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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
other information
Study period:
2013
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
MTDID 28783 was administered via whole-body inhalation exposure for 6 hours per day for 5 consecutive days, to 3 groups (Groups 2-4) of Crl:CD®(SD) rats with the following exception. On study day 2, all surviving 50 ppm group rats (Group 4) were terminated early due to overt signs of toxicity. Target exposure concentrations were 5, 20, and 50 ppm for Groups 2, 3, and 4, respectively. A concurrent control group (Group 1) was exposed to humidified, filtered air on a comparable regimen. Each group consisted of 5 animals/sex. On the day following the final exposure for each group, all animals (5 rats/sex/group; Groups 1-3) were euthanized and subject to necropsy. All animals were observed twice daily for mortality and moribundity. Clinical examinations were performed prior to exposure, at the approximate midpoint of each exposure, and at 0 to 1 hour (+ 0.25 hours) following each exposure. Detailed physical examinations were performed and individual body weights were recorded on all animals within 4 days of receipt (the week prior to randomization [± 2 days]), on the day of randomization, on the first day of exposure, weekly (± 1 day) during the study period, and on the day of the scheduled necropsy. Individual food consumption was collected 1 week prior to randomization (± 2 days), on the day of randomization, weekly (± 1 day) during the study period, and on the day prior to the scheduled necropsy. Urine samples were collected from all animals in the 20 ppm group (Group 3) on study day 4 for possible future analysis. Complete necropsies were conducted on all animals, and selected organs were weighed at the scheduled necropsies. Selected tissues were examined microscopically from all animals. In addition, a liver sample from each animal was collected at the scheduled necropsies for possible future analysis.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Perfluoropropionyl fluoride
EC Number:
207-019-5
EC Name:
Perfluoropropionyl fluoride
Cas Number:
422-61-7
Molecular formula:
C3F6O
IUPAC Name:
pentafluoropropanoyl fluoride
Test material form:
liquid
Specific details on test material used for the study:
MTDID 7908 and MTDID 28783 are the same substance.
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material:
3M Company, Lot 11
- Expiration date of the lot/batch:
No data
- Purity test date:
No data

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
The Spague-Dawley rat is commonly used for repeated dose studies.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 52-57 days old
- Weight at study initiation: Males: 252-303 g, Females: 198-234 g
- Fasting period before study: None
- Housing: Animals were housed individually in clean, stainless steel, wire-mesh cages suspended above cage-board.
- Diet (e.g. ad libitum): PMI Nutrition International, LLC, Certified Rodent LabDiet® 5002, ad libitum
- Water (e.g. ad libitum): Reverse osmosis-treated water, ad libitum
- Acclimation period: 8 days

DETAILS OF FOOD AND WATER QUALITY: The basal diet used in this study, PMI Nutrition International, LLC, Certified Rodent LabDiet® 5002 (meal), is a certified feed with appropriate analyses performed by the manufacturer and provided to WIL Research.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.6-22.2
- Humidity (%): 39-43.4
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 01 March, 2013 To: 06 March, 2013

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Exposures were conducted in four approximately 66-L polycarbonate whole-body inhalation exposure chambers. One chamber was dedicated for each group for the duration of the study. Chamber supply air was provided from a HEPA- and charcoal-filtered, temperature- and humidity-controlled source. All test substance atmosphere chamber exhaust passed through the facility exhaust system, which included charcoal- and HEPA-filtration.
- Exposure chamber volume: 66 L
- Method of holding animals in test chamber: None, whole body
- Source and rate of air: 11L/min
- Temperature, humidity, pressure in air chamber: No temperature data, no humidity data, slight negative pressure.

TEST ATMOSPHERE
- Brief description of analytical method used: Yes, at 1 minute intervals using a MIDAC I-Series Fourier Transform Infrared Spectrometer.
- Samples taken from breathing zone: No data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Test concentrations were analyzed at 1 minute intervals using a MIDAC I-Series Fourier Transform Infrared Spectrometer.
Duration of treatment / exposure:
6 hours per day
Frequency of treatment:
Daily for 5 days.
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Remarks:
Control
Dose / conc.:
5 ppm
Dose / conc.:
20 ppm
Dose / conc.:
50 ppm
No. of animals per sex per dose:
5
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Based on an acute range-finding study.
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: NA
- Post-exposure recovery period in satellite groups: NA
Positive control:
None

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Clinical examinations were performed daily, prior to exposure, during exposure (at the approximate midpoint), and approximately 0-1 hour (+ 0.25 hr) following the end of exposure (designated as 1 hour post-exposure for report presentation purposes). The absence or presence of findings was recorded for individual animals at observations conducted prior to exposure and approximately 0-1 hour following the end of exposure. Only significant findings were recorded at the approximate midpoint of exposure observations. Detailed physical examinations were conducted on all animals within 4 days of receipt (the week prior to randomization [± 2 days]), on the day of randomization, on the first day of exposure, weekly (± 1 day) during the study period, and on the day of the scheduled necropsy. Observations conducted prior to exposure were not performed on days when detailed physical examinations were conducted provided they were conducted prior to exposure.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded within 4 days of receipt (the week prior to randomization [± 2 days]), on the day of randomization, on the first day of exposure, weekly (± 1 day) during the study period, and on the day of the scheduled necropsy. Mean body weights and mean body weight changes were calculated for the corresponding intervals.

