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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: 13-week subchronic repeat dose study in rat
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Guideline study on a structurally-similar substance, potassium cyanide (CAS No. 151-50-8). 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:
reference to same study

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
1989

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD 407
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
As KCN is a relatively weak acid, with a pKa value of 9.11 at 30°C, at the physiological pH of about 7, KCN is distributed in the body as the protonated CN ion, or HCN. Regardless of whether the exposure is to gaseous HCN or a soluble cyanide salt, it is HCN which is absorbed into the blood after oral, dermal or inhalation exposure. The form of cyanide to which exposure takes place, i.e. a simple salt or the free acid, does not influence the distribution, metabolism or excretion from the body. 

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
This study included an extra control group: rats given the amount of water the most water-restricted KCN group consumed during the week previous.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
see 7.5.1.3.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
40-160 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
26-37
Control animals:
yes, concurrent vehicle
other: paired drinking water controls
Details on study design:
see 7.5.1.3.

Examinations

Postmortem examinations (parental animals):
gross pathology and histopathology
Statistics:
Student's t-test, Dunnett's, and RA Fisher's Exact test

Results and discussion

Results: P0 (first parental animals)

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
ca. 80 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: Some decrease in testes weight at higher dose of 140-160 mg/kg bw/day, but this could be due to an interaction between water restriction and test substance. 80 mg KCN/kg bw/d is equivalent to 32 mg CN ion/kg bw/d.

Results: F1 generation

Details on results (F1)

The animals in the high dose group and the paired drinking group were severely emaciated. All other animals showed no substance-related changes in behaviour and external appearance. Food consumption was reduced in relation to increasing dose of KCN, and this reduction was significant in the high dose group. Food consumption for the paired drinking group and the high dose group was similar. The higher the KCN dose, the lower the consumption of drinking water. In all groups, the difference was significantly different from the standard control group. Development of body weight was significantly reduced in the mid and high dose groups. The absolute weight of the testes indicated a slight tendency to decrease in the medium dose group, and was significantly reduced in the high dose group. Histopathologic examination revealed no major findings, especially in the testes.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
An oral subchronic study of KCN in drinking water was undertaken in male CD rats at doses of 40, 80 and 140 mg/kg bw/day for 13 weeks.  An extra control group was included: a “paired-drinking” group consuming only the lowest amount of water imbibed by the high dose treated group. The animals in the high dose group and the paired drinking group were severely emaciated. All other animals showed no substance-related changes in behaviour and external appearance. Food consumption was reduced in relation to increasing dose of KCN, and this reduction was significant in the high dose group. Food consumption for the paired drinking group and the high dose group was similar. The higher the KCN dose, the lower the consumption of drinking water. In all groups, the difference was significantly different from the standard control group.  Increases in body weight were significantly reduced in the mid and high dose groups. In the high dose group, toxicity developed so that the dose was lowered from 160 to 140 at the beginning of the 12th week. There were no substance-related differences between treated and untreated rats in ophthalmology or examination of hearing or dentition. There were no statistically significant differences in haematology or clinical chemistry parameters between treated and untreated group. Proteinuria occurred, and amount of protein in the urine showed a clear correlation with increasing dose of KCN. Urine pH was shifted toward the acidic in all groups except the standard control.  The absolute weights of the adrenals, heart, kidneys, lungs, and thymus were slightly lower in the medium dose group, and significantly lower in the high dose group. The weights of the brain, pituitary gland and liver were signficantly reduced in the high dose group. The absolute weight of the testes indicated a slight tendency to decrease in the medium dose group, and was significantly reduced in the high dose group. Except for the thymus, all other organs in the high dose group showed an increase in relative organ weight. Gross pathology examination revealed no abnormalities except for haemorrhagic centers in the stomach, mostly in animals given high doses of KCN. Histopathologic examination revealed no major findings, especially in the brain, liver, testes, thyroid or kidneys. Histopathological examination of the animals which died prematurely indicated single to multiple erosive defects in the stomachs of animals, primarily those receiving the high dose of KCN. The NOAEL was the mid-dose group receiving 80 mg KCN/kg bw/d, equivalent to 32 mg CN ion/kg bw/d.