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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Remarks:
PBPK modeling
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Jun 1993 to Mar 1995
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:
1995
Report date:
1995

Materials and methods

Objective of study:
absorption
metabolism
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The purpose of this study was to measure the tissue to air partition coefficients and to describe the uptake and distribution kinetics of the test substance via closed chamber recirculating gas uptake methods. Inhalation pharmacokinetics for all chemicals were determined experimentally in Fischer-344 (F-344) male rats. A physiologically based pharmacokinetic (PBPK) model was used to describe mathematically the disposition and metabolism of the chemicals employing chemical specific parameters and apparent whole-body metabolic constants calculated from these experiments.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Trifluoroiodomethane
EC Number:
219-014-5
EC Name:
Trifluoroiodomethane
Cas Number:
2314-97-8
Molecular formula:
CF3I
IUPAC Name:
trifluoroiodomethane
impurity 1
Reference substance name:
Carbon dioxide
EC Number:
204-696-9
EC Name:
Carbon dioxide
Cas Number:
124-38-9
Molecular formula:
CO2
impurity 2
Chemical structure
Reference substance name:
Trifluoromethane
EC Number:
200-872-4
EC Name:
Trifluoromethane
Cas Number:
75-46-7
Molecular formula:
CHF3
IUPAC Name:
Trifluoromethane
Test material form:
gas
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Kingston, NY)
- Age at study initiation: not specified
- Weight at study initiation: 200 – 350 g
- Housing: animals were housed in plastic cages (2-3/cage) with hardwood chip bedding prior to exposure
- Diet: Purina Formulab #5008 ad libitum
- Water: softened water ad libitum
- Acclimation period: not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1
- Humidity (%): 40 - 60
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
inhalation: gas
Vehicle:
other: air
Details on exposure:
Gas Uptake and Metabolic Constants
A closed chamber recirculating gas uptake system with a volume of 8.0 L was used for the estimation of the whole animal metabolic constants (Vmax, km and/or Kf). Three F-344 rats were exposed to each the test substance using a gas uptake system similar to that described by Gargas et al. (1986). Initially, a predetermined concentration of the test substance was introduced into the system so that the concentration in the chamber atmosphere decreases as the chemical is taken up and metabolized by the rat. Five exposure concentrations were performed for 6 hours for the test substance (concentrations were 112, 648, 1228, 2727 and 5867 ppm). Sodium hydroxide (75-150 g) was used as the CO2 absorber for the test substance. Oxygen concentrations were maintained at (21 ± 1%) during the exposures. The system flow was maintained at 2.1 L/min with the flow to the sample loop of the GC at 100 mL/min.
The chemical concentrations in the chamber atmosphere were monitored every 5 min for the first 30 min and every 15 min thereafter using an automated gas sampling valve connected to a HP5890A gas chromatograph. Chromatography was performed on a 25m x 0.53 mm Chrompack PoraPLOT Q (Plot Fused Silica) column. The GC was equipped with a hydrogen flame ionization detector with a temperature of 250°C, helium carrier flow at 12.1 mL/min with make-up flow of 14.2 mL/min, injector at 125°C, and an oven temperature held constant at 125°C.
Duration and frequency of treatment / exposure:
Single exposure for 6 hours
Doses / concentrationsopen allclose all
Dose / conc.:
112 ppm
Dose / conc.:
648 ppm
Dose / conc.:
1 228 ppm
Dose / conc.:
2 727 ppm
Dose / conc.:
5 867 ppm
No. of animals per sex per dose / concentration:
3
Control animals:
no
Details on dosing and sampling:
Partition coefficients were determined by using a modified version of the vial-equilibration technique described by Gargas et al. (1989). Whole tissue was harvested and minced into a tissue slurry versus prepared as a tissue homogenate in saline. Rats used to determine partition coefficients were sacrificed with CO2. Blood was collected from the posterior vena cava using a heparinized syringe. Liver, muscle (quadriceps), and fat (epididymal and perirenal) were also removed for analysis. Blood samples (1.0 mL for all chemicals) were placed in 12.4 mL glass vials and incubated/ mixed for 3 hrs at 37°C with 800 ppm of the test substance in the vial headspace. Whole tissue samples (1.0 g of liver and muscle, and 0.5 g of fat for all chemicals) were minced and incubated/mixed under the same condition as for blood, except fat was equilibrated for 5-8 hrs. Partition coefficients were also determined at 80 and 400 ppm to show that they were concentration independent.
The chemical concentrations in the headspace were analysed using a HP19395A headspace sampler (Hewlett-Packard, Avondale, PA) connected to a HP5890A gas chromatograph (GC) (Hewlett-Packard, Palo Alto, CA) equipped with a hydrogen flame ionization detector. A 12' x 1/8" stainless steel 10% SE-30, WHP 80/100 mesh Chromsorb column was used. GC conditions were set with the detector temperature at 250°C, injector temperature at 125°C, nitrogen carrier gas flow at 30.0 mL/min, and an oven temperature held constant at 60°C.

