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EC number: 207-306-5 | CAS number: 460-19-5
Repeated dose toxicity: inhalation
Administrative data
- Endpoint:
- chronic toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 984
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Ethanedinitrile (CN)2, subchronic (180 days) inhalation toxicity study.
Six months (6h/day, 5 days/week) inhalation exposure was conducted with ethanedinitrile gas using male rhesus monkeys (Macacca mulatta) and male albino rats (Charles River Strain). Fifteen monkeys and 90 rats were divided into three groups of 5 monkeys and 30 rats. One group, the Controls, was exposed to the air; the other two groups were exposed to ethanedinitrile concentrations of 11 or 25 ppm. - GLP compliance:
- no
Test material
- Reference substance name:
- Oxalonitrile
- EC Number:
- 207-306-5
- EC Name:
- Oxalonitrile
- Cas Number:
- 460-19-5
- Molecular formula:
- C2N2
- IUPAC Name:
- carbononitridic cyanide
- Test material form:
- gas
Constituent 1
Test animals
- Species:
- other: rhesus monkey, rat
- Strain:
- other: Macacca mulatta, Sprague-Dawley
- Details on species / strain selection:
- Source: Charles River
- Sex:
- male
Administration / exposure
- Route of administration:
- inhalation: gas
- Type of inhalation exposure:
- whole body
- Vehicle:
- air
- Duration of treatment / exposure:
- 180 days (6h/day, 5 days/week)
postexposure period 14 days, 4 weeks or other - Frequency of treatment:
- 6h/day, 5 days/week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 ppm (nominal)
- Remarks:
- Analytical concentrations ≤1 ppm
- Dose / conc.:
- 11 ppm (nominal)
- Remarks:
- Analytical concentrations 11.2 ± 1.5 ppm
- Dose / conc.:
- 25 ppm (nominal)
- Remarks:
- Analytical concentrations 25.3 ± 3.3 ppm
- No. of animals per sex per dose:
- 5 monkeys per treatment group
30 rats per treatment group - Control animals:
- yes, sham-exposed
Examinations
- Observations and examinations performed and frequency:
- Body weight
Prior to the start of the study, prior to sacrifice, and at least monthly during exposures to verify growth in rats and deprivation maintenance in monkeys.
Behavioral testing (only in monkeys), Clinical observations, Hematology, Clinical Chemistry, Pathology (gross necropsy and microscopic examination)
Observation daily
Behavioural testing
1 day per week for 12 monkeys, and 5 days per week for 3 monkeys (one in each of the groups)
Haematology
Parameters: hematocrit, haemoglobin concentration number of animals: each monkey, 6 rats per exposure level
time points: monkey – 0 day, 30 days, 90 days, 180 days of exposure; rats –2 days, 5 days, 30days, 90 days, 180 days of exposure
Clinical Chemisty
parameters: T3 and T4 number of animals: each monkey, 6 rats per exposure level
time points: monkey – 0 day, 30 days, 90 days, 180 days of exposure rats –2 days, 5 days, 30 days, 90 days, 180 days of exposure; - Sacrifice and pathology:
- Organ weights
Yes; lungs
Gross and histopathology
all dose groups (2 days of exposure and again 5 days, 1 month, 3 months, 180 days – rats; 11 monkeys were similarly sacrificed immediately after the termination of exposures, 3 monkeys – 4 weeks later)
organs: thyroid, liver, kidneys, spleen, heart, lungs, bone marrow, cerebellum, cerebrum - Other examinations:
- ECG in monkeys before exposures and after the last exposure
- Statistics:
- ANOVA, non-parametric tests
Results and discussion
Results of examinations
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One (control) monkey died near the start of the exposures from causes unrelated to the experiment; 3 rats (control) died, 1 (11 ppm), 4 (25 ppm) – was not significantly different from change
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean body weights of rats exposed to ethanedinitrile at 25 ppm was significantly depressed compared to control
- Food efficiency:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No effects on T3 uptake and T4 concentration
- Urinalysis findings:
- not examined
- Description (incidence and severity):
- There was an increase in response rate in all three groups during the exposure period compared to the baseline period. The mean increase was 20%, 14%, 145% in T-CO, T-11 and T-25 subjects, respectively. The rate changes for each group were evaluated statistically by mean of a randomization test for matched pair. The increase in response rate in the T 25 group was marginally significant. The probability that the rate increases in the T-CO and T-11 groups could have occurred by chance was greater than 0.10
- Immunological findings:
- not examined
