Trifluoroiodomethane

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetics

Since no experimental toxicokinetic studies are available for the test substance, only PBPK modelling, the following assessment is based on the available physicochemical properties and results from other toxicological studies.

 

Physico-chemical properties

The substance is a gas with a molecular weight of 195.91 g/mol. The experimental Log P value was determined to be 2.41. The substance has a predicted vapour pressure of 5405 hPa at 25°C. The water solubility was determined to be 1658 mg/L at 23°C. These physico-chemical properties of the substance will enable qualitative judgements of the toxicokinetic behaviour (Guidance on information requirements and chemical safety assessment Chapter R.7.c: Endpoint specific guidance, R.7.12 Guidance on Toxicokinetics).

 

Absorption

GI absorption

A molecular weight below 500 g/mol is favourable for absorption and as the molecular weight is also less than 200, the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. In combination with a moderate log P value (between -1 and 4), the substance is expected to be readily absorbed. No oral single or repeated dose toxicity studies are available to further support this.

 

Respiratory absorption

With a vapour pressure of 5405 hPa and a boiling point of -22.5 °C, the substance is a gas at room temperature and a pressure of 1 atmosphere and consequently readily inhaled. The combination of a moderate log P and moderate water solubility, are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. Hence, the substance is expected to be readily absorbed. Indeed, in experimental inhalation studies, exposure to the substance results in systemic toxicity indicating that the substance is absorbed. In a combined repeated dose/reproductive screening study, rats were exposed (whole body) for 6 hours per day during 14 weeks (Dodd,1999). Results of serum thyroid hormone levels (e.g., T3, T4, rT3, and TSH), indicated concentration-related increases in TSH, T4, and rT3. T3 levels were decreased at the highest dose tested (2%). In a sub-chronic 90 day repeated dose toxicity study (Dodd, 1997), serum chemistry alterations observed in rats of all exposure groups included decreases in T3 and increases in thyroglobulin, rT3, T4, and TSH. Relative organ weight increases (8% group) occurred in the brain, liver, and thyroid glands; decreases were observed in the thymus and testes. A decrease in relative thymus weights and an increase in relative thyroid weights were observed also in rats of the 2 and 4% groups. Histopathological findings included a mild inflammation in the nasal turbinates of rats exposed to 4 or 8%, mild atrophy and degeneration of the testes (4 and 8% groups), and a mild increase in thyroid follicular colloid content in rats of all exposure groups.

 

Dermal absorption

The rate at which gases and vapours partition from the air into the stratum corneum will be offset by the rate at which evaporation occurs. Therefore, although a substance may readily partition into the stratum corneum, it may be too volatile to penetrate further. This can be the case for substances with vapour pressures above 100-10,000 Pa (ca. 0.76-76 mm Hg) at 25°C, though the extent of uptake would also depend on the degree of occlusion, ambient air currents and the rate at which it is able to transfer across the skin. Log P values between 2 and 3 are optimal for dermal absorption, particularly if water solubility is high. The molecular weight falls within the range mentioned in chapter R.7.c to select a default value of 100% skin absorption. Also Log P values and water solubility are favourable for dermal absorption. Since however, the substance is a gas, it is considered unlikely that the substance will penetrate the skin deeper than the stratum corneum and thus dermal absorption under non-occlusive conditions is expected to be low. No experimental data are available to support this.

 

Conclusion absorption

Since it is likely that the substance will primarily be absorbed via the inhalation route and to a lesser extent via the oral route, in the absence of substance-specific absorption data, the default absorption values from the REACH guidance (Chapter 8, R.8.4.2) are used for DNEL derivation, namely: 100% for inhalation and 50% for oral absorption. Although dermal absorption is considered less applicable, the physico-chemical properties of the substance would be favourable for dermal absorption under occlusive conditions. Therefore, an absorption value of 50% for dermal absorption is considered to be a conservative value and an absolute worst case.

 

Distribution

The substance is a gaseous substance with a molecular weight of 195.91 g/mol and, in combination with its water solubility, enables passive diffusion through aqueous channels and pores. The sub-chronic 90 day repeated dose toxicity study in rat (Dodd, 1997), showed changes in relative organ weights in the brain, liver, thyroid glands, thymus and testes, indicating that test substance is distributed throughout the body. The determined log P value of 2.41 suggests distribution into cells and the concentrations may be higher than the extracellular concentration, particularly in fatty tissues.

Accumulation

Substances with log P values of 3 or less would be unlikely to accumulate, with the repeated intermittent exposure patterns normally encountered in the workplace, but may accumulate if exposures are continuous. Since the substance has a log P value of 2.41 and a moderate water solubility, it is not expected that the substance will accumulate in lung, adipose tissue, bone or stratum corneum under normal work-related exposures.

Excretion

The substance is a gas and excretion via exhaled air is therefore expected to be the most important route of excretion. Characteristics favouring urinary excretion include good water solubility and a low molecular weight (below 300 in the rat). With its molecular weight of 195.91 g/mol, urinary excretion may also occur for the systemically available fraction of the substance, but is expected to be a minor route in comparison to exhaled air. Excretion in bile is unexpected for the substance since, in the rat, molecules that are excreted in the bile are amphipathic, hydrophobic/strongly polar and have a high molecular weight. Non-ionized and lipid soluble molecules may be excreted in the saliva, where they may be swallowed again, or in the sweat.

PBPK toxicokinetics

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.

PBPK modelling

Most proposed replacements for Halon 1301 as a fire suppressant are halogenated hydrocarbons. The acute toxic endpoint of concern for these agents is cardiac sensitisation. An approach is described that links the cardiac endpoint as assessed in dogs to a target arterial concentration in humans. Linkage was made using a physiologically based pharmacokinetic (PBPK) model. Monte Carlo simulations, which account for population variability, were used to establish safe exposure times at different exposure concentrations for the test substance. Application of the modeling technique described here not onlymakes use of the conservative cardiac sensitisation endpoint, but also uses an understanding of the pharmacokinetics of the chemical agents to better establish standards for safe exposure. The combined application of cardiac sensitisation data and physiologically based modelling provides a quantitative approach, which can facilitate the selection and effective use of halon replacement candidates.