Registration Dossier

Toxicological information

Exposure related observations in humans: other data

Administrative data

Endpoint:
exposure-related observations in humans: other data
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant study, published in peer reviewed literature, fully adequate for assessment.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1999

Materials and methods

Type of study / information:
Human volunteer pharmacokinetics study
Endpoint addressed:
basic toxicokinetics
Principles of method if other than guideline:
The safety and pharmacokinetics of HFC 227ea were assessed in a double-blind study with 8 (4 male and 4 female) healthy volunteers via whole-body exposure
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): HFC 227
- Molecular formula (if other than submission substance): CF3CHFCF3
- Substance type: organic
- Physical state: gas
- Analytical purity: 99.99%

Method

Ethical approval:
confirmed and informed consent free of coercion received
Details on study design:
The study was a within-subject design that compared rising exposure concentrations of HFC227ea versus CFC 12 and air.

HFC 227ea was compared with CFC 12 (dichlorodifluoromethane) as HFC 227 is used to replace chlorofluorocarbons (CFCs) in refrigerant and aerosol applications, including medical use in metered-dose inhalers.
Exposure assessment:
measured
Details on exposure:
TYPE OF EXPOSURE: inhalation

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: air-conditioned exposure chamber constructed from polyurethane and stainless steel panes (volume 13.6 m3, flow rate approx. 500 l/min)
- Source and rate of air: air supply exposure chamber

TYPE OF EXPOSURE MEASUREMENT: Area air sampling

EXPOSURE LEVELS: 0, 1000, 2000, 4000 and 8000 ppm

EXPOSURE PERIOD: Exposure was for 1 h on eight separate occasions, separated generally by 7 days, two air exposures, two CFC 12 exposures (at 1000 and 4000 ppm), and four exposures (at 1000, 2000, 4000 and 8000 ppm) of HFC227. For one volunteer in the HFC227 study the first exposure to air had to be repeated the following week (the Holter failed during the original exposure) and the next exposure (to 4000 ppm CFC 12) was performed 2 days later. Subsequent exposures were according to schedule up to exposure 5. The subject then became ill (not treatment related) and exposures 6, 7 and 8 wer postponed by 1 week. For a second subject in the HFC227 study exposure session 4 (HFC227, 4000 ppm) had to be repeated (the Holter failed during the original exposure) and subsequent exposure sessions were postponed by 1 week. Volunteers were assigned to an exposure schedule such that males and females were exposed equally over morning and afternoon sessions.

DESCRIPTION / DELINEATION OF EXPOSURE GROUPS / CATEGORIES: Eight healthy nonsmoking volunteers, four males and four females, aged between 20 and 24 years, with normal elecrocardiogram, lung function (peak expiratory flow > 80% predicted normal), body fat volume (<30%) and normal clinical laboratory parameters were enrolled for the study. Volunteers were excluded if they were taking chronic medication, were claustrophobic, or had an alcohol intake of more than 21 units/week. Women were exluded if pregnant or lactating and were tested for pregnancy prioir to enrollment and prior to each exposure. All volunteers gave their written informed consent. The study was approved by the local ethics committee and was carried out in accordance with the provisions of the Declaration of Helsinki.

Results and discussion

Results:
The blood concentration-time profile shows that HFC227 was rapidly absorbed at each exposure concentration in both males and females.
Blood concentration of HFC 227ea in males and females increased rapidly and at 15 min was either maximum (13% of the cases) or near maximum at each exposure concentrations. Blood concentrations appeared to be at steady state, with maximum blood concentrations generally measured (52% of the cases) prior to the final sample taken during exposure. Both maximum concentrations and total AUC increased in relation to exposure concentration, although the increases were not strictly proportional. At each exposure level, maximum blood concentrations were statistically significantly higher in males (P < 0.05) than females. Maximum concentrations were 37, 50, 39 and 31% higher in males at 1000, 2000, 4000 and 8000 ppm, respectively. In accordance with blood concentration, AUC was statistically significantly higher in males (P < 0.05) than females, except at 1000 ppm HFC 227ea. The HFC 227ea AUC was 30, 52, 34 and 41% higher in males at 1000, 2000, 4000 and 8000 ppm, respectively. The blood concentration-time profile shows that HFC 227ea was rapidly cleared at each exposure concentration in both males and females. Elimination was predominantly (>83%) biphasic at each exposure level, gender dependent and exposure concentration independent. In the remainder of the population, a single elimination phase was observed. Elimination appeared to be independent of exposure levels. t1/2 alpha was short and tended to be lower in males than females at each exposure level. t1/2 beta was variable in both males and females (see below).

Mean residence time was statistically significantly (P < 0.05) lower in males than females at each exposure level and independent of exposure concentration (a mean of 36 and 42 min for males and females respectively).

Following the final exposure at 24-h, blood samples was analyzed for HFC 227ea. All samples were below the limit of quantification (0.010 g/ml).

Any other information on results incl. tables

The following half-life times were determined in the experiment:

Test # 1: Half-life 1st: 4.7 min (males) and 7.9 min (females)

Test # 1: Half-life 2nd: 22 min (females, 1000 and 8000 ppm) and 42 min (females, 2000 and 4000 ppm); 37 min (males, 1000 and 8000 ppm); 62 min (males, 2000 ppm); 92 min (males, 4000 ppm)

No metabolites were identified.

Exposure of healthy volunteers to exposure levels up to 8000 ppm HFC 227 did not result in any adverse effect on pulse, blood pressure, electrocardiogram or lung function:

Systolic and diastolic blood pressure measurements showed no trend for a change as a result of exposure. At each time point, there were no statistically significant differences between exposure to HFC 227 at any exposure level compared to air (combined) or CFC12 (combined).

Pulse rate showed no trend or change with time as a result of exposure. At each time point, there were no statistically significant differences between exposure to HFC 227 at any exposure level compared to air (combined) or CFC12 (combined).

Peak expiratory flow showed no difference between the pre- and postexposure values. At each time point, there were no statistically significant differences between exposure to HFC 227 at any exposure level compared to air (combined) or CFC12 (combined).

There were no clinically relevant changes in the ECG traces.

There were neither clinically significant changes in any of the laboratory parameters measured nor any notable adverse events recorded. Specifically there were no central nervous system effects reported or observed and there was no indication of upper respiratory tract irritation.

Applicant's summary and conclusion