- Description (incidence and severity):
- No effects in rats; lungs from control monkeys contained more moisture than lungs from monkeys exposed to ethanedinitrile gas
- Gross pathological findings:
- no effects observed
Effect levels
open allclose all
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- > 25 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 11 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
Target system / organ toxicity
open allclose all
- Critical effects observed:
- no
- System:
- endocrine system
- Critical effects observed:
- no
- System:
- cardiovascular
- Critical effects observed:
- no
- System:
- respiratory system: lower respiratory tract
- Organ:
- lungs
Any other information on results incl. tables
Table8.9.3-3: Results of Behavioral testing
Table 8.9.3-4: Results of Haematology and Clinical chemistry
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Applicant's summary and conclusion
- Conclusions:
- Conclusion
Subchronic 25 ppm ethanedinitrile exposures are marginally toxic, but the evidence on 11 ppm does not support a similar conclusion.
LO(A)EL 25 ppm
NO(A)EL 11 ppm - Executive summary:
Materials and Methods
Ethanedinitrile (Cyanogen)
Specification
Purity
99% pure
Stability
Not stated
Test Animals
Rhesus monkey, albino rats
Strain
Macacca mulatta, Sprague-Dawley
Source
Charles River
Sex
Male monkeys and rats
Age/weight at study initiation
Not stated
Number of animals per group
5 monkeys per treatment group
30 rats per treatment group
Control animals
Yes
Administration/Exposure
Inhalation
Type of exposure
Whole body
Exposure period
180 days (6 h/day, 5 days/week)
Postexposure period
14 days, 4 weeks or other
Concentration
of test substance
Nominal concentrations 0 ppm; 11 ppm; 25 ppm
Analytical concentrations ≤1 ppm; 11.2 ± 1.5 ppm; 25.3 ± 3.3 ppm
Controls
Sham exposed
Body weight
Prior to the start of the study, prior to sacrifice, and at least monthly during exposures to verify growth in rats and deprivation maintenance in monkeys.
Examination
Behavioral testing (only in monkeys), Clinical observations, Hematology, Clinical Chemistry, Pathology (gross necropsy and microscopic examination)
Observation
Daily
Food consumption
No
Water consumption
No
Behavioural testing
1 day per week for 12 monkeys, and 5 days per week for 3 monkeys (one in each of the groups)
Haematology
Parameters: hematocrit, haemoglobin concentration number of animals: each monkey, 6 rats per exposure level
time points: monkey – 0 day, 30 days, 90 days, 180 days of exposure; rats –2 days, 5 days, 30days, 90 days, 180 days of exposure
Clinical Chemisty
parameters: T3 and T4
number of animals: each monkey, 6 rats per exposure level
time points: monkey – 0 day, 30 days, 90 days, 180 days of exposure rats –2 days, 5 days, 30 days, 90 days, 180 days of exposure;
Organ weights
Yes; lungs
Gross and histopathology
all dose groups (2 days of exposure and again 5 days, 1 month, 3 months, 180 days – rats; 11 monkeys were similarly sacrificed immediately after the termination of exposures, 3 monkeys – 4 weeks later)
organs:
thyroid, liver, kidneys, spleen, heart, lungs, bone marrow, cerebellum, cerebrum
Statistics
ANOVA, non-parametric tests
Others
ECG in monkeys before exposures and after the last exposure
Results and Discussion
Clinical symptoms
Behavioral testing
There was an increase in response rate in all three groups during the exposure period compared to the baseline period. The mean increase was 20%, 14%, 145% in T-CO, T-11 and T-25 subjects, respectively. The rate changes for each group were evaluated statistically by mean of a randomization test for matched pair. The increase in response rate in the T‑25 group was marginally significant. The probability that the rate increases in the T-CO and T-11 groups could have occurred by chance was greater than 0.10
Mortality
One (control) monkey died near the start of the exposures from causes unrelated to the experiment; 3 rats (control) died, 1 (11 ppm), 4 (25 ppm) – was not significantly different from change
Body weight
Mean body weights of rats exposed to ethanedinitrile at 25 ppm was significantly depressed compared to control
Water consumption
and compound intake
Not reported
Haematology
No consistent effects
Clinical chemistry
No effects on T3 uptake and T4 concentration
Urinalysis
Not reported
Gross and histopathology
No effects
Organ weight
No effects in rats; lungs from control monkeys contained more moisture than lungs from monkeys exposed to ethanedinitrile gas
Materials amd methods
Ethanedinitrile (CN)2, subchronic (180 days) inhalation toxicity study.
