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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
This study did not utilize a guideline protocol or GLP, although this fact does not invalidate the information obtained. There was minimal information provided on the study substance, fewer animals per dose group were treated, and there is no information on whether test substance concentration was analyzed in the dietary feed. 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.

Data source

Reference
Reference Type:
publication
Title:
Cyanide, protein and iodine interactions in the performance and metabolism of rats
Author:
Tewe OO and Maner JH
Year:
1982
Bibliographic source:
J Environmental Pathol Toxicol Oncol 6:69-77.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Subchronic feeding study (56) days of CD rats on various diets differing in protein content, iodide levels and cyanide levels.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
All cyanide salts ingested will be present, at the physiological pH of the stomach, as HCN.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Weanling rats allocated on the basis of sex and body weight to 8 groups, each with 8 replicates.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
56 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
diets supplemented with 750 ppm KCN
Basis:
other: 40 mg/kg bw/day CN ion
No. of animals per sex per dose:
4 per sex for 8 total
Control animals:
yes, plain diet
Details on study design:
Animals were individually housed in metabolism cages and urine collected and assayed for serum thiocyanate levels.

Examinations

Sacrifice and pathology:
Sacrificed by anesthesia with chloroform and blood obtained by cardiac puncture for determination of serum thiocyanate, proteins using a concentrimeter and protein bound iodine levels.
Other examinations:
The liver and kidney were removed, weighed, and frozen for rhodanese activity
Statistics:
Factorial analysis was carried out on the measured parameters by the method described by Steel and Torrie (1960).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
no effects observed
Details on results:
The presence of cyanide in the diets caused a non-significant reduction in both feed consumption and growth rate. Moverover, on protein deficient diets, the lowest body weight gain among the groups of rats was observed in the animals with cyanide (750 ppm) in the diet. Dietary cyanide significantly increased serum and urinary thiocyanate concentration. Interactions of protein deficiency and dietary cyanide also significantly reduced serum thiocyanate concentrations, while interactions of protein deficiency, cyanide and iodine deficiency reduced kidney protein content.

Effect levels

Dose descriptor:
NOAEL
Effect level:
> 40 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
nominal
Sex:
male/female
Basis for effect level:
other: as mg CN ion/kgbw/day

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 3: Performance of Rats on Variables of Dietary Cyanide, protein and iodine
Parameters   Dietary Variables
  Cyanide (ppm) 0 0 750 750 0 0 750 750
  Potassium iodine (ppm) 32 0 32 0 32 0 32 0
  Crude protein (%) 15 15 15 15 8 8 8 8
Daily feed intake, g   15.6 ± 1.2 16.0 ± 1.0 15.3 ± 1.0 15.0 ± 0.8 8.3 ± 0.5 7.9 ± 0.4 6.2 ± 0.5 6.2 ± 0.5
Daily weight gain, g   4.3 ± 0.5 4.5 ± 0.6 4.1 ± 0.4 4.1 ± 0.4 0.63 ± 0.05 0.59 ± 0.06 0.41 ± 0.06 0.50 ± 0.05
Feed efficiency   3.6 ± 0.19 3.6 ± 0.23 3.7 ± 0.17 3.7 ± 0.22 13.2 ± 0.68 13.4 ± 1.49 15.1 ± 1.90 12.4 ± 0.91
Protein efficiency ratio   1.9 ± 0.09 2.0 ± 0.11 1.8 ± 0.08 1.8 ± 0.10 0.93 ± 0.01 0.92 ± 0.10 0.82 ± 0.19 1.00 ± 0.08
Fresh weight of organs, as % body weight                  
Liver   4.0 ± 0.1 3.9 ± 0.1 3.8 ± 0.08 3.9 ± 0.09 4.2 ± 0.2 4.0 ± 0.2 4.1 ± 0.1 4.1 ± 0.07
Kidney   0.60 ± 0.02 0.59 ± 0.01 0.59 ± 0.01 0.62 ± 0.03 0.87 ± 0.03 0.82 ± 0.08 0.93 ± 0.05 0.85 ± 0.02
56 day growth study. Each value represents mean of 8 rats per treatment ± SEM

Table 4: Metabolic Changes in Rats Fed Varying Levels of Dietary Cyanide, Protein and Iodine
Parameters   Dietary Variables
  Cyanide (ppm) 0 0 750 750 0 0 750 750
  Potassium iodine (ppm) 32 0 32 0 32 0 32 0
  Crude protein (%) 15 15 15 15 8 8 8 8
Serum protein, g/100 ml   6.5 ± 0.07 6.8 ± 0.08 6.4 ± 0.18 6.5 ± 0.18 4.4 ± 0.09 4.4 ± 0.04 4.5 ± 0.04 4.3 ± 0.20
Serum protein bound iodine, microg/100 ml   5.7 ± 0.28 3.7 ± 0.15 5.8 ± 0.20 3.7 ± 0.11 6.1 ± 0.29 3.9 ± 0.13 6.2 ± 0.25 3.9 ± 0.23
Serum thiocyanate, mg/100 ml   1.70 ± 0.05 1.69 ± 0.08 2.36 ± 0.10 2.73 ± 0.14 2.35 ± 0.04 2.37 ± 0.05 2.50 ± 0.19 2.59 ± 0.17
Urinary thiocyanate, mg excreted/100 g feed intake   2.13 ± 0.21 1.96 ± 0.05 5.66 ± 0.96   5.34 ± 0.53 0.75 ± 0.11 0.75 ± 0.34 2.86 ± 0.86 2.07 ± 0.79
Rhodanese activity of tissues. mg thioc/min/g protein  
Liver   31.4 ± 2.5 31.1 ± 1.9 31.4 ± 1.5 30.2 ± 1.7 32.2 ± 1.8 31.1 ± 1.8 30.5 ± 1.5 31.8 ± 1.5
Kidney   26.2 ± 1.0 24.7 ± 0.9 24.3 ± 1.2 25.0 ± 0.8 23.0 ± 1.0 23.0 ± 1.0 24.4 ± 1.4 23.2 ± 1.0
Protein content of tissues. mg/100 g fresh tissue weight                  
Liver   25.8 ± 0.9 24.0 ± 1.1 23.6 ± 0.6 26.1 ± 1.1 23.6 ± 1.2 24.1 ± 1.2 23.0 ± 0.9 23.3 ± 0.8
Kidney   23.0 ± 1.2 21.9 ± 1.2 21.7 ± 1.0 21.7 ± 0.6 17.7 ± 0.9 19.2 ± 1.4 19.9 ± 1.2 19.0 ± 1.2 
Urinary thiocyanate values are those recorded during the first week of the study period. ± SEM

Applicant's summary and conclusion

Conclusions:
Cyanide in a nutritionally adequate diet resulted in weight loss, which was exascerbated in a diet with inadequate protein. This level of 750 ppm cyanide did not cause cyanide intoxication. The NOAEL was greater than 40 mg CN ion/kg bw/d. Serum and urinary thiocyanate levels were increased. In a diet where protein and iodine content was deficient, kidney protein content and rhodanese was significantly reduced.