Hexafluoropropene, oxidized, oligomers, reduced, fluorinated

Endpoint summary

Description of key information

No standard experimental toxicokinetic study is available on Galden LMW. The assessment of toxicokinetic behavior of the substance was based on physico-chemical and toxicological data available in the dataset. 

•Absorption of Galden LMW could potentially occur mainly by the inhalation route, due to the volatile properties;

•Distribution of Galden LMW might occur following absorption through the respiratory tract;

•Metabolism: The structure of the molecule and the terminal groups -CF3 are considered to be stable and not undergo further metabolism. A metabolism leading to production of free fluoride might be cautiously assumed only as a worst case or at least representing the behaviour of the 10% content of CF2H end groups constituting the substance.

•Excretion of Galden LMW metabolites could preferentially occur through bile instead of urine.

Key value for chemical safety assessment

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

REACH indicates in Annex VIII (Section 8.8.1) that an “assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information”.

As far as absorption, distribution, metabolism and excretion are concerned, no direct toxicokinetic data on Galden LMW are available. In order to accomplish the requirement of outlining the TK behaviour of Galden LMW, considerations on its possible activity profile have been derived both on physico-chemical and toxicological data, and QSAR modelling for dermal absorption properties.

The present assessment is organized in two different sections: the first one gives indications on absorption, distribution, metabolism and excretion of Galden LMW on the basis of its most relevant physico-chemical properties. In the second section, experimental data on the available toxicological studies have been assessed. On the ground of physico-chemical and toxicological properties, some considerations have been made for the four TK phases (absorption, distribution, metabolism, excretion).

Some of the toxicological studies were conducted only on Galden LMW chemical analogue H Galden (HFPE). Basing on the structural similarity, toxicological data on H Galden can be used in order to get information on the toxicokinetic behaviour of Galden LMW. The rationale supporting this hypothesis is described in the “RAAF document”.

 

Substance identification

 

Galden LMW

CAS No. 161075-00-9

Molecular weight: 350 - 500 amu

Physical state: clear, colourless and odourless liquid

Water solubility: 0.466 mg/l at 22°C

Log Kow: 5.58 at 20°C

Vapour pressure: 147 - 296 hPa at 20°C

 

 

 1. Physico-chemical properties with impact on toxicokinetics

The physico-chemical properties which could influence the toxicokinetic behaviour of Galden LMW, are summarized as follows:

 

i) Molecular weight: 350 -500 amu

 

According to Table R.7.12-1 from ECHA Endpoint Specific Guidance Chapter R.7C a molecular weight below 500 could favour gastro-intestinal 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 smaller is the molecule the wider is its distribution in body compartments.

 

According to Table R.7.12-6 from ECHA Endpoint Specific Guidance Chapter R.7C a molecular weight above 300 is not favorable for urinary excretion in the rat.

 

 

ii) Physical state: clear, colourless and odourless liquid

 

According to Table R.7.12-3 from ECHA Endpoint Specific Guidance Chapter R.7C being a liquid Galden LMW should be taken up more readily than dry particulates. Absorption of volatile liquids across the skin may be limited by the rate at which the liquid evaporates off the skin surface.

 

 

iii) Water solubility: 0.466 mg/l at 20 °C²

 

According to Table R.7.12-2 from ECHA Endpoint Specific Guidance Chapter R.7C low water solubility enhances penetration to the lower respiratory tract.

 

According to Table R.7.12-3 from ECHA Endpoint Specific Guidance Chapter R.7C a water solubility < 1 mg/l favours very low dermal absorption. As a consequence, Galden LMW should be very little absorbed by dermal route.

 

According to Table R.7.12-4 from ECHA Endpoint Specific Guidance Chapter R.7C small water-soluble molecules and ions will diffuse through aqueous channels and pores. Due to its low water solubility and molecule size, Galden LMW is not likely to diffuse through aqueous channels and pores.

