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Administrative data

Endpoint:
acute toxicity: inhalation
Remarks:
5-day tolerability study
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14 July 2009 to 31 August 2009
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Remarks:
5-day study
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
14 July 2009 to 31 August 2009
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose for cross-reference:
reference to same study
Guideline:
other: In-house protocol for 5-day nose-only inhalation
Principles of method if other than guideline:
In-house protocol. The test substance was administered to test animals via nose-only inhalation for 6 hours per day for 5 consecutive days at targeted vapour dose levels of 42, 84 and 168 ppm. A concurrent control group was exposed to filtered air on a comparable regimen. On the day following the fifth exposure, all test animals were euthanized and subjected to necropsy.
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Lot no. 900638318
- Purity: 99.7%
Species:
rat
Strain:
other: Crl:CD(SD)
Details on species / strain selection:
This species and strain of animal is recognized as appropriate for inhalation studies. The Sprague Dawley rat was selected because it is a widely used strain for which significant historical control data are available.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approximately 7-9 weeks of age at initiation of exposures
- Weight at study initiation: Males - 206-251 g; Females - 147-181 g
- Housing:housed individually
- Diet: ad libitum throughout the study except during restraint acclimation, exposure periods, and prior to the scheduled necropsy.
- Water:ad libitum throughout the study except during restraint acclimation, exposure periods, and prior to the scheduled necropsy.
- Acclimation period: 12 days acclimation/pretest period; 5 days in nose-only exposure tubes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.2°C to 21.8°C
- Humidity (%): 43.1% to 47.5%
- Air changes (per hr): a minimum of 10 fresh air changes per hour
- Photoperiod (hrs dark / hrs light):12 / 12

IN-LIFE DATES: From: 26 July 2009 To: 31 July 2009
Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
other: nitrogen gas mixed with filtered air
Details on inhalation exposure:
In-house protocol. The test substance was administered to test animals via nose-only inhalation for 6 hours per day for 5 consecutive days at targeted vapour dose levels of 42, 84 and 168 ppm. A concurrent control group was exposed to filtered air on a comparable regimen.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyzed exposure concentrations were determined at approximately 35-minute intervals using an appropriate gas chromatography (GC) method. During the method development phase of the study, the stability over time and the spatial homogeneity of the test substance vapour concentration within each test chamber were evaluated. The stability and homogeneity results were considered to be adequate for the purpose of this study. During the method development phase, the test substance exposure systems were monitored for aerosol formation. Aerosol formation was not observed in any test substance exposure system.
Duration of treatment / exposure:
The test substance or compressed air (control group) was administered as a daily 6-hour nose-only inhalation exposure for 5 days.
Frequency of treatment:
The test substance or compressed air (control group) was administered as a daily 6-hour nose-only inhalation exposure for 5 consecutive days.
Dose / conc.:
81 ppm (nominal)
Remarks:
targeted: 42 ppm, actual 40 ppm
Dose / conc.:
169 ppm (nominal)
Remarks:
targeted: 84 ppm; actual: 89 ppm
Dose / conc.:
219 ppm (nominal)
Remarks:
targeted: 168 ppm; actual: 168 ppm
No. of animals per sex per dose:
5/sex/dose
Control animals:
yes
Details on study design:
The test substance exposure concentrations were selected by the Sponsor based on toxicity information from structurally related materials and levels needed to provide adequate safety margins based on estimated human exposure levels.
Positive control:
None
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed twice daily, once in the morning and once in the afternoon, for mortality and moribundity.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical examinations were performed 3 times daily, prior to exposure, during exposure (at the approximate midpoint), and approximately 0-1 hour following the end of exposure (designated as 1 hour post-exposure for report presentation purposes).

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded during the pretest period, prior to randomization, and prior to the first (study day 0) and last (study day 4) exposures.

FOOD CONSUMPTION AND COMPOUND INTAKE: Individual food consumption was recorded for 1 week during the pretest period and on study days 0 and 4.
Sacrifice and pathology:
On the day following the fifth exposure, all test animals were euthanized and subjected to necropsy. Microscopic examination was performed on all animals in the control and 168 ppm groups (Groups 1 and 4, respectively) at the scheduled necropsy. Gross lesions were examined from all animals.
Statistics:
All statistical tests were performed using appropriate computing devices or programs.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
All clinical findings in the test substance-treated groups were noted with similar incidence in the control group, were limited to single animals, were not noted in a dose-related manner and/or were common findings for laboratory rats of this age and strain.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test substance-related macroscopic findings at the scheduled necropsy. All macroscopic findings noted were considered to be spontaneous and/or incidental in nature and unrelated to test substance administration.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test substance-related microscopic findings. All findings observed were consistent with normal background lesions in clinically normal rats of the age and strain used on this study and were considered spontaneous and/or incidental in nature and unrelated to test substance administration.
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Key result
Dose descriptor:
NOAEL
Effect level:
168 ppm (analytical)
Based on:
test mat.
Remarks:
highest concentration tested
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical signs
gross pathology
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
Critical effects observed:
no
Conclusions:
Based on the results of this study, exposure of rats to the test substance via 6-hour nose-only inhalation for 5 consecutive days at exposure concentrations ≤168 ppm did not result in any test substance-related effects or dose-limiting toxicity. Therefore, the no-observed-adverse-effect level (NOAEL) for nose-only inhalation exposure of the test substance to rats for 5 consecutive days was 168 ppm, the highest exposure concentration tested.
Executive summary:

