Succinonitrile

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity

Remarks:

other: Dietary administration of food, fumigated with hydrogen cyanide

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1955

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

This is an older study conducted prior to establishment of OECD test guidelines. Experimental data was reviewed by the ECETOC Task Force, author of the 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)”, 2007. The report is a weight of evidence approach to an extensive body of literature, much of which was undertaken prior to development of guidelines. The report was peer reviewed by the scientific non-governmental organization (NGO), which judged the data to be reliable with restrictions.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Chronic toxicity for rats of food treated with hydrogen cyanide

Author:

Howard, JW and RF Hanzal

Year:

1955

Bibliographic source:

Agricultural Food Chemistry, 3: 325-329

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Version / remarks:

Well-designed study; precedes establishment of guideline

Principles of method if other than guideline:

This is a two year dietary study which was conducted prior to establishment of the OECD guideline. The diet consisted of standard rat chow which was fumigated with HCN for 24 hours. The numbers of animals, handling of animals, analytical verification, assessment of results and statistical analysis are generally consistent with current protocols.

GLP compliance:

no

Remarks:

The study was conducted prior to establishment of GLP.

Test material

Test material information

Constituent 1

Reference substance name:

Hydrogen cyanide

EC Number:

200-821-6

EC Name:

Hydrogen cyanide

Cas Number:

74-90-8

IUPAC Name:

cyanide

Details on test material:

Hydrogen cyanide was used as a fumigant of the food provided to the animals.

Test animals

Species:

rat

Strain:

other: Carworth Farms

Sex:

male/female

Administration / exposure

Route of administration:

other: Dietary administration of food, fumigated with hydrogen cyanide

Vehicle:

other: standard rat chow

Details on exposure:

Rat chow was fumigated with hydrogen cyanide for 24 hours, then placed in a sealed container to avoid volatilization of the cyanide.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

2 years

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100 and 300 ppm/day
Basis:
actual ingested

No. of animals per sex per dose:

10 rats per sex per dose group

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

No gross signs of toxicity were observed.

Mortality:

no mortality observed

Description (incidence):

No gross signs of toxicity were observed.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No overall effects except in females given 100 ppm with increased body weight due to one female with a tumor.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No effects of HCN fumigation on intake of food.

Food efficiency:

not examined

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Description (incidence and severity):

Hematological values determined on representative rats initially and at termination of the study appear to be within normal limits.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Plasma and red blood cell levels of thiocyanate were elevated over that of controls in both the 100 and 300 ppm groups. No other clinical chemisty findings were significant. Cyanide was inconsistently detected in selected organs in the high dose group.

Urinalysis findings:

not specified

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Relative organ weight of experimental and test groups appeared to be within normal limits.

Gross pathological findings:

no effects observed

Description (incidence and severity):

In all groups (including controls): pale granular livers, renal medullary congestion, small spleens, enlarged adrenals, atrophied encysted and inflamed genital organs, enharged hemorrhagic pituitaries, and ear infections.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No evidence of histopathology due to HCN feeding.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No effects related to cyanide exposure.

Details on results:

Carworth Farms rats (10/sex/group), for 2 years, were fed diets fumigated with HCN. The concentration of HCN in the diets was determined analytically. Special jars were used in order to limit volatilisation of HCN from the food. The food was changed every two days. The dietary concentrations were 100 and 300 mg/kg on the first of 2 days and decreased to about 50 and 80 ppm respectively on the second day. In a preliminary study, 300 mg/kg had been identified as the maximum level that did not result in immediately decreased food intake. The animals did not accept higher concentrations due to reduced palatability. Survival, body-weight gain, food intake, and clinical behaviour were not different between treated and control groups in the two year study. Absolute and relative organ weights (organs examined: liver, kidney, spleen, brain, heart, adrenals, testes and ovaries) were also comparable to controls. No treatment-related histopathological changes were observed in the organs examined (heart, lung, liver, spleen, gastro-intestinal tract, kidneys, adrenals, thyroid, testes, uterus, ovaries, cerebrum, cerebellum and brain). The NOAEL in this study was approximately 8.2 mg HCN/kg bw/d, or 7.9 mg CN ion/kg bw/d.

Relevance of carcinogenic effects / potential:

In a 2-year cancer bioassay, hydrogen cyanide demonstrated no evidence of carcinogenicity at concentrations up to 300 ppm.

Effect levels

Dose descriptor:

NOAEL

Effect level:

300 ppm (analytical)

Sex:

male/female

Basis for effect level:

other: No tumors were observed in rats fed a diet of food treated with HCN, at concentrations up to 300 ppm, equivalent to 7.9 mg CN ion/kg bw/d, for 2 years.

Remarks on result:

not determinable

Remarks:

no NOAEL identified. Effect type:carcinogenicity (migrated information)

Any other information on results incl. tables

There was observed a random distribution of mortality, no dose-response relationship was observed with HCN intake.

Applicant's summary and conclusion

Conclusions:

In a 2-year cancer bioassay, Carworth Farms rats (10/sex/group) were fed diets fumigated with HCN, at dose levels of 100 and 300 mg/kg. The animals did not accept higher concentrations due to reduced palatability. Survival, body-weight gain, food intake, and clinical behaviour were not different between treated and control groups in this study. Absolute and relative organ weights were also comparable to controls. No treatment-related histopathologic changes were observed in the organs examined. The NOAEL in this study was the high dose of 300 ppm, equivalent to 8.2 mg HCN/kg bw/d, or 7.9 mg CN ion/kg bw/d.