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
The rat showed two discernible phases: a rapid equilibration phase that lasted up to 60 min followed by a slow linear uptake phase.
Type:
distribution
Results:
The test substance has low solubility (partitioning) in blood and tissues

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Gas Uptake Studies
The inhalation uptake of the test substance was reported in a study from Armstrong Laboratories in 1994 (Gas uptake kinetics of Bromotrifluoromethane (Halon 1301) and its proposed replacement Iodotrifluoromethane). The rat showed two discernible phases: a rapid equilibration phase that lasted up to 60 min followed by a slow linear uptake phase. Simulation of uptake of the test substance required some attribution of metabolic capacity by the rats. Attribution of both saturable (Vmaxc = 0.375, Km= 0.1) and first order (Kfc= 1.6) metabolism and a chamber loss of 2.7% is shown compared to no metabolism with the same chamber loss rate. The upper curve with each set of data represents the no metabolism condition. Attribution of saturable (Vmaxc = 0.375, Km = 0.1) metabolism alone and a chamber loss of 4% is shown compared to no metabolism with a chamber loss of 2.7%. Comparing the simulations with metabolism and the simulations without metabolism, virtually overlapping each other. This indicates a lack of discrimination between first order metabolism and chamber loss for the test substance. The constants and rates used for each of the preceding simulations are summarised in Table 2 in ‘Any other information of results, incl. tables’.
Details on distribution in tissues:
Partition Coefficients
Shown in Table 1 in 'Any other information on results incl. tables' are the rat tissue to air partition coefficients determined for the test substance, which were used in the PBPK model optimisation. Due to the extremely low partition coefficient for FC-218, higher amounts of rat tissue were used.
Transfer into organs
Test no.:
#1
Transfer type:
other: tissue to air partition coefficients
Observation:
slight transfer

Any other information on results incl. tables

Table 1. Partition coefficients

Partition Coefficients

Test

substance

(n=10)
Blood:air PB 1.73 ± 0.28
Liver:air PLA 1.27 ± 0.21
Fat:air PFA 10.35 ± 0.82
Rapidly perfused:air PRA 1.27 ± 0.21
Slowly perfused:air PSA 1.32 ± 0.18

Table 2. Summary of metabolic constants and chamber loss rates used in simulating uptake of the test substance by rats

Vmaxc Km Kfc CHAMBER
mg/h/kg mg/L l/h/kg LOSS/h
0.375 0.1 1.6 2.7%
0 10000 0.0 2.7%
0.375 0.1 0.0 4.0%
0 10000 0.0 2.7%
0.375 0.1 1.6 2.7%
0.375 0.1 0.0 4.0%

Applicant's summary and conclusion

Conclusions:
1. The PBPK model adequately describes the uptake of the test substance from the chamber atmosphere during the exposure experiments.
2. The test substance has low solubility (partitioning) in blood and tissues and had minimal, if any, enzymatic metabolism in rats.
3. Further experimentation is needed to determine the identity of the second peak in the metabolism of the test substance.
Executive summary:

The purpose of this study was to measure the tissue to air partition coefficients and to describe the uptake and distribution kinetics of the test substance via closed chamber recirculating gas uptake methods. Inhalation pharmacokinetics for all chemicals were determined experimentally in Fischer-344 (F-344) male rats. A physiologically based pharmacokinetic (PBPK) model was used to describe mathematically the disposition and metabolism of the chemicals employing chemicalspecific parameters and apparent whole-body metabolic constants calculated from these experiments.

This simulation approach for analysis of gas uptake data has been shown to distinguish between single and multiple metabolic pathways of several previously studied dihalomethanes and numerous other volatile organic compounds. Simulation of the test substance required some attribution of metabolism (saturable and first order) by the rats beyond losses to the system. Another indication that the test substance was disappearing beyond that taken up by the chamber is demonstrated by the chromatograms of the chamber air. As gas uptake experiments progressed, a second peak appeared and increased in size. This could represent a metabolite resulting from the metabolism of the chemical by the rats or could represent a product resulting from spontaneous breakdown of the test substance in the chamber. The product appeared only when live rats were in the chamber with the presence of the parent chemical. However, further experiments would be necessary to determine the identity and origin of the second chromatographic peak.