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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
12 March 1992 to 27 July 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted under GLP conditions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Liquid
Details on test material:
- Name of test material (as cited in study report: T-5452
- Substance type: Colourless liquid
- Physical state: Liquid
- Lot/batch no.: 102
- Storage condition of test material: Ambient in steel drums supplied

Test animals

Species:
rat
Strain:
other: Sprague-Dawley CD
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (U.S.A.) Ltd., Portage, Michigan, U.S.A.
- Age at study initiation: Approximately 6 weeks
- Weight at study initiation: Males: 234-238 g, Females: 187-190 g
- Fasting period before study: No data
- Housing: 5 of the same sex to a cage in suspended cages with stainless steel sides and stainless steel mesh floors.
- Diet (e.g. ad libitum): SDS Rat and Mouse No. 1 modified diet (Special Diets Services, Witham, Essex, England) ad libitum.
- Water (e.g. ad libitum): Tap water ad libitum.
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26
- Humidity (%): 37-61
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12-12
IN-LIFE DATES: From: 12 March 1992 To: 27 July 1992

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: no vehicle
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Vapour was produced by metering the liquied from a central pressurised reservoir, mounted on a load cell, to a helical copper tube immerced in a water bath maintained at 80 C. Vapour emerging from the tube was mixed with air which had been pre-warmed by being passed at a rate of 40 L/min through a second copper tube, also immersed in the water bath. The vapour/air mixture was passed through a nylon tube to the base of a glass column where it was mixed with diluent air introduced at a rate of 110 L/min. A serparate reservoir and vaporiser was used for each dose level.
- Method of holding animals in test chamber: Rats were held within individual compartments of stainless steel wire mesh cages during exposure.
- Source and rate of air: Pre-warmed air at a rate of 40 L/min (vapour) and prewarmed air at 110 L/min (diluent air).
- Method of conditioning air: Water bath.
- System of generating particulates/aerosols:
- Temperature, humidity, pressure in air chamber: Approx. 23.5-24.5 C, Approx. 31-45 % RH, 10 mm of water below ambient.
- Air flow rate: 150 L/min total
- Air change rate: No data.
TEST ATMOSPHERE
- Brief description of analytical method used: Atmospheres were monitored throughout exposure by Miran 1A-CVF infra-red gas analysers.
- Samples taken from breathing zone: no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Atmospheres were monitored throughout exposure by Miran 1A-CVF infra-red gas analysers.
Duration of treatment / exposure:
6 hours per exposure
Frequency of treatment:
5 days a week for 13 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
4971 ppm, 15094 ppm, and 49589 ppm
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: No data
- Rationale for selecting satellite groups: Randomly by a computer program.
- Post-exposure recovery period in satellite groups: 4 weeks
Positive control:
None

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily, prior to loading and immediately following unloading from the chambers on exposure days.
- Cage side observations checked in appendix 4 were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice daily, prior to loading and immediately following unloading from the chambers on exposure days.
BODY WEIGHT: Yes
- Time schedule for examinations: At group allocation, them weekly, commecing 1 week before the start of dosing and continuing throughout the study.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each cage of rats was recorded weekly commencing one week prior to the start of exposures until the end of the study.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: All rats examined prior to allocation.
- Dose groups that were examined: All
HAEMATOLOGY: Yes
- Time schedule for collection of blood: During week 13 (main group), week 17 for satellite group.
- Anaesthetic used for blood collection: Yes (ether).
- Animals fasted: Yes, overnight.
- How many animals: All animals.
- Parameters checked in table 8 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: During week 13 (main group), week 17 for satellite group.
- Animals fasted: Yes, overnight
- How many animals: All animals.
- Parameters checked in table 9 were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
All analyses were carried out separately for males and females.
(i) If the data consisted predominantly of one particular value (relative frequency of the mode
exceeds 75 %) the proportion of animals with values different from the mode was analysed by
appropriate methods. Otherwise:
(ii) Bartlett's test (1) was applied to test for heterogeneity of variance between treatment; where
significant (at the 1% level) heterogeneity was found, a logarithmic transformation was tried
to see ifa more stable variance structure could be obtained.
(iii) If no significant heterogeneity was detected (or if a satisfactory transformation was found), a
one-way analysis of variance was carried out. If significant heterogeneity of variance was
present, and could not be removed by a transformation, the Kruskal-Wallis analysis of ranks
(2) was used.
(iv) Except 'for pre-exposure data, analyses of variance were followed by Student's; 't' test and
Williams' test (3) for a dose-related response, although only Williams' test was reported. The
Kruskal--Wallis analyses were followed by Shirley's test (4), the non-parametric equivalent of
the 't' and Williams' tests.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
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:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: No abnormal clinical signs were observed. Rat no. 70 from the control group died in the holding cage before exposure during week 9 of the study. The cause of death is unknown.
BODY WEIGHT AND WEIGHT GAIN: No treatement related effects were observed.
FOOD CONSUMPTION AND COMPOUND INTAKE: No treatement related effects were observed.
OPHTHALMOSCOPIC EXAMINATION: No treatement related effects were observed.
HAEMATOLOGY: No treatement related effects were observed.
CLINICAL CHEMISTRY: No treatement related effects were observed.
ORGAN WEIGHTS: No treatement related effects were observed.
GROSS PATHOLOGY: No treatement related effects were observed.
HISTOPATHOLOGY: NON-NEOPLASTIC: No treatement related effects were observed.

