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EC number: 207-306-5 | CAS number: 460-19-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Effects on fertility
Link to relevant study records
- Endpoint:
- reproductive toxicity, other
- Remarks:
- A 90-Day Oral (Drinking Water) Toxicity Study of Soduium Cyanide in Male Fisher F344/DuCrl Rats with a 70-Day Recovery Period
- Type of 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:
- guideline study
- Justification for type of information:
- Ethanedinitrile, hydrogen cyanide (HCN), potassium cyanide and sodium cyanide can be considered as a chemical category, along with and acetone cyanohydrin (ACH, also known as 2-hydroxy-2-methylpropanenitrile), based on structural similarity, common breakdown/metabolic products in physical and biological systems, and similar physico-chemical properties. Particular attention is paid to the dissociation constant of HCN. Ethanedinitrile breaks down in aqueous solution into cyanide ion (CN-) and cyanate ion (OCN-) (Cotton and Wilkinson 1980). Ethanedinitrile due to its low log Kow (0.07) and relatively high solubility in water (2.34 g/L) needs to get dissolved in aqueous solutions in lungs to enter the body. The rate of hydrolysis of ethanedinitrile is very fast (Ajwa 2015). Also, in the vast majority of environmental and physiologic conditions, the cyanide salts will dissolve in water to form hydrogen cyanide. The physico-chemical hazards and toxicity therefore result from the activity of 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 the chemical category inclusive hydrogen cyanide, sodium and potassium cyanides. 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 ethanedinitrile to a chemical category does not result in a less protective regulatory status.
- Qualifier:
- according to guideline
- Guideline:
- other: OECD408
- GLP compliance:
- yes (incl. QA statement)
- Species:
- rat
- Strain:
- Fischer 344/DuCrj
- Sex:
- male
- Route of administration:
- oral: drinking water
- Vehicle:
- water
- Remarks:
- reverse osmosis water
- Details on exposure:
- Drinking water offered continuously for a minimum of 91 consecutive days.
- Duration of treatment / exposure:
- minimum 91 days
- Frequency of treatment:
- continuously
- Dose / conc.:
- 3 ppm
- Dose / conc.:
- 10 ppm
- Dose / conc.:
- 30 ppm
- Dose / conc.:
- 100 ppm
- Dose / conc.:
- 300 ppm
- No. of animals per sex per dose:
- 10 main study
10 recovery study - Control animals:
- yes
- other:
- Sperm parameters (parental animals):
- Motility
Cauda epididimis, LT WT
Cauda epididimis KT CONC
Sperm morphology
Testis, LT WT
Testis LT CONC
Sperm production rate
Seminal vesicle, Prostate - Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Reproductive function: sperm measures:
- no effects observed
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 100 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- organ weights and organ / body weight ratios
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- organ weights and organ / body weight ratios
- Key result
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Remarks on result:
- not measured/tested
- Key result
- Reproductive effects observed:
- no
- Conclusions:
- There were no statistically significant differences when the ad libitum control group (Group 1)
was compared to the restricted water control group (Group 2) and the test substance-treated
groups, or when the restricted water control group was compared to the 300 ppm group. While
mean values for sperm motility, cauda epididymides and testes weights, and sperm production
rate in the 300 ppm group were slightly lower compared to the ad libitum control group (Group
1), most individual values remained within the range of values observed in the ad libitum control
group (Group 1) and therefore this was attributed to biological variation and was not considered
test substance-related. - Endpoint:
- fertility, other
- Remarks:
- study on male fertility
- Type of information:
- read-across based on grouping of substances (category approach)
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- This study was performed prior to establishment of guideline protocols. It is sufficiently documented to allow assessment of the validity of its conclusions.
