001% (1 ppm), 0.002%, 0.01%, 0.05% or 0.2% acrylonitrile in drinking water, or to the same amount of the chemical given through daily gavage, for 7, 21 or 60 days.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
7, 21 or 60 days
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.0001%, 0.002%, 0.01%, 0.05%, 0.2%
Basis:
nominal in water
No. of animals per sex per dose:
3-5 (females)
Control animals:
yes, concurrent vehicle

Results and discussion

Effect levels

Dose descriptor:
NOAEL
Effect level:
4 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Treatment-related effects occurred consistently at the 100 ppm level via drinking water, with 20 ppm representing a NOAEL (equivalent to an intake of 4 mg/kg bw/d).

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

In general, no overt signs of intoxication was noted and mortality only occurred in the 2000 ppm dose group, in which 2/18 rats died from severe bilateral adrenal hemorrhage and necrosis. Decreased water and food intake was observed in both the 2000 and the 500 ppm drinking water groups and following 100 mg/kg bw twice daily by gavage. Adrenal weights were decreased in 7, 14, and 21 day studies in rats receiving 500 and 2000 ppm in drinking water, accompanied in the 2000 ppm group by polyuria. Pair-fed controls to the 2000 ppm group also showed a decreased relative adrenal weight, but urinary output was normal. However, animals given the equivalent of 2000 ppm (100 mg/kg bw twice daily) by gavage showed an enlargement of the adrenals, again accompanied by polyuria. Following 60 days administration in drinking water, there was also a significant increase in adrenal weight that was particularly prominent in the group given 60 mg/kg bw (equivalent to 500 ppm) daily. Histological examination of the adrenals from rats administered 500 and 2000 ppm in drinking water for 7, 14, or 21 days revealed atrophy in the adrenal cortex (especially the zona fasciculata). In contrast, cellular hyperplasia with normal size or slightly shrunken cells was seen in the adrenals from rats given equivalent amounts by gavage and in animals administered 500 ppm in drinking water for 60 days.

Plasma levels of corticosterone showed a dose-dependent decrease in rats administered 100, 500 or 2000 ppm in drinking water, with larger decreases being seen when acrylontrile was administered by gavage. The decrease noted in the 2000 ppm group (14 days administration) was even more marked in pair-fed controls. Plasma aldosterone levels were less affected by administration of acrylonitrile Effects were only seen at high levels and after prolonged exposure. A significant decrease was observed only after administration by gavage of 60 mg/kg bw for 60 days.

Other effects reported in these studies were increased liver weights following a 21-day administration period, with a decrease being reported after 60 days. Kidneys were enlarged in the 100 ppm group after 60 days of administration and in the 500 ppm group after 21 days. Hyperplasia was observed in regions of the gastric mucosa of rats receiving 100 and 500 ppm in drinking water for at least 21 days. Treatment-related effects occurred consistently at the 100 ppm level via drinking water, with 20 ppm representing a NOAEL (equivalent to an intake of 4 mg/kg bw/d).

Applicant's summary and conclusion

Conclusions:
The results suggest that the effects of acrylonitrile on the adrenals were in part attributable to its inherent toxicity and the consequences of decreased food and especially water intake (probably due to its unpalatability in drinking water even at 20 ppm).
Executive summary:

The stated aim of this study was to investigate the sub-acute and sub-chronic toxicity of acrylonitrile to the adrenals, stomach and duodenum by correlating biochemical, functional and morphologic investigations, and to elucidate the mechanism of toxicity of acrylonitrile. Rats were exposed to 0, 0.0001% (1 ppm), 0.002%, 0.01%, 0.05% or 0.2% acrylonitrile in drinking water, or to the same dose level administered by gavage, for 7, 21 or 60 days. Acrylonitrile caused a time- and dose-dependent decrease in plasma corticosterone levels; aldosterone was affected only by the high dose level and prolonged time of exposure. Young rats were noted to be more susceptible than adults to this action of acrylonitrile. The adrenal cortex, especially the zona fasciculata, was atrophic in rats exposed through drinking water. At dose levels of 0.05% and 0.2%, administration also caused decreased food intake and body weight gain. The adrenals were enlarged with a hyperplastic zona fasciculata after daily gavage doses of acrylonitrile. Ingestion of the chemical did not interfere with compensatory enlargement of the adrenal gland following unilateral adrenalectomy. On the other hand, the ACTH-induced elevation of corticosterone plasma concentration was significantly attenuated by acrylonitrile in drinking water. Electron microscopy of the adrenal glands revealed no consistent changes in the steroid-producing cells. The authors postulate that accelerated turnover of circulating corticoids and/or interference with the secretion or action of ACTH may primarily be responsible for the decreased plasma levels of corticosterone and aldosterone in rats that ingest acrylonitrile. The mucosa in the stomach at the junction of the forestomach and glandular region of animals that had ingested acrylonitrile was hyperplastic. The corpus also showed regional mucosal hyperplasia. Changes were associated with an elevated concentration of non-protein sulphydryls mostly in the mucosa of the glandular stomach. A similar, less prominent elevation also occurred in the proximal duodenum. The results of the study suggest that the effects of acrylonitrile on the adrenals were in part attributable to its inherent toxicity and the consequences of decreased food and especially water intake (probably due to its unpalatability in drinking water even at 20 ppm)