Oxalonitrile

Specific investigations: other studies

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

endocrine system modulation

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

Principles of method if other than guideline:

Cyanogen (CN)2, subchronic (180 days) inhalation toxicity study.
A 6-month (6 hr/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

Type of method:

in vivo

Specific details on test material used for the study:

ethanedinitrile 99%

Species:

other: albino rats and Rhesus monkeys

Strain:

other: Charles River Sprague-Dawley COBS, Macacca mulatta

Sex:

male

Details on test animals or test system and environmental conditions:

Source: Charles River

Route of administration:

inhalation: gas

Vehicle:

air

Duration of treatment / exposure:

180 days

Frequency of treatment:

6h/d, 5d/w

Post exposure period:

no/ 2 weeks/ 4 weeks

Dose / conc.:

0 ppm

Dose / conc.:

11 ppm

Remarks:

analytical 11.2 ±1.5 ppm

Dose / conc.:

25 ppm

Remarks:

analytical 25.3 ±3.3 ppm

No. of animals per sex per dose:

rats: 30 per exposure group
monkeys: 5 per exposure group

Control animals:

yes

Examinations:

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
Behavioural 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 Chemistry
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, 30days, 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 months, 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

Details on results:

Clinical symptoms

Behavioural 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.

Haematology
No consistent effects

Clinical chemistry
No effects on T3 uptake and T4 concentration

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

Test	Tested organism	Concentration Dose	Result	Reference
180-day inhalation of ethanedinitrile	rhesus monkeys	11 or 25 ppm ethanedinitrile 6 h/d 5 d/w	No relevant changes in triiodothyronine and thyroxine blood levels	Lewis et al. 1984

Conclusions:

The 6 months study in rats and monkeys revealed no adverse effect relevant for human health, as a change in the morphology, physiology, or, life span of organisms, that would result in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress, or an increase in susceptibility to other influences (Lewis et al. 1984). Further the study did not reveal an endocrine mode of action or the adverse effect relevant for human health as a consequence of the endocrine mode of action. There was no significant change in the measured blood levels of the thyroid hormones, triiodothyronine (T3) and its prohormone, thyroxine (T4), in exposed animals compared to control, or any pathological effect found on endocrine organs (Lewis et al. 1984). There is no study reporting the endocrine disruption caused by ethanedinitrile.

Executive summary:

Materials and methods Cyanogen (CN)2, subchronic (180 days) inhalation toxicity study. A 6-month (6 hr/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 histopathologic 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

Reference 2

Endpoint:

phototoxicity

Remarks:

Test not needed, because active substance does not absorb electromagnetic radiation in the range 290–700 nm.

Conclusions:

Test not needed, because active substance does not absorb electromagnetic radiation in the range 290–700 nm.

Executive summary:

Test not needed, because active substance does not absorb electromagnetic radiation in the range 290–700 nm.

Description of key information

There was no significant change in the measured blood levels of the thyroid hormones, triiodothyronine (T3) and its prohormone, thyroxine (T4), in exposed animals compared to control, or any pathological effect found on endocrine organs (Lewis et al. 1984). There is no study reporting the endocrine disruption caused by ethanedinitrile.

Ethanedinitrile does not absorb electromagnetic radiation in the range 290–700 nm.