- Justification for type of information:
- Ethanedinitrile, hydrogen cyanide (HCN), potassium cyanide and sodium cyanide can be considered as a chemical category, along with and acetone cyanohydrin (ACH, also known as 2-hydroxy-2-methylpropanenitrile), based on structural similarity, common breakdown/metabolic products in physical and biological systems, and similar physico-chemical properties. Particular attention is paid to the dissociation constant of HCN. Ethanedinitrile breaks down in aqueous solution into cyanide ion (CN-) and cyanate ion (OCN-) (Cotton and Wilkinson 1980). Ethanedinitrile due to its low log Kow (0.07) and relatively high solubility in water (2.34 g/L) needs to get dissolved in aqueous solutions in lungs to enter the body. The rate of hydrolysis of ethanedinitrile is very fast (Ajwa 2015). Also, in the vast majority of environmental and physiologic conditions, the cyanide salts will dissolve in water to form hydrogen cyanide. The physico-chemical hazards and toxicity therefore result from the activity of 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 the chemical category inclusive hydrogen cyanide, sodium and potassium cyanides. 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 ethanedinitrile to a chemical category does not result in a less protective regulatory status.
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Method: other: similar to OECD
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Route of administration:
- inhalation
- Details on exposure:
- Male Sprague Dawley rats were exposed by the inhalation route for 48 exposure days (69 days on study) and mated with unntreated females to assess male fertility. Exposure of males was continued through the day of the last mating opportunity (58 exposure days). Animals were exposed in 10 M3 Rochester type chambers.
- Duration of treatment / exposure:
- Exposure period: 6 hrs/day
premating exposure period (males): 48 days
premating exposure period (females): 0 days - Frequency of treatment:
- 5 days/week
- Remarks:
- Doses / Concentrations:
0, 10, 28.5 & 57.2 ppm
Basis:
nominal conc.
males only were treated - Control animals:
- yes, historical
- Parental animals: Observations and examinations:
- Males were weighed and given a thorough physical examination once per week and assessed for clinical signs of toxicity before and after exposure. Males were sacrificed at the end of the study, about three weeks after the last exposure. The tissues and organs of the thoracic, abdominal and scrotal cavities were examined for gross lesions and testes, epididymides, prostate glands and seminal vesicles preserved.
- Postmortem examinations (parental animals):
- Mated females were necropsied on gd 13 and external surfaces, tissues and organs of the thoracic and abdominal cavities examined.
- Reproductive indices:
- Pregnancy status was determined as was the number of total nidations, number of resorptions, live implantations and corpora lutea. The tissues and organs of the thoracic, abdominal and scrotal cavities were examined for gross lesions and testes, epididymides, prostate glands and seminal vesicles preserved.
- Dose descriptor:
- NOEC
- Remarks:
- systemic effects
- Effect level:
- 57.2 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- clinical signs
- mortality
- gross pathology
- other: Equivalent to 61.9 mg/m3 CN anion.
- Remarks on result:
- other: Only at 57.2 ppm did the rats show lower mean body weights but the difference was not statistically significant from controls.
- Remarks:
- Local effects: Dose dependent red nasal discharge and encrustations consistent with slight irritancy observed in the 90 day inhalation study also in the rat.
- Critical effects observed:
- no
- Dose descriptor:
- NOEL
- Generation:
- F1
- Effect level:
- 57.2 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- Critical effects observed:
- no
- Reproductive effects observed:
- not specified
- Conclusions:
- Male Sprague Dawley rats were exposed by the inhalation route to acetone cyanohydrin (0, 10, 28.5 and 57.2 ppm), 6 hr/day, 5 days/week for 48 exposure days (69 days on study) and mated with untreated females to assess male fertility. Exposure of males was continued through the day of the last mating opportunity (58 exposure days). Animals were exposed in 10 m3 Rochester type chambers. Males were weighed and given a thorough physical examination once per week and assessed for clinical signs of toxicity before and after exposure. Males were sacrificed at the end of the study, about three weeks after the last exposure. The tissues and organs of the thoracic, abdominal and scrotal cavities were examined for gross lesions and testes, epididymides, prostate glands and seminal vesicles preserved.
Mated females were necropsied on GD13 and external surfaces, tissues and organs of the thoracic and abdominal cavities examined. Pregnancy status was determined as was the number of total nidations, number of resorptions, live implantations and corpora lutea.