 

According to Table R.7.12-6 from ECHA Endpoint Specific Guidance Chapter R.7C low water solubility is not favourable for urinary excretion.

 

 

iv) Log Kow: 5.58

 

According to Table R.7.12-1 and R.7.12-2 from ECHA Endpoint Specific Guidance Chapter R.7C substances with a moderately high log Kow value (>4) may be taken up by micellular solubilisation. This mechanism may be of particular importance for those that are also poorly soluble in water.

 

According to Table R.7.12-3 from ECHA Endpoint Specific Guidance Chapter R.7C high Log Kow values (>4) may limit the rate of penetration between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high.

 

 

v) Vapour pressure:147 - 296 hPa at 20°C

 

According to Table R.7.12-2 from ECHA Endpoint Specific Guidance Chapter R.7C Galden LMW is a volatile liquid.

 

According to Table R.7.12-4 from ECHA Endpoint Specific Guidance Chapter R.7C 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.

 

According to Table R.7.12-6 from ECHA Endpoint Specific Guidance Chapter R.7C volatile liquid and volatile metabolites may be excreted as vapours in exhaled air.

 

Table 1: Physico-chemical properties affecting the TK phase

 

TK phase	Physico-chemical properties affecting the TK phase
Gastrointestinal absorption	structure (ionization); molecular weight; water solubility; log Kow
Dermal absorption	physical state; molecular weight; structure; water solubility; log Kow; vapour pressure
Respiratory absorption	vapour pressure; log Kow; water solubility
Distribution	molecular weight; water solubility; log Kow
Excretion	structure (ionization, polarity); physical state; molecular weight; water solubility; log Kow

2. Absorption, distribution, metabolism and excretion

 

As Galden LMW is a volatile liquid, the three routes of exposure (oral, dermal and inhalation) have been considered in order to delineate the toxicokinetic profile of the substance. As far as the repeated-dose toxicity is concerned, a 28-day study was performed on Galden LMW. On the basis of the analogue approach, some useful information have been derived even from repeated-dose toxicity and reproductive toxicity studies on H Galden. In this context it is worth to reiterate that the adopted read across represents a worst case approach, since the presence of –OCF2H as terminal groups in H Galden, gives to the product more reactivity and polarity (higher water solubility and lower Log Kow) than those observed for Galden LMW and it is considered to represent the behaviour of the 10% content of CF2H end groups constituting the substance.

 

2. a. Absorption

 

Gastrointestinal (via the oral route): a 28-day oral toxicity study in rats was conducted on Galden LMW for evaluating the effects of repeated administration [iv]. Galden LMW was administered by gavage once a day for 4 consecutive weeks to groups of 5 males and females of Sprague Dawley Crl: CD (SD) BR rats at the doses of 250, 500 and 1000 mg/kg/day.

No substance-related deaths and clinical signs were observed. Body weight showed only a very slight retarded growth at the highest dose which was considered of no toxicological relevance. Food intake was unaffected by treatment. Laboratory investigations and post-mortem examinations did not reveal changes attributable to Galden LMW administration. Since no signs of systemic toxicity were present, there is no clear evidence that Galden LMW absorption has occurred.

This is also supported by an acute oral toxicity study in rats[v](administration by gavage) where no clinical signs at the necropsy observation, indicate no clear evidence of systemic absorption. through the gastrointestinal tract.

 

According toTable R.7.12-1 from ECHA Endpoint Specific Guidance Chapter R.7C, absorption of Galden LMW through the gastrointestinal tract is possible based on molecular weight (350-500 amu). Nevertheless, according to the above quoted guidance, low water solubility (0.47 mg/l at 20°C) makes Galden LMW not readily dissoluble into gastrointestinal fluids. Here, the complete absence of ionisable groups within the structure of the molecule could further limit its absorption.

