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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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
This is a guideline study by U.S. EPA National Toxicology Program on sodium cyanide. These experimental data were 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:
study report
Title:
Unnamed
Year:
1993
Report date:
1993

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EPA OPP 82-1 (90-Day Oral Toxicity)
Version / remarks:
Precedes current guideline of 870.3100 (1998)
Deviations:
yes
Remarks:
pH of drinking water was 8.5.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Sodium cyanide
EC Number:
205-599-4
EC Name:
Sodium cyanide
Cas Number:
143-33-9
Molecular formula:
CNNa
IUPAC Name:
sodium cyanide
Details on test material:
The test material was characterized by NTP, and purity was 99.9%. Test material administered is sodium cyanide, (CAS 143-33-9), but is present as hydrogen cyanide in the GI tract. The pKa is approximately 9, so at physiological pH and 37 °C, all cyanide species are present in the non-ionized form of hydrogen cyanide.

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
Male and femaile rats were obtained from Taconic Laboratory Animals and Services, Germantown, NY. B6C3F1 mice were obtained from Simonsen Laboratories (Gilroy, CA).They were approx 31 days of age at receipt and were quarantined 11 days; the animals were 6 weeks when the studies began. Sera obtained from blood samples were analyzed for anitbody titiers to rodent viruses and were negative.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
The water in treatment groups was pH 8.5. No information is given for the pH of water consumed by control animals. As the pKa of cyanides is 9.36 at 20 degrees C, the cyanide would be in the form of hydrogen cyanide in the drinking water of this study. At 25 degrees C, hydrogen cyanide undergoes a phase change from liquid to vapour. The authors of this study suspected volatilization of the cyanide from the drinking water.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Drinking water formulations were periodically analyzed by visible light spectroscopy. All formulations for dosing were within 10% of the thoretical concentrations when analyzed within 2 days of preparation. Water bottles were changed at least once every 4 days. For the first, middle and last mixing periods, samples of drinking water at each dose level were taken from the animal room water bottles on the last day of use and analyzed form sodium cyanide. Five of 15 animal room samples for rats and 11 of 15 animal rooms for mice were more than 10% lower than the theoretical concentrations. This was thought due to volatilization. Results of referee analyses performed by Midwest Research Institute were in agreement with study laboratory results.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily ad libitum in water
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 3, 10, 30, 100 and 300 ppm
Basis:
other: measured in water
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Groups of 10 males and females comprised a "base" study. A second experiment was done with a "clinical toxicology" group of 10 males and females, where animals were maintained in metabolism cages and were used to generate more detailed clinical chemistry and hematology data.