The test substance was administered via nose-only inhalation for 6 hours per day for 5 consecutive days to 3 groups (Groups 2, 3, and 4) of rats. Target exposure concentrations were 42, 84, and 168 ppm for Groups 2, 3, and 4, respectively. A concurrent control group (Group 1) was exposed to filtered air on a comparable regimen. Each group consisted of 5 animals/sex. On the day following the fifth exposure, all animals were euthanized and subjected to necropsy.

 

The animals were observed twice daily for mortality and moribundity. Clinical examinations were performed 3 times daily (prior to exposure, at the approximate exposure midpoint, and approximately 0 to 1 hour following the end of exposure), and detailed physical examinations were performed for randomization and during the exposure phase on study days 0 and 4. Individual body weights and food consumption were recorded at least weekly during the pretest phase and on study days 0 and 4. Complete necropsies were performed on all animals, and the liver, lungs, and kidneys were weighed at the scheduled necropsy. The kidneys, larynx, liver, lungs, nasal cavity (with turbinates), pharynx, trachea, and urinary bladder were examined microscopically from all animals in the control and 168 ppm group (Groups 1 and 4, respectively). Gross lesions were examined microscopically from all animals (when possible).

 

There were no test substance-related effects on survival or clinical observations. There were no apparent test substance-related effects on body weights, body weight changes, food consumption, organ weights, or macroscopic and microscopic findings at any exposure concentration.

 

Based on the results of this study, exposure of rats to the test substance via 6-hour nose-only inhalation for 5 consecutive days at exposure concentrations ≤168 ppm did not result in any test substance-related effects or dose-limiting toxicity. Therefore, the no-observed-adverse-effect level (NOAEL) for nose-only inhalation exposure of the test substance to rats for 5 consecutive days was 168 ppm, the highest exposure concentration tested.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report date:
2010

Materials and methods

Test guideline
Guideline:
other: In-house nose-only inhalation study
Principles of method if other than guideline:
In-house protocol. The test substance was administered to test animals via nose-only inhalation for 6 hours per day for 5 consecutive days at targeted dose levels of 42, 84 and 168 ppm. A concurrent control group was exposed to filtered air on a comparable regimen. On the day following the fifth exposure, all test animals were euthanized and subjected to necropsy.
GLP compliance:
yes
Test type:
other: 5-day tolerability study
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2,2,3,3,4,4,5,5-octafluoropentyl methacrylate
EC Number:
206-596-0
EC Name:
2,2,3,3,4,4,5,5-octafluoropentyl methacrylate
Cas Number:
355-93-1
Molecular formula:
C9H8F8O2
IUPAC Name:
2,2,3,3,4,4,5,5-octafluoropentyl methacrylate
Test material form:
liquid
Specific details on test material used for the study:
- Source and lot/batch No.of test material: Lot no. 900638318
- Purity: 99.7%

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approximately 7-9 weeks of age at initiation of exposures
- Weight at study initiation: Males - 206-251 g; Females - 147-181 g
- Housing: housed individually
- Diet: ad libitum throughout the study except during restraint acclimation, exposure periods, and prior to the scheduled necropsy.
- Water: ad libitum throughout the study except during restraint acclimation, exposure periods, and prior to the scheduled necropsy.
- Acclimation period: 12 days acclimation/pretest period; 5 days in nose-only exposure tubes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.2 °C to 21.8 °C
- Humidity (%): 43.1% to 47.5%
- Air changes: a minimum of 10 fresh air changes per hour
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 26 July 2009 To: 31 July 2009

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
other:
Remarks:
nitrogen gas mixed with filtered air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Vapors of the test substance were generated using 1-, 2-, and 3-jet Collison nebulizer for Exposure Systems 2, 3, and 4, respectively as follows: Using a regulator compressed nitrogen was supplied to the nebulizer to generate an aerosol of the test substance. Additional test substance was manually added to the nebulizer during the exposure as needed. Prior to entering the nose-only system, all test substance aerosol was vaporized or removed by a liquid trap. A siphon was placed in-line prior to the nose-only system to adjust the concentration as needed. Using a rotameter-type flow meter, a portion of the test substance atmosphere was siphoned to the in-house vacuum source. Filtered supply air was mixed with the test substance atmosphere prior to entering the nose-only system. Control animals were exposed to compressed nitrogen mixed with filtered supply air using an exposure regimen equivalent to the test substance exposures. Aerosol formation was not observed in any test substance exposure system.