 

On the whole, taking into consideration experimental data and physico-chemical properties absorption of Galden LMW through the gastrointestinal tract is not likely to occur. Like suggested by table R.7.12-1 from ECHA Endpoint Specific Guidance Chapter R.7C, the slight retardation in body weight growth registered at 1000 mg/kg/day could be due to discomfort caused by the presence of a large volume of the test substance in the stomach because of low absorption.

Considering the physico-chemical properties and the lack of adverse effects at the limit dose of 1000 mg/kg/day for 28 days, it is unlikely that the substance is readily absorbed through the gastro-intestinal tract. However, because of the molecular weight below 1000 and uncertainty on the potential mechanisms of absorption, a default of 100% absorption is used for the risk assessment.

 

Dermal: an acute dermal toxicity study was conducted in rats [vi]. Five male and five female HanRcc: WIST (SPF) rats were treated with Galden LMW at 2000 mg/kg by dermal application.

No deaths occurred during the study and no macroscopic findings were observed at necropsy. Since no systemic or local signs of toxicity were observed during the study period, there is no clear evidence of absorption through the dermal route.

Dermal absorption seems unlikely to happen even on the basis of dermal irritation and skin sensitisation studies. According to Table R.7.12-3 from ECHA Endpoint Specific Guidance Chapter R.7C, if a substance is a skin irritant or corrosive, damage to skin surface may enhance penetration. This possibility can be excluded because an acute dermal irritation study in rabbits [vii] clearly shows that Galden LMW is to be considered non irritant for the skin under the experimental conditions adopted. The same guidance quoted above even states that if a substance is identified as a skin sensitiser then some uptake must have occurred although it may only have been a small fraction of the applied dose. Nevertheless this is not the case of Galden LMW since the results from a skin sensitisation study [viii] show that, under the experimental conditions applied, Galden LMW does not appear to have sensitising capacity.

 

Global considerations on dermal absorption, based on the relevant physico-chemical properties identified following Table R.7.12-3 from ECHA Endpoint Specific Guidance Chapter R.7C in section 1, are summarized as follows.

 

Galden LMW is a low boiling-point and highly volatile liquid (the vapour pressure at 25°C is above 10 kPa). Absorption of volatile liquids across the skin may be limited by the rate at which the liquid evaporates from the skin surface[ix]. Probably Galden LMW could partition into the stratum corneum, but it would be too volatile to penetrate further.

 

Even molecular weight and water solubility are not particularly favourable for dermal absorption.

Since there must be sufficient solubility in water to partition from the stratum corneum into the epidermis, if the water solubility is below 1 mg/l, dermal uptake is likely to be low.

Moreover Log Kow > 4 may limit the rate of penetration between the stratum corneum and the epidermis.

 

Dermal absorption potential was also assessed in the model IH SkinPerm (v2.04). The model is predicting dermal absorption behaviour from the physico-chemical properties. Using both the instantaneous (splash exposure) and the continuous deposition models and assumptions corresponding to optimised exposure conditions, the results showed that whatever the quantity and duration of use only 0.1 % of the quantity deposited by direct contact was found to migrate to the stratum corneum and reaching the systemic circulation, while ca. 99% of the substance is volatilized within seconds of contact. When predictions are made using a MW adjusted with the density to account for the lower molar volume compared to mass typical of fluorinated molecules, the fraction of the quantity deposited on skin that was absorbed was around 1%, with a maximum of 27.1 mg absorbed in the continuous exposure model.

In addition, the modeling for exposure to vapours indicated that very low amounts would deposit onto the skin to be absorbed even under conditions close to the DNEL.

On the whole, both experimental toxicity data and the most relevant physico-chemical properties would seem to exclude a significant absorption through the skin.

Therefore, considering the logKow value, the low water solubility, molecular weight, and high volatility favoring evaporation, the amount absorbed dermally is expected to be less than 10%.

