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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1981
Reference Type:
publication
Title:
Comparison of Subchronic inhalation toxicity of five Aliphatic Nitriles in rats.
Author:
Roloff V, Short R, Ribelin W and Dietich M
Year:
1985
Bibliographic source:
Toxicologist 5(1); p.30.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: Similar to OECD
Deviations:
yes
Remarks:
Exposure 5 days per week rather than 7 days per week
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
IUCLID4 Test Substance: as prescribed by 1.1-1.4
98.5% Acetone cyanohydrin, certificate of analysis

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
inhalation: gas
Duration of treatment / exposure:
28 days
Frequency of treatment:
6 hr/day, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
control, 9.2, 29.9, and 59.6 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
Exposure of male and female rats to doses of 0, 32, 104 and 208 mg/m3 acetone cyanohydrin in air. (minimum of 19
exposures). Whole animal exposures in 10m3 Rochester type inhalation chambers. Group sizes of ten male and ten female
rats.

Examinations

Observations and examinations performed and frequency:
Animals were observed during exposure and weighed and thoroughly examined for gross signs of toxicity weekly.
Overnight urine was analysed for thiocyanate. Blood (collected at necropsy) was analysed for basic hematological
parameters and a range of serum chemistry.
Sacrifice and pathology:
Animals were necropsied and selected tissues (adrenals, bone marrow,
heart, liver, kidneys, lungs, spleen, stomach, thyroid, trachea and nasal turbinates) examined microscopically.

Results and discussion

Results of examinations

Details on results:
Irritation of the eyes and or/nose and breathing difficulties in the mid (29.9 ppm) and high (59.6 ppm) exposure groups and hypoactivity in the high (59.6 ppm) exposure group were observed during exposure. Signs associated with anoxia/hypoxia, such as respiratory distress, tremors and/or
convulsions, foaming at the mouth, and prostrate were observed following the first exposure in four high exposure (59.6 ppm) males. Three of these animals subsequently died. Chromorhinorrhea and signs of irritation about the eyes were also observed at pre and post-exposure periods. All
hematologic, biochemical and relative organ weight changes were within the biological variation observed in the rat. Serum and urine thiocyanate were elevated in all exposure groups. No gross or microscopic lesions attributable to acetone cyanohydrin were observed.

Effect levels

open allclose all
Dose descriptor:
NOEC
Effect level:
9.2 ppm
Sex:
male/female
Basis for effect level:
other: Based upon irritation and breathing effects; Equivalent to 32 mg/m3
Dose descriptor:
LOEC
Effect level:
29.9 ppm
Sex:
male/female
Basis for effect level:
other: Equivalent to 104 mg/m3

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The deaths that occured in the high dose group happened after the first exposure and can therefore be assumed to be due to acute toxicity. This is consistent with the reported LC50 of 62.5 ppm and LC100 of 124 ppm (Smyth et al., 1962).


Potassium cyanide and sodium cyanide can be considered as a chemical category, along with hydrogen cyanide (HCN) and acetone cyanohydrin (ACH, also known as 2-hydroxy-2-methylpropanenitrile), based on structural similarity, similar physico-chemical properties and common breakdown/metabolic products in physical and biological systems. Particular attention is paid to the dissociation constant of HCN. In the vast majority of environmental and physiologic conditions, the cyanide salts will dissolve in water to form hydrogen cyanide. The physico-chemical hazards and toxicity result from the activity of this common proximal toxicant, HCN.An ECETOC Task Force, in the 2007 ECETOC Joint Assessment of Commodity Chemicals ( JACC ) Report No. 53, “Cyanides of Hydrogen, Sodium and Potassium, and Acetone Cyanohydrin (CAS No. 74-90-8, 143-33-9, 151-50-8 and 75-86-5)” supports the development of this chemical category. Hydrogen cyanide (Index No.006-006-00-X) and salts of hydrogen cyanides (Index No.006-007-00-5) are both listed in Annex VI,Table 3.1 of Regulation (EC) No. 1272/2008, entry 006-007-00-5, and are restricted in comparable ways taking into account physical characteristics. Thus, the assignment of potassium cyanide and sodium cyanide to a chemical category does not result in a less protective regulatory status.



Applicant's summary and conclusion

Conclusions:
A 28-day inhalation toxicity study was performed using acetone cyanohydrin in male and female Sprague/Dawley rats. Effects observed during exposure included Irritation of the eyes and or/nose and breathing difficulties in the mid (29.9 ppm) and high (59.6 ppm) exposure groups and hypoactivity in the high (59.6 ppm) exposure group. Signs associated with anoxia/hypoxia, such as respiratory distress, tremors and/or convulsions, foaming at the mouth, and prostrate were observed following the first exposure in four high exposure (59.6 ppm) males. Three of these animals subsequently died. Chromorhinorrhea and signs of irritation about the eyes were also observed at pre and post-exposure periods. All hematologic, biochemical and relative organ weight changes were within the biological variation observed in the rat. Serum and urine thiocyanate were elevated in all exposure
groups. No gross or microscopic lesions attributable to acetone cyanohydrin were observed. The NOEL (no effect level) based upon irritation and
breathing effects was established as 32 mg/m3 (9.2ppm).
Hydrogen cyanide (Index No.006-006-00-X) and salts of hydrogen cyanides (Index No.006-007-00-5) are both listed in Annex VI, Table 3.1 of Regulation (EC) No. 1272/2008, entry 006-007-00-5, and are restricted in comparable ways taking into account physical characteristics. Thus, the assignment of potassium cyanide and sodium cyanide to a chemical category does not result in a less protective regulatory status.