TEST ATMOSPHERE
- Brief description of analytical method used: Analyzed exposure concentrations were determined at approximately 35-minute intervals using a gas chromatograph (GC)
- Samples taken from breathing zone: yes

Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
6 h
Remarks on duration:
The test substance or compressed air (control group) was administered as a daily 6-hour nose-only in halation exposure for 5 consecutive days.
Concentrations:
Nominal: 81, 169, 219 ppm; Targeted: 42, 84, 168 ppm; Actual: 40, 89, 168 ppm

The test substance exposure concentrations were selected by the Sponsor based on toxicity information from structurally related materials and levels needed to provide adequate safety margins based on estimated human exposure levels.
No. of animals per sex per dose:
5/sex/dose
Control animals:
yes
Remarks:
concurrent control group was exposed to filtered air on a comparable regimen
Details on study design:
All animals were observed twice daily, once in the morning and once in the afternoon, for mortality and moribundity.

Clinical examinations were performed 3 times daily, prior to exposure, during exposure (at the approximate midpoint), and approximately 0-1 hour following the end of exposure (designated as 1-hour post-exposure for report presentation purposes).

Individual body weights were recorded during the pretest period, prior to randomization, and prior to the first (study day 0) and last (study day 4) exposures. Final body weights (fasted) were recorded on the day of the scheduled necropsy.

Individual food consumption was recorded for 1 week during the pretest period and on study days 0 and 4.

A complete necropsy was conducted on all animals. The following were collected: kidneys, larynx, liver, and lungs.

Liver and lung weights were recorded at scheduled necropsy.
Statistics:
All statistical tests were performed using appropriate computing devices or programs.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
other: NOAEL
Remarks:
5 days
Effect level:
168 ppm
Based on:
test mat.
Exp. duration:
6 h
Remarks on result:
other: 5-day tolerability study
Mortality:
No mortality observed
Clinical signs:
other: All clinical findings in the test substance-treated groups were noted with similar incidence in the control group, were limited to single animals, were not noted in a dose-related manner and/or were common findings for laboratory rats of this age and stra
Body weight:
No effects observed
Gross pathology:
There were no test substance-related macroscopic findings at the scheduled necropsy. All macroscopic findings noted were considered to be spontaneous and/or incidental in nature and unrelated to test substance administration.
Other findings:
There were no test substance-related microscopic findings. All findings observed were consistent with normal background lesions in clinically normal rats of the age and strain used on this study and were considered spontaneous and/or incidental in nature and unrelated to test substance administration.
No effects observed for organ weight findings.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results of this study, exposure of rats to the test substance via 6-hour nose-only inhalation for 5 consecutive days at exposure concentrations ≤168 ppm did not result in any test substance-related effects or dose-limiting toxicity. Therefore, the no-observed-adverse-effect level (NOAEL) for nose-only inhalation exposure of the test substance to rats for 5 consecutive days was 168 ppm, the highest exposure concentration tested.
Executive summary:

The test substance was administered via nose-only inhalation for 6 hours per day for 5 consecutive days to 3 groups (Groups 2, 3, and 4) of rats. Target exposure concentrations were 42, 84, and 168 ppm for Groups 2, 3, and 4, respectively. A concurrent control group (Group 1) was exposed to filtered air on a comparable regimen. Each group consisted of 5 animals/sex. On the day following the fifth exposure, all animals were euthanized and subjected to necropsy.

The animals were observed twice daily for mortality and moribundity. Clinical examinations were performed 3 times daily (prior to exposure, at the approximate exposure midpoint, and approximately 0 to 1 hour following the end of exposure), and detailed physical examinations were performed for randomization and during the exposure phase on study days 0 and 4. Individual body weights and food consumption were recorded at least weekly during the pretest phase and on study days 0 and 4. Complete necropsies were performed on all animals, and the liver, lungs, and kidneys were weighed at the scheduled necropsy. The kidneys, larynx, liver, lungs, nasal cavity (with turbinates), pharynx, trachea, and urinary bladder were examined microscopically from all animals in the control and 168 ppm group (Groups 1 and 4, respectively). Gross lesions were examined microscopically from all animals (when possible).

There were no test substance-related effects on survival or clinical observations. There were no apparent test substance-related effects on body weights, body weight changes, food consumption, organ weights, or macroscopic and microscopic findings at any exposure concentration.

Based on the results of this study, exposure of rats to the test substance via 6-hour nose-only inhalation for 5 consecutive days at exposure concentrations≤168 ppm did not result in any test substance-related effects or dose-limiting toxicity. Therefore, the no-observed-adverse-effect level (NOAEL) for nose-only inhalation exposure of the test substance to rats for 5 consecutive days was 168 ppm, the highest vapour exposure concentration tested. Applying the ideal gas law, the NOAEL for nose-only inhalation exposure of the test substance to rats for 5 consecutive days was 2 mg/L, the highest vapour exposure concentration tested.

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