 

Inhalation: an acute toxicity study by inhalation was conducted in Sprague Dawley CD rats [x]; rats were whole body exposed to an atmosphere containing 9.47% (v/v) of Galden LMW. The acute inhalation LC50 of Galden LMW to rats was in excess of 9.47% (v/v) in air and neirther macroscopic abnormalities nor local signs of irritation were found. Repeated dose toxicity studies by inhalation are available for the analogue H Galden.

According to Table R.7.12-2 from ECHA Endpoint Specific Guidance Chapter R.7C if signs of systemic toxicity are present then absorption has occurred.

 

Both in a 28-day inhalation toxicity study and in a 90-day inhalation toxicity study, increment in the liver weight and adaptive metabolic centrilobular hepatocytic hypertrophy indicated that systemic effects and therefore absorption occurred.

Altogether the above reported results from sub-acute and sub-chronic toxicity studies correspond to systemic effects implying that absorption of H Galden has occurred.

 

Global considerations on inhalatory absorption, based on the relevant physico-chemical properties identified following Table R.7.12-2 from ECHA Endpoint Specific Guidance Chapter R.7C in section 1, are summarized as follows:

Galden LMW is a low boiling-point and volatile liquid and therefore it is available for inhalation as a vapour. The log Kow value (5.58) is favourable for absorption directly across the respiratory tract epithelium by passive diffusion. On the basis of its lipophilicity and water solubility, Galden LMW may be taken up by micellular solubilization. Moreover the low water solubility of the substance could enhance its penetration to the lower respiratory tract, followed by systemic absorption.

 

On the whole, both experimental toxicity data on the chemical analogue H Galden together with the most relevant physico-chemical properties of test item, especially the moderate vapour pressure, suggest the inhalatory absorption of Galden LMW is likely to occur but only at a minimal level.

 

 

2. b. Distribution

 

Chapter R.7C from ECHA Endpoint Specific Guidance quotes that once a chemical has entered the blood stream, it may exert its toxic action directly in the blood or in any target tissue or organ to which the circulatory system transports or distributes it. It is the blood flow through organs, the ability of a substance to cross membranes and capillaries, and its relative affinity for the various tissues that determine the rate of distribution and the target tissues.

Effects on rat liver (elevation in weight and centrilobular epathocyte hypertrophy) observed in the repeated dose toxicity studies by inhalation^{11, 12, 13}indicate that H Galden entered systemic circulation.

Global considerations on inhalatory absorption, based on the relevant physico-chemical properties identified following Table R.7.12-4 from ECHA Endpoint Specific Guidance Chapter R.7C in section 1, are summarized as follows: Galden LMW has an average molecular weight smaller than H Galden, so its distribution should be wider. On the whole, experimental toxicity data on the chemical analogue H Galden, together with the most relevant physico-chemical properties of the assessed substance, suggest the distribution of Galden LMW, following absorption by inhalation, is likely to occur.

 

2. c. Metabolism

 

According to ECHA Endpoint Specific Guidance Chapter R.7C, it is very difficult to predict the metabolic changes a substance may undergo on the basis of physico-chemical information alone. Although it is possible to look at the structure of a molecule and identify potential metabolites, it is by no means certain that these reactions will occur in vivo. It is even more difficult to predict the extent to which it will be metabolised along different pathways and what species differences exist. Consequently, experimental data shall help in the assessment of potential metabolic pathways.

No experimental data are available for Galden LMW, but some assumptions on its metabolism can be made basing on a sub-acute toxicity study by inhalation on H Galden¹². Increased urinary fluoride level and increased water consumption were considered to be associated with metabolic breakdown of the test material releasing free fluoride but in the absence of any hystopathology in the kidney this is considered not to be indicative of overt toxicity. As a result of hepatic metabolism, it is deemed reasonable to hypothesize that the fluorinated chain of H Galden could undergo a progressive breakdown till the releasing of free fluoride.

For Galden, the absence of hydrogenated terminal groups, might impact on enzymatic degradation of Galden LMW molecule. In fact, the terminal groups -CF3 are considered to be stable and not undergo further metabolism.

