2,2,3,3,4,4,5,5-octafluoropentyl methacrylate

Repeated dose toxicity: inhalation

Administrative data

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

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

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

Reason / purpose for cross-reference:

reference to same study

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

Specific details on test material used for the study:

- Source and lot/batch No.of test material: Lot no. 900638318
- Purity: 99.7%

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

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.

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.

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.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

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 2-methylprop-2-enoate

Test material form:

liquid

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%

Test animals

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

Administration / exposure

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.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

81 ppm (nominal)

Remarks:

targeted: 42 ppm, actual 40 ppm

Doses / concentrations 2

Dose / conc.:

169 ppm (nominal)

Remarks:

targeted: 84 ppm; actual: 89 ppm

Doses / concentrations 3

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

Examinations

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.

Results and discussion

Results of examinations

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

Effect levels

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

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

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.