No adverse toxic effects were observed in male rats exposed by the inhalation route to acetone cyanohydrin at exposure concentrations up to 60 ppm using a 6 hour/day, 5 day/week schedule for 58 days.
In particular, no effects were observed on body weight, clinical signs or lesions detectable at necropsy. Red nasal discharge and encrustations consistent with slight irritancy observed in the 90 day inhalation study also in the rat. No treatment related male fertility effects were observed in any exposure level groups. Acetone cyanohydrin did not exhibit reproductive toxicity in male rats exposed by inhalation to up to 60 ppm, with a NOAEC of 57.2 ppm, equivalent to 64.3 mg/m3.
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 ethanedinitrile to a chemical category does not result in a less protective regulatory status. - Endpoint:
- two-generation reproductive toxicity
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
- Endpoint:
- reproductive toxicity, other
- Remarks:
- other: 13-week subchronic repeat dose study in rat
- Type of information:
- read-across based on grouping of substances (category approach)
- Adequacy of study:
- weight of evidence
- Study period:
- 1989
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Justification for type of information:
- Ethanedinitrile, hydrogen cyanide (HCN), potassium cyanide and sodium cyanide can be considered as a chemical category, along with and acetone cyanohydrin (ACH, also known as 2-hydroxy-2-methylpropanenitrile), based on structural similarity, common breakdown/metabolic products in physical and biological systems, and similar physico-chemical properties. Particular attention is paid to the dissociation constant of HCN. Ethanedinitrile breaks down in aqueous solution into cyanide ion (CN-) and cyanate ion (OCN-) (Cotton and Wilkinson 1980). Ethanedinitrile due to its low log Kow (0.07) and relatively high solubility in water (2.34 g/L) needs to get dissolved in aqueous solutions in lungs to enter the body. The rate of hydrolysis of ethanedinitrile is very fast (Ajwa 2015). Also, in the vast majority of environmental and physiologic conditions, the cyanide salts will dissolve in water to form hydrogen cyanide. The physico-chemical hazards and toxicity therefore result from the activity of 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 the chemical category inclusive hydrogen cyanide, sodium and potassium cyanides. 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 ethanedinitrile to a chemical category does not result in a less protective regulatory status.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD 407
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- 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
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- daily
- 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
- Postmortem examinations (parental animals):
- gross pathology and histopathology
- Statistics:
- Student's t-test, Dunnett's, and RA Fisher's Exact test
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 80 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- water consumption and compound intake
- other: 80 mg KCN/kg bw/d is equivalent to 32 mg CN ion/kg bw/d.
- Dose descriptor:
- NOAEL
- Remarks:
- P0 fertility parameters in a subchronic study
- Generation:
- other: In a subchronic study no F1 generation is produced and thus no effect levels for this generation can be assessed
- Effect level:
- ca. 140 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: testes weight P0
- Dose descriptor:
- NOEL
- Remarks:
- P0 fertility parameters in a subchronic study
- Generation:
- other: In a subchronic study no F1 generation is produced and thus no effect levels for this generation can be assessed
- Effect level:
- ca. 80 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- 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.
- Critical effects observed:
- no
- Key result
- Reproductive effects observed:
- not specified
- 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.
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 ethanedinitrile to a chemical category does not result in a less protective regulatory status. - Endpoint:
- fertility, other
- Remarks:
- study on female fertility
- Type of information:
- read-across based on grouping of substances (category approach)
- Adequacy of study:
- supporting study
- Reliability:
- 1 (reliable without restriction)
- Justification for type of information:
- Ethanedinitrile, hydrogen cyanide (HCN), potassium cyanide and sodium cyanide can be considered as a chemical category, along with and acetone cyanohydrin (ACH, also known as 2-hydroxy-2-methylpropanenitrile), based on structural similarity, common breakdown/metabolic products in physical and biological systems, and similar physico-chemical properties. Particular attention is paid to the dissociation constant of HCN. Ethanedinitrile breaks down in aqueous solution into cyanide ion (CN-) and cyanate ion (OCN-) (Cotton and Wilkinson 1980). Ethanedinitrile due to its low log Kow (0.07) and relatively high solubility in water (2.34 g/L) needs to get dissolved in aqueous solutions in lungs to enter the body. The rate of hydrolysis of ethanedinitrile is very fast (Ajwa 2015). Also, in the vast majority of environmental and physiologic conditions, the cyanide salts will dissolve in water to form hydrogen cyanide. The physico-chemical hazards and toxicity therefore result from the activity of 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 the chemical category inclusive hydrogen cyanide, sodium and potassium cyanides. 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 ethanedinitrile to a chemical category does not result in a less protective regulatory status.