 

 

2. d. Excretion

 

According to ECHA Endpoint Specific Guidance Chapter R.7C, the majour routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the GI mucosa).

According to ECHA Endpoint Specific Guidance Chapter R.7C, the excretion processes involved in the kidney are passive glomerular filtration through membrane pores and active tubular secretion via carrier processes. On the ground of Galden LMW molecular weight and water solubility the product is not likely prone for urinary excretion.

Biliary excretion involves active secretion rather than passive diffusion[xi]. In the rat it has been found that substances with molecular weights below around 300 do not tend to be excreted into the bile[xii]. There are species differences and the exact nature of the substance also plays a role[xiii]. The excretion of compounds via bile is highly influenced by hepatic function as metabolites formed in the liver may be excreted directly into the bile without entering the bloodstream. Additionally, blood flow as such is a determining factor.

On the basis of the available data biliary excretion can not be excluded but there are no supportive experimental data confirming this hypothesis.

 

 

3. Conclusion

 

As far as absorption, distribution, metabolism and excretion are concerned, no direct toxicokinetic data on Galden LMW are available. In order to accomplish the requirement of outlining the TK behaviour of Galden LMW, considerations on its possible activity profile have been derived both on physico-chemical and toxicological data.

 

On the whole the following conclusions on ADME (absorption, distribution, metabolism, excretion) of Galden LMW can be proposed, basing both on physico-chemical properties and toxicological data. All these assumption represent a worst case hypothesis based on the analogue approach with H Galden:

 

·   Absorption of Galden LMW could potentially occur mainly by the inhalation route; no systemic exposure is expected via the dermal route.

·   Distribution of Galden LMW might occur following absorption through the respiratory tract;

·   Metabolism: The structure of the molecule and the terminal groups -CF3 are considered to be stable and not undergo further metabolism.

·   Excretion of Galden LMW metabolites could preferentially occur through bile instead of urine.

 

References

[i]Method of analysis PF 29-142 and PF 29-143, 2012

[ii]Nichetti S. (2013): Galden LMW – Determination of Water Solubility, Chemservice CH – 729/2012

[iii]Bernini G et al, Determination of the vapor pressure for low boiling point Galden fluids with Druck pressure trasducer, 1992

[iv]Ammanati E, “Galden HT70: 4 week oral toxicity study in rats”, RBM Exp. No. 910558, 1993

[v]Gillio Tos E, “ Galden HT70: acute toxicity study in rats”, RBM Exp. No. 920247, 1992

[vi]Ott M, “ Galden HT70: acute dermal toxicity study in rats”, RCC Study N. A69107, 2006

[vii]Gillio Tos E, “ Galden HT70: acute dermal irritation study in rabbits”, RBM Exp. No. 929249, 1992

[viii]Fava L, “Skin sensitisation test in guinea pigs of the test article Galden HT70 (Buhler test) ”, RBM Exp. No. 929250, 1992

[ix]Pryde DE and Payne MP, Refinements to an existing knowledge based system for predicting the potential for dermal absorption. IR/EXM/99/07. Sheffield, UK, Health and Safety Laboratory, 1999

[x]Jackson GC, “ Galden HT70 acute inhalation toxicity in rats 4-hour exposure”, Huntingdon Life Science Ltd, AST 7/960524, 1997

[xi]Smith R, Factors affecting biliary excretion.The excretory function of the bile. Chapmann & Hall London, 1973

[xii]Renwick, AG, Toxicokinetics - pharmacokinetics in toxicology. In Hayes AW (ed.)Principles and Methods of Toxicology. Raven Press, New York, 103, 1994

[xiii]Hirom PC, Millburn P, Smith RL and Williams RT, Species variations in the threshold molecular-weight factor for the biliary excretion of organic anions.Biochem. J, 129, 1071-1077, 1972