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Toxicological information

Acute Toxicity: inhalation

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Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Similar to a guideline study, but precedes development of OECD protocols. Well documented study performed in a laboratory wthe significant expertise in inhalation toxicology.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981
Report Date:
1981

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
precedes establishment of guideline
Deviations:
yes
Remarks:
no data on characterization of material; no necropsies performed, however, some clinical chemistry data was obtained.
GLP compliance:
no
Remarks:
precedes establishment of GLP standards, but is of high quality
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Hydrocyanic acid gas, Matheson Gas Products Co., Haskell No. 13,697.

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male
Details on test animals and environmental conditions:
Test Animals: Rats were housed in pairs in stainless steel cages with food and water available ad libitum The animal room temperature (26 oC), humidity (60-70%) and light cycle (7 AM 0 5 PM) were controlled automatically. After a quarantine and acclimatization period, rats weighing 250 ± 25 g were selected for the test exposures. During the exposure, rats were either restrained in whole body holders and exposed head only to the test gas, or were allowed free movement inside the chamber. During some exposures, restrained and unrestrained rats were exposed simultaneously.

For selected non-lethal exposures, polyethylene cannulas were placed in the femoral arteries of rats anesthetized with 50 mg/kg sodium pentobarbital. The cannulated rats were caged individually and used after a 24-hour post-surgery recovery peiod.

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure:
other: head only and whole body
Vehicle:
not specified
Details on inhalation exposure:
Exposure system: The rectangular exposure chamber was constructed of ½ inch sheets of polymethylmethacrylate, 48 inches long and 18 inches tall by 14 inches deep, and had an approximate internal volume of 175 liters.
The animal exposure ports were located medially on the front panel. The animal head space was separated from the rest of the chamber by a hinged box which was swung down to start an exposure. This permitted the exposure to begin instantenously once a satisfactory steady state chamber concentration of the test material was obtained.
The test-gas chamber atmospheres were obtained with continuous flow-through generation. Gas concentrations were generated by dilution of commercial bottled gas (Matheson Gas Products, East Rutherford, NJ).

Chamber Analytical: Concentrations of HCN were continuously monitored by infrared spectrophotometry. This method was validated by gas chromatography.

Respiratory Rate: Respiratory rate was monitored by recording pressure fluctuations due to breathing in a body plethysmograph. A pressure transducer (Gould Statham PM6) coupled the plethysmograph to a signal amplifier and recorder (Gould 2800). Respiratory rate (breaths/minute) was measured for 1 minute every 5 minutes for the 10-minute control period prior to exposure. Respiratory rate was monitored continuously during the first 5 minutes of exposure and thereafter recorded at 5-minute intervals. A mean percent decrease in respiratory rate was calculated for each rat. The groupmean, a mean of the individual means, was used to graphically determine the RD25.


Analytical verification of test atmosphere concentrations:
yes
Remarks:
Continuously by infrared spectrophotometry. The method was validated by gas chromatography
Duration of exposure:
> 5 - < 60 min
Remarks on duration:
4 groups: 5, 15, 30 and 60 min
Concentrations:
up to approximately 11,000 ppm HCN. The principle of "concentration x time" was employed.
No. of animals per sex per dose:
4-7
Control animals:
no
Statistics:
Statistical Methods: The LC50 (median lethal concentration) was calculated by the method described in Probit analysis (D.J. Finney, Cambridge University Press, Cambridge, 1977). The RD25 (concentration causing a 25% reduction in respiratory rate) was obtained by graphical methods.

Results and discussion

Effect levels
Sex:
male
Dose descriptor:
LC50
Effect level:
63 ppm
Based on:
test mat.
95% CL:
> 52 - < 79
Exp. duration:
1 h
Remarks on result:
other: In restrained rats. See data table for LC50 for other time periods.
Mortality:
Significantly lower LC50s for restrained rats were observed for the 30- and 60-minute exposure periods, compared with free-moving rats.
HCN exposure caused death during exposure periods, compared with other noxious gases which result in death in the 14-day period after exposure ceases.
Clinical signs:
The concentration at which the respiratory rate decreased 50% is 125 ppm
Body weight:
In rats which survived for 7 days after exposure, body weight was significantly decreased. In restrained rats exposed for 60 min, average weight loss was about 34%, while in free-moving rats, average weight loss was about 15%.
Gross pathology:
No necropsy performed.

Any other information on results incl. tables

Lapin CA 1981 LC50s in Study of Inhalation Toxicity of Common Combustion Gases
Group Time (min) Concentration (ppm) resulting in LD50 (Average and 95% CI)
    Restrained Unrestrained
1 5 398 369
    370-431 350-395
2 15 163 196
    131-189 181-209
3 30 85 173
    59-110 163-188
4 60 63 139
    52-79 120-155

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 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

Interpretation of results:
Toxicity Category II
Remarks:
Migrated information as listed in Table 3.1 of Regulation (EC) No. 1272/2008 Criteria used for interpretation of results: EU
Conclusions:
Hydrogen cyanide is a highly toxic compound by the inhalation route. Toxicity is higher in restrained animals compared with free-moving animals. There is a clear (concentration x time) relationship: the longer the exposure time, the lower the concentration which results in lethality of exposed animals. The LC50 for 60 min in restrained rats is 63 ppm. For a 30 min time period, the LC50 is 85 ppm, and for a 5 min time period, the LC50 is 369 ppm.
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.