Registration Dossier

Administrative data

Description of key information

No mortality following 4 hours exposures as high as 405000 ppm (1887300 mg/m3) in rats or  1 hour exposure as high as 100000 ppm (466000 mg/m3) in rabbits.

Key value for chemical safety assessment

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The number of animals and parameters met and exceeded the criteria in the OECD 403 guideline. Rabbits are not the standard species for this study and exposure time was 1 hour. This study was conducted under GLP conditions and is sufficiently robust for this to be considered a reliable study.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Principles of method if other than guideline:
To evaluate the acute toxicity of the test material under conditions simulating exposure from an automobile accident in the rabbit, the most sensitive species following repeated exposure.
GLP compliance:
yes
Remarks:
US laboratory, no certificate available
Test type:
other: acute inhalation toxicity study in rabbits
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:Robinson Services, Inc., Mocksville, North Carolina 27028
- Age at study initiation:Approximately 5 to 6 months
- Weight at study initiation: Phase 1 - non pregnant female 3178 gm, presumed pregnant female 3153 gm; phase 2 males 2994 gm, females (non pregenant) 3258 gm, females - presumed pregnant 3444 gm
- Fasting period before study: no
- Housing:individually in suspended cages with grid bottoms
- Diet : ad libitum except during exposure
- Water: ad libitum except during exposure
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature :17 to 21 °C
- Humidity :32 to 64%
- Air changes (per hr): 10 to 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: November 2011
Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1.0 m3 glass and stainless steel exposure chamber
- Exposure chamber volume: 1000 liters
- Method of holding animals in test chamber: animals housed in suspended stainless steel cages
- Source and rate of air: 210-225 liters/minute air
- System of generating particulates/aerosols:not applicable - substance is a gas
- Method of particle size determination:TSI Aerodynamic Particle Sizer
- Treatment of exhaust air:in-house filtering system, which consisted of a coarse filter, a HEPA filter and activated charcoal
- Temperature, humidity, pressure in air chamber:19 to 22 °C, 49 to 66%
- Supplemental oxygen was provided

TEST ATMOSPHERE
- Brief description of analytical method used: MIRAN Ambient air analyzer
- Samples taken from breathing zone: yes



TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Exposure essentially all gas only. No substantial differences between test chambers and controls.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): not relevant

Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
ca. 1 h
Concentrations:
0, 50000 or 100000 ppm (233000 or 466000 mg/m3)
No. of animals per sex per dose:
Phase 1 - 1 non pregnant female, 1 presumed pregnant female
Phase 2 - 5 males, 6 presumed pregnant (GD12) females, 5 non pregnant females per dose
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
- body weight - Phase 1 - daily (prior to exposure and for 2 days following exposure), Phase 2 - prior to exposure and study days 3,5,8, and 15 (gestation days 14, 16, 19, and 26 for presumes pregnant females.
- Detailed physical examinations - daily
- Examinations made at least once during exposure
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, and metabolism (urine was collected in 12 hour intervals for 48 hours after the end of the exposure and analyzed by 19F-NMR and LC/MS-MS.)
Statistics:
The cumulative body weight change from baseline and body weights in Phase 2 were identified as continuous. Test substance treated groups were then compared to the control using appropriate statistical tests.
Sex:
male/female
Dose descriptor:
LCLo
Effect level:
> 100 000 ppm
Based on:
test mat.
Exp. duration:
1 h
Remarks on result:
other: including pregnant females
Mortality:
No mortality was observed in any group
Clinical signs:
other: No clinical signs of toxicity were observed in any group
Body weight:
No effects on body weight observed in any group
Gross pathology:
No gross pathology observed in any group
Other findings:
- Organ weights: no effect observed in any group
- Histopathology:no effect observed in any group
- Potential target organs: none
- Urinary metabolites:The predominant urinary metabolites were S-(3,3,3-trifluoro-2-hydroxypropanyl)-mercaptolactic acid and N-acetyl-S-(3,3,3-trifluoro-2-hydroxypropanyl)-L-cysteine whose signal intensities in 19F-NMR spectra represented more than 78% of total 19F related signals in all urine analyzed samples. Quantification of the mercapturic acid metabolite isomers by LC/MS-MS showed no difference in the mean recovery of this metabolite between female (43.11 ± 22.35 µmol) and pregnant female rabbits (50.47 ± 19.72 µmol) excreted in urine within 48 hours. With the exception of one yet unidentified metabolite (12-17% female rabbits and < 7% male rabbits of the six main metabolites), no differences in urinary metabolite pattern or quantity of metabolites excreted were observed between the different groups.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
In conclusion, no lethality and no clinical signs of toxicity were observed in male, female, or presumed pregnant female (gestation day 12) rabbits exposed for one hour to the test substance at concentrations as high as 100000 ppm (466000 mg/m3).
Executive summary:

In conclusion, no lethality and no clinical signs of toxicity were observed in male, female, or presumed pregnant female (gestation day 12) rabbits exposed for one hour to the test substance at concentrations as high as 100000 ppm (466000 mg/m3). According to the CLP regulation (EC No 1272/2008), a one hour inhalation exposure can be extrapolated to a 4 hour value by dividing by a factor of 2 for gases. Using this conversion, it is estimated that an equivalent 4 hour exposure would be 50000 ppm (233000 mg/m3).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Value:
466 000 mg/m³

Additional information

In an OECD 403 guideline study, 10 Sprague Dawley rats (5 males and 5 females) were exposed to 201600 or 405000 ppm (939456 or 1887300 mg/m3) HFO-1234yf in atmosphere for 4 hours. No mortality was observed within 14 days after the exposure. Decreased breathing rates were reported for 2 males and 2 females at 201600 ppm and in all animals exposed to 405000 ppm. The lowest lethal dose (LDLo) was > 405000 ppm (highest exposure level tested) for this study.

In another study conducted for the USEPA, 15 males (5/group) and 28 female (6/group presumed pregnant and 5/group 1 and 3) rabbits were exposed to air (Group 1) , 50000 ppm (233000 mg/m3; group 2), or 100000 ppm (466000 mg/m3: group 3) for 1 hour. As requested by the USEPA, the presumed pregnant females were exposed on gestation day 12. No signs of toxicity including viability, clinical signs, body weights or histopathology of selected organs were observed at any concentration. The NOAEC was 100000 ppm (highest exposure tested).


Justification for selection of acute toxicity – inhalation endpoint
Based on results from the developmental toxicity studies, rabbits appear to be more sensitive than rats.

Justification for classification or non-classification

No lethality or significant toxicity was observed following a 4 hour exposure of up to 405000 ppm (1887300 mg/m3) in rats or a 1 hour exposure of up to 100000 ppm (466000 mg/m3) in rabbits. Therefore the substance does not need to be classified for acute toxicity according to EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) N0.1272/2008.