FOOD CONSUMPTION: Individual food weight data was collected 1 week prior to randomization (± 2 days), on the day of randomization, weekly (± 1 day) during the study period, and on the day prior to the scheduled necropsy. Food intake was calculated as g/animal/day.

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
Urine samples were collected from all animals in the 20 ppm group (Group 3) on study day 4. The animals were fasted overnight while in metabolism cages. After collection, samples were transferred to the WIL Research Sample Processing Department and stored at approximately -70°C. The urine samples were shipped to the Sponsor for possible future analysis.
Sacrifice and pathology:
A complete necropsy was conducted on all animals. Animals were anesthetized by isoflurane inhalation and euthanized by exsanguination. The necropsies included, but were not limited to, examination of the external surface, all orifices, and the cranial,
thoracic, abdominal, and pelvic cavities, including viscera. The following tissues and organs were collected and placed in 10% neutral-buffered formalin (except as noted):

Kidneys (2)
Liver
Lungs
Gross lesions (if any)

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Test substance-related clinical observations were limited to the 50 ppm group males and females found dead or terminated early and included red and/or yellow material on various body surfaces (nose, forelimb[s], urogenital area, and/or anogenital area), increased respiration rate, and/or labored respiration. Additionally, increased respiration rate and/or labored respiration were noted at the approximate midpoint of exposure in the
50 ppm group males and/or females on study day 1.
All other clinical findings in the test substance-exposed 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:
mortality observed, treatment-related
Description (incidence):
There were 6 unscheduled deaths limited to the 50 ppm group males and females on study days 1 and 2. All five 50 ppm group males were found dead on study days 1 and 2. One 50 ppm group female was found dead on study day 2. Based on the unscheduled deaths in the 50 ppm group males and females, the remaining 50 ppm group females were euthanized and examined macroscopically on study day 2. The cause of death for the five 50 ppm group males and the one 50 ppm group female was acute inflammation in the lungs. Hemorrhage in the lungs was an additional cause of death in two 50 ppm group males (animal nos. 7453 and 7456).

Acute inflammation of the lungs was moderate in unscheduled death animals and was characterized by a multifocal to diffuse thickening of the alveolar walls by a mixed inflammatory cell infiltration, including lymphocytes and neutrophils. Alveolar macrophages were present in alveoli. Perivascular and peribronchiolar infiltrations of neutrophils, eosinophils, and lymphocytes were prominent features of the lesion, as was interstitial edema in the perivascular and peribronchiolar areas.
In addition to acute inflammation of the lungs, the lungs of unscheduled death animals also had mild to moderate alveolar edema and mild to severe congestion. In the 50 ppm group males, minimal or moderate alveolar hemorrhage was present. Other test substance-related findings in the unscheduled death animals were moderate dilatation of renal tubules (in 3 out of five 50 ppm group males), mild to moderate vacuolation of tubular epithelium (in 2 out of five 50 ppm group males), and minimal to moderate mineralization of the collecting ducts (in 2 out of five 50 ppm group males). The tubules affected by dilatation and vacuolation were primarily the distal tubules in the cortex. These changes in the kidney were limited to the unscheduled death 50 ppm group
males. The significance of these renal changes or their association with test substance exposure is not clear.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weights were unaffected by test substance exposure. There were no statistically significant differences when the control and test substance-exposed groups were compared.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption was unaffected by test substance exposure.
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
Description (incidence and severity):
Urine was collected but 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):
There were test substance-related, statistically significant, higher absolute and relative lung weights in the 5 and 20 ppm group males, and in the 5 and 20 ppm group females. Lung weights were also elevated in the 50 ppm group but no statistical analysis was performed.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Test substance-related gross observations were present in the lungs and mediastinal lymph nodes. The lungs were reported as not fully collapsed with additional notations of dark red discoloration and/or dark red areas in the 50 ppm group males and in the 20 and 50 ppm group females.
In the 5 and 20 ppm group males and females, enlarged mediastinal lymph nodes were present and considered test substance-related.
The gross findings in the lungs correlated to acute inflammation (in the 50 ppm group males and females) and to subacute inflammation (in the 20 ppm group females). The enlarged mediastinal lymph nodes correlated to lymphoid hyperplasia of the mediastinal lymph nodes.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In the 50 ppm early death males and 50 ppm unscheduled and scheduled necropsy females, the lungs had moderate acute inflammation. Acute inflammation of the lungs was also the test substance-related lesion in the 50 ppm group females that were subjected to early termination at study day 2. Acute inflammation explains the higher lung weights in the 50 ppm group males and females. Moderate acute inflammation was considered adverse. In the 5 and 20 ppm group males and females (examined macroscopically on study day 5), there was test substance-related subacute inflammation of the lungs. This change was characterized by numerous features, including thickening of the alveolar walls by histologic appearance was consistent with a reactive lymph node draining an area of subacute inflammation in the lungs. Hyperplasia of mediastinal lymph nodes was not present in the 50 ppm group males or females, presumably due to the early deaths or termination at study days 1 and 2. Hyperplasia of lymphoid tissue in mediastinal lymph nodes was considered nonadverse and a compensatory change.