- Principles of method if other than guideline:
- Method: other
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- female
- Route of administration:
- inhalation
- Duration of treatment / exposure:
- Exposure period: 6 hrs/day
Premating exposure period (males): 0 days
Premating exposure period (females): 21 days
Duration of test: 36 days
FREQ. of TrEatment: 5 day/week - Remarks:
- Doses / Concentrations:
10.7, 30.4 & 58.6 ppm
Basis: - Control animals:
- yes, historical
- Dose descriptor:
- NOEC
- Remarks:
- systemic effects
- Effect level:
- 58.6 ppm
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- other: corresponds to 63.4 mg CN/m3
- Remarks on result:
- other: no adverse systemic effects observed
- Remarks:
- Local effects: Dose-dependent red nasal discharge and encrustations are consistent with slight irritancy observed in the 90 day inhalation study also in the rat.
- Dose descriptor:
- NOEC
- Generation:
- F1
- Effect level:
- 58.6 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- other: corresponds to 63.4 mg CN-/m3
- Critical effects observed:
- no
- Reproductive effects observed:
- not specified
- Conclusions:
- 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 ethanedinitrile to a chemical category does not result in a less protective regulatory status.
- Endpoint:
- toxicity to reproduction
- Remarks:
- other: 13-week subchronic study with information on reproductive organs.
- Type of information:
- read-across based on grouping of substances (category approach)
- Adequacy of study:
- supporting study
- Study period:
- 1993
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Remarks:
- This is a guideline study of sodium cyanide (CAS No. 143-33-9). 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.
- Justification for type of information:
- Ethanedinitrile, hydrogen cyanide (HCN), potassium cyanide and sodium cyanide can be considered as a chemical category, along with and acetone cyanohydrin (ACH, also known as 2-hydroxy-2-methylpropanenitrile), based on structural similarity, common breakdown/metabolic products in physical and biological systems, and similar physico-chemical properties. Particular attention is paid to the dissociation constant of HCN. Ethanedinitrile breaks down in aqueous solution into cyanide ion (CN-) and cyanate ion (OCN-) (Cotton and Wilkinson 1980). Ethanedinitrile due to its low log Kow (0.07) and relatively high solubility in water (2.34 g/L) needs to get dissolved in aqueous solutions in lungs to enter the body. The rate of hydrolysis of ethanedinitrile is very fast (Ajwa 2015). Also, in the vast majority of environmental and physiologic conditions, the cyanide salts will dissolve in water to form hydrogen cyanide. The physico-chemical hazards and toxicity therefore result from the activity of 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 the chemical category inclusive hydrogen cyanide, sodium and potassium cyanides. 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 ethanedinitrile to a chemical category does not result in a less protective regulatory status.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: Precedes establishment of EPA 870.3100, 90-day Oral Toxicity in Rats
- Deviations:
- yes
- Remarks:
- ; pH of drinking water is 8.5; difficulty maintaining dose level in drinking water.
- Principles of method if other than guideline:
- This experiment preceeds establishment of this method. This is a standard 90-day subchronic protocol with histopathology of the reproductive organs, vaginal cytology and examination of sperm parameters including motility
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- This study also utilized B6C3F1 mice, males and females. Rats were obtained from Taconic Laboratory Animals and Services, Germantown, NY. Mice were obtained from Simonsen Laboratories (Gilroy, CA). Rats and mice 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.
- Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on 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 for cyanides is 9.36 at 20 degrees C, the form of cyanide present in the water is hydrogen cyanide. Authors suspected volatilization of the cyanide in the drinking water (phase change from liquid to vapour at 25 degrees C).
- Details on mating procedure:
- No mating occurred in this protocol.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Concentrations were periodically analyzed by spectrophotometric measures. 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:
- water ad libitum
- Remarks:
- Doses / Concentrations:
0, 3, 10, 30, 100 and 300 ppm
Basis:
analytical conc. - No. of animals per sex per dose:
- 10
- Control animals:
- other: given water, but there is no information about whether the pH was adjusted to 8.5, as with cyanide groups.
- Details on study design:
- See discussion 7.5.1.2.
The pH of the water with test material was 8.5. - Parental animals: Observations and examinations:
- Clinical signs, food and water consumption values, haematology, clinical chemistry and urinalysis.
- Oestrous cyclicity (parental animals):
- Vaginal cytology according to Morrissey et al, 1988, were used to determine estrous cycle stage.
- Sperm parameters (parental animals):
- Sperm motility, spermatid counts and sperm head counts
- Postmortem examinations (parental animals):
- haematology and clinical chemistry, body weight, organ weights (absolute and relative), histopathology.
- Statistics:
- Arcsine transformations were used on data expressed as proportions. Multivariate analysis of vaginal cytology data was performed. Other measures were analyzed with analysis of continuous variables by Williams (1971) or Dunnett (1955).
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No treatment-related clinical signs attributable to NaCN were seen in rats or mice.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean body weight at necropsy was decreased compared to controls in the 300 ppm dose group in rats.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Mean body weight at necropsy was decreased compared to controls in the 300 ppm dose group in rats.
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance intake: Water consumption by all rats and mice in the 100 and 300 ppm groups was less than that by the controls.
- Reproductive function: oestrous cycle:
- effects observed, treatment-related
- Description (incidence and severity):
- Female rats at 100 and 300 ppm spent significantly more time in proestrus and diestrus compared with controls. No effects were observed in mice.
- Reproductive function: sperm measures:
- effects observed, treatment-related
- Description (incidence and severity):
- Male rats and mice: decreased absolute testis weight (300 ppm); decreased absolute & relative weights of cauda epididymus. In rats only, decreased sperm motility at all doses; decreased sperm heads at 300 ppm.
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEL
- Remarks:
- Rat
- Effect level:
- 100 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: No adverse effect level is 100 ppm, equivalent to 12.5 mg CN ion/kg bw/day, as body weight changes occurred at the higher dose of 300 ppm. Effects could be impacted by decreases in water consumption.
- Remarks on result:
- other: for reproductive parameters, see F1 generation results
- Dose descriptor:
- NOAEL
- Remarks:
- Mouse
- Effect level:
- 300 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
- Remarks on result:
- other: for reproductive parameters, see F1 generation results
- Critical effects observed:
- no
- Dose descriptor:
- LOEL
- Remarks:
- Rat: P0 fertility parameters in a subchronic study
- Generation:
- other: In a subchronic study no F1 generation is produced and thus no effect levels for this generation can be assessed
- Effect level:
- 3 ppm (analytical)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other:
- Dose descriptor:
- NOEL
- Remarks:
- Rat: P0 fertility parameters in a subchronic study
- Generation:
- other: In a subchronic study no F1 generation is produced and thus no effect levels for this generation can be assessed
- Effect level:
- 30 ppm (analytical)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: Prolonged pro-oestrus and dioestrus: No dose-response relationship was evident; possibly spurious.
- Dose descriptor:
- NOEL
- Remarks:
- Mouse: P0 fertility parameters in a subchronic study
- Generation:
- other: In a subchronic study no F1 generation is produced and thus no effect levels for this generation can be assessed
- Effect level:
- 30 ppm (analytical)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: Relative cauda epididymis weight was decreased in rats given 100 ppm, compared to controls , equivalent to 8.6 mg CN-/kg bw/day. Authors believe these effects to be mild.
