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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
26/08/2016 - 24/10/2016
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report Date:
2016

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
impurity
Test material form:
gas: vapour

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
The rats held in the restraint tubes were connected to the chamber to start exposure after supplying the test atmosphere to the chamber. The rats were dismounted from the chamber to terminate exposure 6 hours after the start of exposure.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
GC: GC-14B (Shimadzu Corp.)
Recorder: D-7500 (Hitachi, Ltd., Tokyo, Japan)
Syringe: Micro syringe (10 and 100 μL: Hamilton Company, NV, USA) 1 mL gastight syringe (#1001: Hamilton Company)
Sampling bag: 1.56 L of inner volume (actual inner volume, Smart bag: GL Sciences Inc., Tokyo, Japan)
Duration of treatment / exposure:
6 hours
Frequency of treatment:
5 times a week for 2 weeks
Doses / concentrationsopen allclose all
Dose / conc.:
2 500 ppm (nominal)
Dose / conc.:
13.56 mg/L air (analytical)
Remarks:
2,540 ppm
Dose / conc.:
5 000 ppm (nominal)
Dose / conc.:
26.95 mg/L air (analytical)
Remarks:
5,050 ppm
Dose / conc.:
10 000 ppm (nominal)
Dose / conc.:
54.76 mg/L air (analytical)
Remarks:
10,260 ppm
No. of animals per sex per dose:
6
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
Daily observation was conducted from the first day of exposure to the day of necropsy.
The observation frequency was shown below:
Exposure day: twice a day (before and after exposure)
Other day: once a day
Sacrifice and pathology:
All animals were subjected to necropsy on day 15.
The animals were subjected to necropsy after the euthanization by exsanguination from the abdominal aorta after blood collection.
Statistics:
Initially, variance was assessed using Bartlett's test (significance level: 5%). When the
variance was homogeneous, multiple comparison test was conducted using Dunnett's
method. When the variance was heterogeneous, multiple comparison test was
conducted using Steel test. The multiple comparison tests were conducted by two-tailed
test with significance level of 1% and 5%.
The numerical data obtained from the animals subjected to the recovery period, variance
was assessed using F test (significance level: 5%). When the variance was
homogeneous, group difference comparison test was conducted using t-test, otherwise
Aspin-Welch test was applied (two-tailed test, significance level: 1% and 5%).

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
In the 10,000 ppm group, drowsiness and ataxic gait were observed in males and females at observation after exposure. Moreover, rale was sporadically observed in females of this group after exposure.
Mortality:
mortality observed, treatment-related
Description (incidence):
On day 7, one female of the HCFO-1233yd 10000 ppm group died after exposure.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant lower body weights were noted in males of the HCFO-1233yd 10000 ppm group on each measurement day on and after day 4 in comparison with those of the control group.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no remarkable changes in the ophthalmological findings from the pre-exposure period to the exposure period. Several spontaneous findings were noted in a few animals including the control group.
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Males of the HCFO-1233yd 5000 and 10000 ppm groups indicated statistically significant lower values of WBC and lymphocytes count in comparison with those of the control group.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Males of the HCFO-1233yd 10000 ppm group indicated statistically significant lower value of ALP in comparison with that of the control group. Females of the HCFO1233yd 10000 ppm group indicated higher value of ALAT and lower value of ALP. The low value of ALP does not have toxicological significance.

As no exposure concentration dependent change, lower value of ASAT was noted in females of the HCFO-1233yd 5000 ppm group. This change was considered to be incidental.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Males of the HCFO-1233yd 10000 ppm group had statistically significant higher value of the body weight-relative liver weight and lower value of the absolute spleen weight in comparison with those of the control group. In females, the HCFO-1233yd 5000 ppm group had a higher value of the body weight-relative liver weight, the HCFO-1233yd 10000 ppm group had higher values of the absolute and body weight-relative liver weights, and lower value of the body weight-relative spleen weight.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Edema of the lungs was observed in female of the HCFO-1233yd 10000 ppm group, which died after exposure.

No abnormalities attributable to the test substance were noted in males or females in the animals subjected to the necropsy after the exposure period. Unilateral small testis was found in one male of the HCFO-1233yd 2500 ppm group. Since this finding did not have exposure concentration dependency, it was considered to incidental change.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEC
Effect level:
26.95 mg/L air (analytical)
Based on:
test mat.
Sex:
male
Basis for effect level:
organ weights and organ / body weight ratios
Key result
Dose descriptor:
NOAEC
Effect level:
13.56 mg/L air (analytical)
Based on:
test mat.
Sex:
female
Basis for effect level:
organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
Subacute inhalation toxicity of HCFO-1233yd in rats was evaluated by repeated 14-day inhalation exposure.

The actual exposure concentrations were 2540 ppm (13.56 mg/L), 5050 ppm (26.95 mg/L), and 10260 ppm (54.76 mg/L) to the target exposure concentrations of 2500, 5000, and 10000 ppm, respectively.

In the HCFO-1233yd 10000 ppm group, one female died on day 7. Edema of the lungs was observed in this animal. When the test substance was exposed at 10000 ppm, drowsiness and ataxic gait were observed in males and females, rale was observed in females. Males indicated lower value of body weight. Higher value of ALAT was induced by the test substance exposure in females. In organ weight, higher value of the liver and lower value of the spleen were noted in males and females. In the HCFO-1233yd 5000 ppm group, there was higher value of the liver weight in females. Drowsiness and ataxic gait suggested that the test substance has anesthetic action.

Since the changes in WBC and lymphocytes count in the HCFO-1233yd 5000 and 10000 ppm groups indicated exposure concentration dependency, it was not able to rule out the possibility of attributable to the test substance in these changes. However, the observed values were within the background data of the test facility. Therefore, it was concluded that the changes in hematology were not adverse effects by the test substance.
Executive summary:

The test substance exposure at 54.76 mg/L resulted in the changes of clinical sign, body weight, blood chemistry, and organ weight.  Since, the similar change in organ weight was also noted in females exposed to 26.95 mg/L, it is concluded that no-observed-adverse effect-level of the test substance is 26.95 mg/L in males and 13.56 mg/L ppm in females as actual concentration in this study.