(1Z)-1-Chloro-2,3,3-trifluoroprop-1-ene

Repeated dose toxicity: inhalation

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

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

(1Z)-1-chloro-2,3,3-trifluoroprop-1-ene

EC Number:

824-458-3

Cas Number:

1263679-68-0

Molecular formula:

C3H2ClF3

IUPAC Name:

(1Z)-1-chloro-2,3,3-trifluoroprop-1-ene

impurity 1

Reference substance name:

(1E)-1-Chloro-2,3,3-trifluoroprop-1-ene

Cas Number:

102687-65-0

Molecular formula:

C3H2ClF3

IUPAC Name:

(1E)-1-Chloro-2,3,3-trifluoroprop-1-ene

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 / concentrations

Doses / concentrations 1

Dose / conc.:

2 500 ppm (nominal)

Doses / concentrations 2

Dose / conc.:

13.56 mg/L air (analytical)

Doses / concentrations 3

Dose / conc.:

5 000 ppm (nominal)

Doses / concentrations 4

Dose / conc.:

26.95 mg/L air (analytical)

Doses / concentrations 5

Dose / conc.:

10 000 ppm (nominal)

Doses / concentrations 6

Dose / conc.:

54.76 mg/L air (analytical)

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 euthanisation 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(Z) 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(Z) 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(Z) 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(Z) 10000 ppm group indicated statistically significant lower value of ALP in comparison with that of the control group. Females of the HCFO1233yd(Z) 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(Z) 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(Z) 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(Z) 5000 ppm group had a higher value of the body weight-relative liver weight, the HCFO-1233yd(Z) 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(Z) 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(Z) 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

1

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

2

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(Z) 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(Z) 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(Z) 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(Z) 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.