- Dose descriptor:
- NOAEL
- Remarks:
- Mouse: P0 fertility parameters in a subchronic study
- Generation:
- other: In a subchronic study no F1 generation is produced and thus no effect levels for this generation can be assessed
- Effect level:
- 300 ppm (analytical)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: no effects found on pro-oestrus and dioestrus
- Critical effects observed:
- no
- Reproductive effects observed:
- not specified
- Conclusions:
- NaCN was applied via drinking water to F344 rats and B6C3F1 mice for 13 weeks. At the highest dose level (300 ppm) rats absorbed an average dose of 12.5 mg CN ion/kgbw/d, and mice absorbed an average dose of 26.5 mg CN ion/kgbw/d. Survival and bodyweight at this dose were similar to that of the control group. No effects were observed in thyroid structure or function. No changes in gross or microscopic histopathology occurred in testes, epididymis or ovaries. Caudal epididymis weight was significantly reduced (absolute and relative) in treated rats , and sperm motility was decreased in all dose levels. In rats receiving 300 mg/l NaCN, the left epididymal and testis weights and the number of spermatid heads per testis were also lower than in the controls. These finding can be explained by decreased water consumption due to palatability issues, dehydration and stress. Pro-oestrus and dioestrus time was prolonged in female rats of the 100 and 300 mg/l groups compared to controls, without a clear dose-related response. According to the authors these effects cannot unequivocally be attributed to cyanide exposure. A NOAEL of 100 mg/l for rats (equivalent to 4.9 mg CN ion/kgbw/d) and 300 mg/l in mice (equivalent to 26.5 mg CN ion/kgbw/d) can be derived from this study. Other studies are available which provide relevant information on rats where water intake was matched with animals consuming cyanide salts in drinking water (Leuschner, et. al., 1989).
Referenceopen allclose all
No adverse toxic effects were observed in male rats exposed
by the inhalation route to acetone cyanohydrin at exposure
concentrations up to 60ppm using a 6hour/day, 5 day/week
schedule for 58 days.
In particular, no effects were observed on body weight,
clincial signs or lesions detectable at necropsy. Red nasal
discharge and encrustations consistent with slight irritancy
observed in the 90 day inhalation study also in the rat. No
treatment related male fertility effects were observed in
any exposure level groups. Acetone cyanohydrin did not
exhibit reproductive toxicity in male rats exposed by
inhalation to up to 60 ppm.
Examination of the details of the study supports the proposition that physiologically significant water restriction occurred in the study, leading to the observed minor reproductive effects including effects in the cauda epididymus which is the site of maturation of spermatids. These potentially represent nonspecific dehydration and stress effects, which can be considered adaptive and may be considered in the NOEL determinations, but not NOAEL determinations.
Water consumption was reduced at 100 and 300 mg/l, up to a 40% decrease. Corresponding decreases in urine excretion and increases in urine specific gravity were reported in rats. A significant decrease in body-weight gain was observed in male rats and a nonsignificant decrease in final mean body weight in female mice exposed to 300 mg/l NaCN, but no such decrease was seen in female rats or male mice. Minor effects judged to be insignificant physiologically were observed in male reproductive parameters. The left and caudal epididymal weights of all male rats and the 300 mg/l male mice were significantly lower than those of the controls. In rats receiving 300 mg/l NaCN, the 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 in the range of normal values reported from different laboratories. In mice, no changes in sperm motility were observed. Pro-oestrus and dioestrus time was prolonged in female rats of the 100 and 300 mg/l groups compared to controls, without a clear dose-related response. No such effects occurred in female mice. NOAELs of 100 ppm for rats and 300 ppm for mice can be derived from this study. According to the authors, the effects on pro-oestrus and dioestrus time cannot unequivocally be attributed to cyanide exposure. Decreases in the weight of the cauda epididymis and the testes, as well as decreases in sperm motility, are consistent with dehydration and stress, and may not be causally associated with exposure to CN anion.
Justification for classification or non-classification
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