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Description of key information

Short description of key information on bioaccumulation potential result: 
In accordance with Regulation (EC) No 1907/2006 Annex VIII section 8.8.1, a toxicokinetics study is not required as assessment of the toxicokinetic behaviour of the substance has been derived from the relevant available information. This assessment is located within the discussion of the endpoint summary for toxicokinetics, metabolism and distribution.

Key value for chemical safety assessment

Additional information

According to REACH Annex VIII (Section 8.8.1) an assessment of the toxicokinetic behaviour of perfluoromethylvinylether (PMVE), to the extent that can be derived from the relevant available information, is reported as follows.

 

As far as absorption, distribution, metabolism and excretion are concerned, no direct toxicokinetic data on PMVE is available. Therefore, in order to assess the toxicokinetics of PMVE, the available physico-chemical and toxicity data have been considered. As supporting information, the properties of similar structures like flunarens have also been considered, including desflurane, isoflurane and sevoflurane.

 

Substance identification

Name

Perfluoromethylvinyl ether

Desflurane

Isoflurane

Sevoflurane

CAS No.

1187-93-5

57041-67-5

26675-46-7

28523-86-6

Molecular weight

166.022

168.0

184.5

200.1

Molecular formula

C3F6O

C3H2F6O

C3H2ClF5O

C4H3F7O

Structural formula

 see attached document

 see attached document

 see attached document

 see attached document

 

(1) Reference:ChemIDplus Lite

United StatesNational Library of Medicine

URL: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?CHEM

Search undertaken: 14/9/12

 

1. PMVE Physico-chemical properties with impact on toxicokinetics

 

In section 1 the physico-chemical properties, which could influence the toxicokinetic behaviour of the substance, are summarized.

 

i)                    Molecular weight: 166.022

 

According to Table R.7.12-1 from ECHA Endpoint Specific Guidance Chapter R.7C a molecular weight below 500 can favor gastrointestinal absorption.

According to Table R.7.12-3 from ECHA Endpoint Specific Guidance Chapter R.7C a molecular weight between 100 and 500 is not particularly favourable for dermal uptake.

 

According to Table R.7.12-4 from ECHA Endpoint Specific Guidance Chapter R.7C the lower molecular weight potentially enables PMVE distribution.

 

According to Table R.7.12-6 from ECHA Endpoint Specific Guidance Chapter R.7C a molecular weight below 300 is one of the factors favorable for urinary excretion.

 

ii)                  Water solubility: 31,5 mg/l at 28°C

 

According to Table R.7.12-3 from ECHA Endpoint Specific Guidance Chapter R.7C a water solubility between 1-100 mg/l is indicative of low to moderate dermal absorption.

  

iii)                 Partition coefficient octanol/water: log Kow 2.04[1]

 

According to Table R.7.12-1 from ECHA Endpoint Specific Guidance Chapter R.7C moderate log Kow values (between -1 and 4) are favorable for gastrointestinal absorption.

 

According to Table R.7.12-2 from ECHA Endpoint Specific Guidance Chapter R.7C moderate log Kow value (between -1 and 4) are favorable for absorption directly across the respiratory tract epithelium by passive diffusion.

 

According to Table R.7.12-3 from ECHA Endpoint Specific Guidance Chapter R.7C log Kow values between - 1 and 4 can favour dermal absorption especially if the substance is water soluble.

 

According to Table R.7.12-4 from ECHA Endpoint Specific Guidance Chapter R.7C if the molecule is lipophilic (log Kow >0) it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.

 

iv)                Vapour pressure: 505,5 kPa at 20°C[2]

 

According to Table R.7.12-2 from ECHA Endpoint Specific Guidance Chapter R.7C, since its vapor pressure is greater than 25 kPa PMVE is a highly volatile substance and it is available for inhalation as a vapour.

 

The previous considered physico-chemical properties, which could affect the toxicokinetic profile of PMVE, are summarized in the following table:

 

 

TK process

Affected by (where specific data is available)

Gastrointestinal absorption

Structure, molecular weight; log Kow, water solubility

Dermal absorption

Physical state, molecular weight, water solubility; log Kow, vapour pressure

Respiratory absorption

Log Kow ; vapour pressure, water solubility, Inhalation toxicity data

Distribution and urinary excretion

Molecular weight, water solubility, log Kow, target organs, signs of toxicity, physical state (for excretion by exhaled air)

 

 

2. Absorption

Gastrointestinal (via oral route): because of its gaseous nature, PMVE is not likely to be absorbed orally.Studies of toxicity by the oral route are not consequently available; nevertheless a passage through the gastrointestinal tract has been speculated on the basis of relevant physico-chemical properties identified according toECHA Endpoint Specific Guidance Chapter R.7C section R.7.