Six months (6h/day, 5 days/week) inhalation exposure was conducted with ethanedinitrile gas using male rhesus monkeys (Macacca mulatta) and male albino rats (Charles River Strain). Fifteen monkeys and 90 rats were divided into three groups of 5 monkeys and 30 rats. One group, the Controls, was exposed to the air; the other two groups were exposed to ethanedinitrile concentrations of 11 or 25 ppm.
Results and discussion
At the end of the 6 months exposure, there were no differences in hematologic or clinical chemistry (T3, T4) parameters attributable to the inhalation exposure to ethanedinitrile. The electrocardiograms, and gross pathologic and histopatologic examinations of the test animals were normal when compared with the control animals. Total lung moisture content was significantly lower in monkeys exposed to either 11 ppm or 25 ppm ethanedinitrile than in control animals; no differences were found in rats. Body weights were significantly lower in rats exposed to 25 ppm than in controls.
There was a doubling of the rate of responding on a variable interval 2.9 min schedule of reinforcement in monkeys exposed to 25 ppm ethanedinitrile, and increases were also seen in the monkeys exposed to 11 and 0 ppm; the increases were transitory as the rate returned to control levels before exposures were terminated.
Conclusion
Subchronic 25 ppm ethanedinitrile exposures are marginally toxic, but the evidence on 11 ppm does not support a similar conclusion.
LO(A)EL 25 ppm
NO(A)EL 11 ppm
Table8.9.3-3: Results of Behavioral testing
Operant Response Rate (mean number of responses/hour)
Group
Animal number
baseline
exposure
T – CO
2
491
818
8
1064
1036
15
1091
954
18
109
436
Mean
689
811
T – 11
2
327
791
4
1064
1391
5
600
1036
11
191
464
16
1745
845
Mean
785
905
T –25
1
627
1254
6
245
1173
10
191
409
12
191
464
17
273
355
Mean
305
731
Table 8.9.3-4: Results of Haematology and Clinical chemistry
Rats
Monkeys
Day
group
2
5
30
90
180
0
30
90
180
Hemoglobin concentration (g/100 mL)
T–CO
13.7
15.8
15.5
14.6
14.4
14.0
13.2
14.0
13.7
T–11
14.5
16.1
16.5
14.4
15.3
13.5
12.1
13.2
12.8
T–25
14.4
15.8
15.2
15.2
15.3
13.3
12.0
12.9
13.3
Hematocrit Value (%)
T–CO
44
48
48
45
38
43
39
43
41
T–11
46
49
48
44
39
42
36
41
39
T–25
47
50
46
45
39
40
36
40
40
T3% Uptake
T–CO
47.4
46.9
45.9
48.4
41.2
25.8
22.3
27.9
24.8
T–11
47.7
46.5
45.8
48.6
44.2
33.6
28.7
31.5
30.4
T–25
47.8
46.4
43.6
47.0
41.6
32.0
24.4
29.9
26.2
T4mg/100 mL
T–CO
5.6
5.3
5.2
7.8
3.4
7.5
7.7
7.2
10.4
T–11
5.6
3.9
4.3
7.1
5.1
6.4
6.4
5.5
7.7
T–25
4.6
3.8
4.6
8.4
4.3
8.4
7.8
9.2
9.5
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