Carbonyl difluoride

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Remarks:

5 days of 1-hour exposure

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Remarks:

Limited details. The test material is not fully characterized

Data source

Reference

Reference Type:

publication

Title:

Biochemical changes ssociated with toxic exposures to polytetrafluoroethylene pyrolysis products

Author:

Scheel L.D, McMillan L., Phipps F.

Year:

1968

Bibliographic source:

Am. Ind. Hyg. Ass. J. 29(1):49-53

Materials and methods

Principles of method if other than guideline:

- Principle of test: repeated exposure to sublethal concentrations of PTFE pyrolysis products
- Short description of test conditions: the treatment consisted in 1-hour exposure during 5 consecutive days, followed by 17 days of post-exposure
- Parameters analysed / observed: body weight, urine parameters, some haematological parameters

GLP compliance:

not specified

Remarks:

Study conducted prior to GLP standards

Test material

Specific details on test material used for the study:

The test material is not pure carbonyl fluoride, but polytetrafluoroethylene pyrolysis products considered to contain a majority of gaseous COF2 and other particles (saturated fluorocarbon fragments).

Test animals

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Greenacres Controlled Flora stock

IN-LIFE DATES: From 16-JAN-1967 to 7-FEB-1967

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure:

not specified

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION:
The major pyrolysis product resulting from destruction of plastic material above 300°C consists of carbonyl fluoride. All other products were saturated fluorocarbon fragments or carbon dioxide.

TEST ATMOSPHERE
- Brief description of analytical method used: hydrolysable fluoride analysis (no further details)
- the atmosphere consisted of PTFE pyrolysis products (gases, mainly COF2) and particles.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

hydrolyzable fluoride analysed is expressed as ppm carbonyl fluoride

Duration of treatment / exposure:

1-hour exposure each day to PTFE pyrolysis products containing hydrolysable fluoride, expressed as ppm carbonyl fluoride

Frequency of treatment:

5 consecutive days, followed by a 3-day recovery period

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

52 ppm

Remarks:

day 1
hydrolyzable fluoride analysis expressed as ppm COF2

Doses / concentrations 2

Dose / conc.:

43 ppm

Remarks:

day 2
hydrolyzable fluoride analysis expressed as ppm COF2

Doses / concentrations 3

Dose / conc.:

29 ppm

Remarks:

day 3
hydrolyzable fluoride analysis expressed as ppm COF2

Doses / concentrations 4

Dose / conc.:

25 ppm

Remarks:

day 4
hydrolyzable fluoride analysis expressed as ppm COF2

Doses / concentrations 5

Dose / conc.:

9 ppm

Remarks:

day 5
hydrolyzable fluoride analysis expressed as ppm COF2

No. of animals per sex per dose:

20 in exposed group
10 in control group

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: sublethal concentration
- Post-exposure recovery period in satellite groups: no information

Positive control:

no

Examinations

Observations and examinations performed and frequency:

BODY WEIGHT: Yes
- Time schedule for examinations: on day 1 of treatment, on the last day of treatment (day 5), then on 3 instances during the recovery period (day 3,7 and 17 of the recovery period).

HAEMATOLOGY: Yes, before, during (day 4) and after (day1, 4, 8 and 17) exposure.
- total white blood cells count
- neutrophils
- lymphocytes

CLINICAL CHEMISTRY:
Succinic dehydrogenase activity was examined in the rat kidney and lung, using the method of Shelton and Rice (J. Natl. Cancer INst. 18:117 (1957).

URINALYSIS: Yes
- Time schedule for collection of urine: on day 1 of treatment (after exposure), on the last day of treatment (day 5), then on 3 instances during the recovery period (day 3, 7 and 18 of the recovery period/post exposure).
- Metabolism cages used for collection of urine: Yes, 10 treated and 10 control rats; for a 24-hour urine collection.
- Parameters checked in table 1 were examined: Analysis of glucose, protein, ketones, occult blood, specific gravity, urinary fluoride.
- Animals fasted: Not specified

Sacrifice and pathology:

GROSS PATHOLOGY: No data
HISTOPATHOLOGY: Some information provided, not fully developped in the publication

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Signs of toxicity preceeding death showed extreme malaise and weakness.

Mortality:

mortality observed, treatment-related

Description (incidence):

A total of nine animals out of 40 (22%) died during the study (no details on sex):
1 animal was found dead on day 3 of treatment, 3 on day 4, 1 on day 5, 3 on day 1 post-exposure, and 1 on day 3 post-exposure.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Decreased body weight (30%) was observed following the 5x1-hr daily exposures.
Recovery was observed 18 days following cessation of treatment.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

There was no marked change in total white blood cells.
Following exposure, there was a marked increase in neutrophils, concommittant with an decrease in lymphocytes. Levels partially recovered within the 18-day post-exposure period. This was seen as a sign of acute noninfectious inflammatory response.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Succinic dehydrogenase activity was examined in the rat kidney and in lung.
There was an increased activity in the lung tissue (described as severe pathological change), but activity was inhibited to < 5% of the normal activity in kidney after 5 days of a daily 1-hr exposure. There was a return to normal level after 17 days post-exposure period.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

There was an increase in urinary fluoride detected after 5 days of 1-hr exposure, then level gradually decreased during the recovery period.
day 1: 3 µg/ml,
day 5: 42 µg/ml
day 18 post-exposure, the fluoride level was still 4 times that of the controls
Protein, glucose and ketones were detected in urine after 5 days of exposure (see Table 1), but were no longer present after 17 days of post-exposure period.

Description (incidence and severity):

Liver tissue of treated animals showed enlarged nuclei and fatty infiltration of hepatocytes.

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Enlarged nuclei and fatty infiltration of the liver cells.

Any other information on results incl. tables

Table 1: Results of urine examination in exposed animals:

parameters	Exposure day 1	exposure day 5	post-exposure day 3	post-exposure day 7	post-exposure day 18
protein	present	present	present	no	no
glucose	no	present	no	no	no
ketones	no	present	present	present	no
blood	no	no	present	no	no

Applicant's summary and conclusion

Executive summary:

Five consecutive daily 1-hour exposure of rats to PTFE pyrolysis products caused an increased of urinary fluoride, marked body weight loss, increased succinic dehydrogenase activity in lungs, while it was decreased in liver.

Nine out of 40 exposed animals died during the course of the study.

Inflammatory response was observed during the exposure period as evidenced by decreased neutrophils and increased lymphocytes. Recovery was observed within 17 days after the cessation of exposure.

The level of urinary fluoride returned to lower levels during the post-exposure period, although still 4-fold higher than in controls.

The signs of toxicity are attributed to the exposure to carbonyl fluoride generated during the pyrolysis of PTFE, and which is thought to be hydrolyzed in the body fluids.