 

Being PMVE a highly volatile gas it is unlikely that oral absorption will directly occur. The possibility that only a minimal oral absorption also occurs is very remote.Because of its gaseous nature, PMVE could be eventually absorbed through mouth mucosa.Nevertheless, as reported in R.7.12.2.1 from ECHA Endpoint Specific Guidance Chapter R.7C, mouth absorption is minimal and if at all, occurs by passive diffusion.

In any case, moreover, the PMVE structure does not contain hydrolizable groups so the potential absorption in the gastrointestinal tract is independent from pH.

 

Dermal:As PMVE is a gas with a molecular weight under 500 and a log Kow between -1 and 4 dermal absorption can not be excluded. Nevertheless it is important to note that the log Kow of 2.04 is an average value obtained from two different QSAR calculations and however it would fall in the low-medium range favorable for dermal absorption. On the basis of a slight water solubility, it is unlikely that PMVE might cross viable epidermis and dermis, till reaching the vascular network and entering systemic circulation. Based on the high vapour pressure of PMVE, this substance may readily partition into the stratum corneum but will be too volatile to penetrate further.

 

Inhalation: to be absorbed by inhalation a gas should be soluble in water and sufficiently lipophilic to cross the alveolar and capillary membranes.Following the indications reported in ECHA Endpoint Specific Guidance Chapter R.7C section R.7.12, PMVE has a moderate log Kow which is favourable for absorption, but the modest water solubility would decrease the amount absorbed per breath.On the basis of chemical structure similarity with PMVE, the methyl-ethyl ether desflurane (1,2,2,2-tetrafluoroethyl difluoromethyl ether) has been considered as far as inhalatory absorption is concerned. Desflurane is a volatile anesthetic whose clinical utility is due to a low blood/air partition coefficient (0.42)[3].

 

A similar blood/air partition coefficient is expected even for PMVE, suggesting that this gas would slightly dissolve in blood and most of it would remain in the alveolar space. Moreover other fluorinated anesthetics, resembling the chemical structure of PMVE, show low blood/air partition coefficients. Particularly these are 1.4 and 0.65 at 37°C, for isoflurane and sevoflurane respectively[4].

 

In an acute inhalation toxicity study[5], Sprague-Dawley rats did not show any sign of local irritation in the respiratory tract as well as no deaths or clinical signs, during the 14 day observation period after acute exposure to PMVE (4h, 20 mg/l = 2945 ppm).Moreover no gross pathological abnormalities were observed on the basis of post mortem examination.This evidence suggests that the potential absorption is quite low.

 

In a combined repeated dose toxicity study with a reproduction/developmental toxicity screening test (OECD 422)[6], minimal regeneration (grade 1 of 4) of the renal tubular epithelium was observed in 10/12 male rats and 9/12 female rats exposed to 1500 ppm of PMVE.This finding was test substance related and correlated with increased absolute and relative kidney weights in females exposed to 1500 ppm.These effects on kidneys were not observed in any animal at lower exposure (0, 60, 300 ppm). The presence of signs of systemic toxicity in kidney at the highest dose group suggests that if absorption is occurring at the lower dose groups, that the concentration of PMVE is not sufficient to exert a systemic toxicological effect.

 

On the whole, based on its physical state and the physico-chemical properties reported in section 1, the most likely route of exposure for PMVE is the inhalatory one. The experimental data from the assessed toxicity studies support a systemic absorption by inhalation.

 

3. Distribution

Gross pathology observations from the repeated dose toxicity study6revealed that PMVE caused a related slight increase in the kidney absolute and relative weight only in females rats exposed to 1500 ppm.This increase was statistically significant (parametric comparison to control – Dunnett/Tamhane-Dunnett Test) correlated with the microscopic finding of minimal renal tubular regeneration in the 1500 ppm males and females.In the males exposed to 1500 ppm PMVE no statistically significant increase in absolute or relative kidney weight was observed, but microscopic examination revealed regeneration of tubular epithelium however.This histological change seems to have no consequences on renal functionality since this is not associated with relevant PMVE clinical pathology parameters.

These effects on kidneys, following exposure by inhalation, indicate absorption and distribution of PMVE.