Examinations

Observations and examinations performed and frequency:
histopathology, clinical chemistry, hematology, urine chemistry and clinical signs
Sacrifice and pathology:
autopsy and histopathology on high dose group and controls; body weight, absolute and relative weight of selected organs, clinical chemistry and haematology.
Statistics:
Analysis of variance according to Williams (1971) or Dunnett (1955). Nonparametric multiple comparisons methods of Shirley (1972) or Dunn (1964).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs were observed that were considered related to test material exposure.
Mortality:
no mortality observed
Description (incidence):
No clinical signs were observed that were considered related to test material exposure.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weights & mean body weight gains of male rats in the 10 and 300 ppm groups were less than those of controls. No significant differences were observed in female rats. Body weight (female mice) at 300 ppm was not significantly less than controls
Food consumption and compound intake (if feeding study):
not specified
Description (incidence and severity):
No information provided.
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Water consumption of all rats in the 100 and 300 ppm groups was more than 10% less than that of controls. In mice, water consumption by males and females in the 100 and 300 ppm groups was less than that of controls.
Ophthalmological findings:
not examined
Description (incidence and severity):
No mention of ophthalmoscopic exam performed.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
There were many instances of values suggesting a toxicity to red blood cells: decreased mean cell volume, mean cell volume and mean cell Hb, hematocrit; increased nucleated erythrocytes. Authors describe these as minor and of no clinical significance.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Male rats (300 ppm) displayed many significant alterations at the early time points, including increased BUN, creatinine, albumin, alanine aminotransferase, alkaline phosphatase, Sorbitol Dehydrogenase, N-acetyl-b-D-glucosaminidase, ribonuclease.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Urine volume was significantly decreased (40%) from control values in the 300 ppm group of male rats; specific gravity and protein content was increased; pH was decreased. Male rats in the 3 ppm group also had decreased urine volume (25%).
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Female rats & mice: increased absolute and relative liver weights (300 ppm); male mice: increased relative liver & kidney weights. Male rats and mice: increased absolute testis weight (300 ppm); decreased absolute & relative weights of cauda epididymus.
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
Water consumption was reduced in the 100 and 300 mg/l groups with corresponding decreases in urine excretion and increases in urine specific gravity. Urinary thiocyanate levels were increased in the 10 to 300 mg/l groups. A decrease in final body weight and body-weight gain was observed in male rats exposed to 300 mg/l NaCN, but not in females. The authors state that no other treatment-related clinical signs were observed; no treatment-related changes in haematology, clinical chemistry, gross pathology or histopathology were observed. The thyroid and CNS (in particular the corpus callosum) were examined thoroughly for any histopathological changes. No morphological differences, compared to controls, were observed with regard to follicle size, colloid staining or follicular epithelium in the thyroid of rats receiving NaCN. In histological sections of the brain there was no sign of treatment-related degenerative changes in the corpus callosum. The caudal epididymal weights of all male rats were significantly lower than those of the controls. In rats receiving 300 mg NaCN/L, left epididymal and testis weights and the number of spermatid heads per testis were also lower than in the controls. Sperm motility in all exposed male rats was less than in the controls, but the changes were not considered biologically significant by the authors and were in the range of normal values reported from different laboratories. These may be considered a result of water deprivation and may be adaptive responses. Pro-oestrus and di-oestrus times were prolonged in female rats of the 100 and 300 mg/l groups compared to controls, without a clear dose response. According to the authors these effects cannot unequivocally be attributed to cyanide exposure. The NOAEL was 300 mg/l or 12.5 mg CN ion/kgbw, the highest dose used in this study.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
rat
Effect level:
300 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The NOAEL is 300 ppm (equivalent to 12.5 mg CN ion/kg bw/d).
Dose descriptor:
NOAEL
Remarks:
Mouse
Effect level:
300 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant differences in body weight in the 300 ppm group, compared to controls. This corresponds to 26.5 mg CN-/kg bw/d.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

When reviewing the existing studies on cyanides, the ECETOC Task Force concluded that this is one of only three well-controlled repeated-dose studies.Administration of sodium cyanide at concentrations up to 300 ppm in drinking water to rats for 13 weeks resulted in no significant adverse effects on body weights, organ weights, histopathology or clinical pathology parameters. The NOAEL (excluding reproductive organs) was 300 mg/l or 12.5 mg CN ion/kg bw, the highest dose used in this study. The authors conclude that while assessments of thyroid hormone levels (T3, T4 or TSH) were not performed in this study, the evaluations that were done (histopathological evaluation of thyroid gland and brain) provided no evidence of thyroid or neurological effects. The results indicate that subchronic administration of NaCN at concentrations that caused no clinical signs of toxicity or significant reductions of body-weight gain was not thyrotoxic or neurotoxic.Althoughit has been argued that the rat may not be an ideal surrogate for humans for some end-points, it appears to be more sensitive with regard to goitrogenic effects and therefore has an built-in margin of safety with regard to likely effects in humans. In those three studies, no effects on the thyroid weight or histopathology have been observed up to the highest dose tested. As the administered dose levels were limited by the acute toxicity of cyanide it can be concluded that thyroid toxicitywill not occur in animals at concentrations that are not acutely toxic.

Applicant's summary and conclusion

Conclusions:
Administration of sodium cyanide at concentrations up to 300 ppm in drinking water to rats for 13 weeks resulted in no significant adverse effects on body weights, organ weights, histopathology or clinical pathology parameters. Minor effects were observed in caudal epididymides weight, sperm motility, and sperm head counts, which were not considered by the authors to be of toxicological significance. The NOAEL (excluding reproductive organs) was 300 mg/l or 12.5 mg CN ion/kgbw, the highest dose used in this study. The authors conclude that while assessments of thyroid hormone levels (T3, T4 or TSH) were not performed in this study, the evaluations that were done (histopathological evaluation of thyroid gland and brain) provided no evidence of thyroid or neurological effects (Hébert, 1993). The results indicate that subchronic administration of NaCN at concentrations that caused no clinical signs of toxicity or significant reductions of body-weight gain was not thyrotoxic or neurotoxic.

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