In the unscheduled death 50 ppm group males, there was renal tubular dilatation, renal tubular vacuolation, and mineralization of the medulla. The dilatation
was characterized by dilated proximal tubules in the cortex. These tubules were empty and lined by flattened epithelial cells. Vacuolation of renal tubules was mostly within the distal convoluted tubules of the cortex, and these tubules were swollen by clear, finely vacuolated to foamy cytoplasm. Two males had minimal or moderate mineralization in the medulla, and this mineralization consisted of conglomerates of mineralized material causing disruption of the collecting ducts. There was no associated inflammation. With moderate mineralization, there was dilatation of the collecting tubules. Since these kidney changes (dilatation, vacuolation, and mineralization) were limited to unscheduled death males and no similar lesions were present in scheduled necropsy males or females at any dose level, the relationship of these changes with test substance exposure is uncertain.

There were no other test substance-related histologic changes. Remaining histologic changes were considered to be incidental findings unrelated to administration of the test substance. There was no test substance-related alteration in the prevalence, severity, or histologic character of those incidental tissue alterations.
Histopathological findings: neoplastic:
no effects observed

Effect levels

Key result
Dose descriptor:
LOAEL
Effect level:
5 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
histopathology: non-neoplastic
organ weights and organ / body weight ratios

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
5 ppm
System:
respiratory system: lower respiratory tract
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes

Applicant's summary and conclusion

Conclusions:
Based on the results of the study, the Lowest Observed Adverse Effect Level (LOAEL) is 5 ppm following 6 hour exposures for 5 days.
Executive summary:

The study evaluated the 5-day repeat exposure inhalation toxicity potential of MTDID 28783 in male and female Sprague Dawley rats. The study was a conducted according to a WIL Research standard protocol. The study was conducted in the spirit of GLP but was not GLP compliant. MTDID 28783 was tested as a gas. Rats (5/sex/dose) were exposed, whole body, to 5, 20, or 50 ppm of MTIDD 28783 for 6 hours per day on five consecutive days. Control rats (5/sex) were placed in a separate chamber on the same schedule without the addition of the test material. Animals were observed for mortality and moribundity (twice daily), clinical signs (prior to exposure, at the midpoint of each exposure, and at 0 to 1 hour following each exposure) detailed physical examinations and body weights (at randomization, on the first day of exposure, and at necropsy). Urine samples were collected from the 20 ppm group on Study Day 4 for possible future analysis. At termination on Day 5 following exposure, necropsy was performed on all animals and the lungs, kidneys, brain, spleen, thymus and livers were collected, weighed and the livers were frozen for possible future analysis. Test substance-related deaths occurred in the 50 ppm group males (Day 1, 5/5) and females (Day 2, 1/5 found dead, 4/5 terminated due to moribund condition). Clinical observations prior to death in the 50 ppm animals during exposures included red and/or yellow material on various body surfaces, increased respiration rate and labored respiration. No abnormal clinical observations were observed in the other treatment or control groups. No test-substance-related effects on body weights or food consumption were noted in any animals. Upon necropsy dark red areas were noted in the 50 ppm males and the 20 and 50 ppm females. Higher absolute and relative lung weights were noted in the 5 and 20 ppm males and females as well as the 50 ppm females when compared with controls. Mild to moderate subacute inflammation of the lung, hyperplasia of the peribrochioloar lymphoid tissue, and lymphoid hyperplasia of the mediastinal lymph nodes in the 5 and 20 ppm group males and females was observed. In addition, acute inflammation of the lung in the 50 ppm group females and alveolar edema in the 20 and 50 ppm group females as well as 50 ppm group males was observed. Based on the results of the study, the Lowest Observed Adverse Effect Level (LOAEL) is 5 ppm following 6 hour exposures for 5 days.

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