In terms of the distribution of PMVE, following absorption in the respiratory tract, it is hypothesized that this substance is rapidly distributed to highly perfused tissues such as liver and kidneys. Distribution to the liver is assumed as metabolism of PMVE is likely to occur in the liver. Distribution to the kidneys is supported by long term and carcinogenicity studies on fluranes that show that, as assumed for PMVE, distribution concerns the kidney as the target organ4.

 

4. Metabolism

No direct evidences are available concerning biotransformation of PMVE. Some information on metabolism can be speculated with reference to data on gaseous flurane compounds.

The resemblance of the general structure of PMVE with desflurane allows further assumptions on PMVE metabolism to be made. The enzymatic reactions using PMVE as a substrate can be speculated based on a possible candidate for read across..Human metabolism of desflurane has been characterized bothin vitroandin vivo[7]. The metabolism of all fluranes takes place mainly in the liver, and to a lesser extent in the kidneys and the lungs. The fluranes are metabolized in the liver by cytochrome P450, especially by the isoenzyme CYP2E1, and the oxidative route is dominant4.In particular desflurane is metabolized by CYP2E1 to inorganic fluoride and trifluoracetic acid4.The low degree of desflurane metabolism is due to low blood/gas and low blood/tissue solubility.Fluoride ions are nephrotoxic, but since desflurane is metabolized to a very low extent the risk of nephrotoxicity due to the liberation of inorganic fluoride is very low[8].

 

A similar biotrasformation pathway might be considered for PMVE, which could act as a substrate for the same isoform of cytochrome P450 responsible for fluranes oxidation.It is known that CYP2E1 recognizes different substrates such as fluranes, aromatics and other different structures.It is therefore possible that the presence of the double bond in the PMVE molecule should not alter the possibility that CYP2E1 recognizes it as a substrate.

 

It is possible that the very low amount of the substance (PMVE) that enters systemic circulation is oxidized by CYP2E1 in the liver or directly in the kidney, with the potential production of low levels of fluoride ions.These could be responsible for the effect on kidneys observed in the repeated dose toxicity study on rats3.

 

5. Excretion

As with the majority of alkenes and vinyl ethers4, PMVE might be excreted almost principally in the exhaled air due to low metabolism and low blood solubility. Since desflurane is expected to be eliminated more rapidly than other fluranes3, it is plausible that a rapid exhalation would occur even for PMVE.

 

According to the ECHA Endpoint Specific Guidance Chapter R.7C table R.7.12-6 PMVE molecular weight is compatible with an hypothetical urinary excretion, but no experimental evidences are available to verify this. From considering metabolism data and comparison with fluranes4, it is speculated that a possible excretion of very low levels of fluoride ions in the urine could be present, but there are no available data supporting this hypothesis. Percutaneous loss estimated in human volunteers amounted to less than 0.4% for desfluranes4, so this route of excretion should not be relevant for PMVE.

 

6. Conclusions

Based on the considerations above reported, known physico-chemical properties of PMVE, the most likely toxicokinetic profile of PMVE may consist of a rapid absorption by inhalation followed by a poor dissolution in blood indicating low rate of absorption through inhalation route.

Most of PMVE would tend to remain in the alveolar region of the respiratory tract and to be excreted in exhaled air. The quantity that is expected to enter blood, distribute in the body and, thanks to a high perfusion rate, is expected to be metabolized in the liver or kidney by CYP2E1.

 

Assuming that only a very low amount of the inhaled PMVE is actually absorbed and potentially metabolized by CYP2E1, the most likely route of elimination for the possible metabolites is via the urine.


[1]Average value from 2 calculations (estimations by KOWIN [1.42])

[2]Value reported in Solvay SDS

[3]Smiley R.M. at al, Metabolism of desflurane and isoflurane to fluorine ion in surgical patients, Can J Anaesth, 38:8, 965-968, 1991

[4]Saber A.T. and Hougaard K.S., Isoflurane, sevoflurane and desflurane, The Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals, 43(9), NR 2009

[5]McDonald P., Ethene trifluoro acute inhalation toxicity study in rats, Inversek Research International, Report No. 5063, 1988 (Data owner: Solvay)

[6]Malley A.L., Company Study report No: DUPONT-20813: "H-27649: combined dose-toxicity study with a reproduction/developmental toxicity screening test" (OECD 422)

[7]Sharasch E.D., Metabolism and toxicity of the new anesthetic agents, Acta Anaesthesiol Belg1996;47:7-14

[8]Reichle F.M. and Conzen P.F., Halogenated inhalational anaesthetics. Best Pract Res Clin Anaesthesiol;17:29-46, 2003