Effect levels

Dose descriptor:
NOAEL
Effect level:
ca. 49 589 ppm (analytical)
Sex:
male/female
Basis for effect level:
other: overall effects clinical signs; mortality; body weight; food consumption; ophthalmoscopic examination; haematology; clinical chemistry; gross pathology; organ weights; histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Analogue substance info is referenced in the Category Reporting Format---> attached in section 13.

Applicant's summary and conclusion

Conclusions:
The No Observed Adverse Effect Level for the test article under the conditions of the study was 49589 ppm.
Executive summary:

Perfluoro-N-methylmorpoline has been used as a Read Across-Analogue to derive a NOAEL for FC-770 Repeat Dose Inhalation requirement. The target and the source molecule are both members of a category of chemicals referred to as ‘Perfluoro-compounds C5 through C18'. PFCs are inert fluids composed of a complex combination of organic compounds resulting from the distillation of electrochemically fluorinated (ECF) compounds. This class consists of branched, linear and cyclic perfluorinated hydrocarbons having carbon numbers predominantly in the range of C5-C18 and boiling in the range of approximately 25 C to 255 C (77 F – 491 F). Perfluorinated amine and ether compounds may also be present. The compounds within this class of materials are all fully fluorinated and do not contain functional groups. As such, the materials within this class are all chemically and biologically inert. PFCs have high Henry’s constants which dictates, their low potential for interaction with biological membranes. The available data on this class of material demonstrates very consistent properties with regard to human health and environmental impact. The commonalities within this class are not surprising given the underlying physical/chemical properties

The 90 day inhalation toxicity of the test article was tested in Sprague-Dawley CD rats. Rats were whole-body exposed to the test article for 6 hour a day, 5 days a week, for 13 weeks at dose levels of 4971, 15094, and 49589 ppm. Control rats were similarly exposed to air on the same schedule. A satellite group was observed for an additional 4 weeks after sacrifice of the main group. Clinical signs were recorded twice daily, usually prior to loading and immediately following unloading from the chambers on exposure days. Body weights were recorded at group allocation, then weekly commencing one week prior to the start of exposures until the end of study. The quantity of food consumed by each cage of rats was recorded weekly commencing one week prior to the start of exposures until the end of the study. The eyes of all rats were examined prior to allocation and at study conclusion. Blood samples (fasted) were taken from all main group rats during week 13 and from the satellite group on week 17. Haematology and clinical chemistry parameters were examined from the blood samples. At week 13 (main group) and week 17 (satellite group) the animals were sacrificed and subject to gross necropsy. Microscopic examination of the tissues listed in Table 11 was also conducted. No treatment related changes in any parameters were observed due to test article exposure. The No Observed Adverse Effect Level for the test article under the conditions of the study was 49589 ppm.