Vinyl acetate

Endpoint summary

Description of key information

Short description of key information on absorption rate:

A value of 90% absorption during risk assessment was recommended (EU RAR, 2008).

Key value for chemical safety assessment

Absorption rate - dermal (%):

90

Additional information

INTRODUCTION

The toxicokinetics of vinyl acetate have recently been reviewed in detail under the EU Existing Substances Regulations (EU RAR, 2008). This short summary extracts from that publicly available review including additional critical toxicokinetic information that supports the risk assessment of vinyl acetate.

MODE OF ACTION CONTEXT FOR VINYL ACETATE TOXICIKINETICS

The toxicity and carcinogenicity of vinyl acetate is related to its extensive, rapid metabolic conversion to acetaldehyde and acetic acid, with concomitant production of tissue-acidifying protons. Metabolic clearance of acetaldehyde and acetic acid, as well as processes controlling cellular pH serve to reduce tissue exposure to these metabolites, providing some protection against toxicity. These metabolic processes occur in most tissues, including those at the points of contact for inhalation and oral exposures, generally leading to higher exposures to the metabolites in these tissues and lower systemic exposure. Thus, it is important to consider not just the kinetics of vinyl acetate itself, but the kinetics and exposure-tissue dose relationships for the metabolites, especially in the portal of entry tissues such as the oral cavity and nose, the target tissues for vinyl acetate. Further information on acetaldehyde and acetic acid can be obtained from reports e.g. prepared by the German MAK commission.

OCERVIEW OF TOXICOKINETIC DATA

The toxicokinetics of vinyl acetate in the nasal tissues is well described, with more limited datasets for oral and dermal exposure. The toxicokinetic database includes information on:

- Respiratory uptake and estimated systemic bioavailability following inhalation exposure;

- The rapid metabolic conversion of vinyl acetate to acetic acid and its effect on intracellular pH;

- The identification, activity and distribution of the enzymes involved in the metabolism of vinyl acetate and its metabolites acetaldehyde and acetic acid;

- Systemic bioavailability after oral or dermal exposure;

- Tissue distribution of vinyl acetate and/or metabolites ;

- The preparation and experimental validation of PBPK models in support of risk assessment; and,

- Absorption values and scaling factors for risk assessment recommended in the EU RAR.

A summary containing the key toxicokinetic data and related conclusions supporting the risk assessment of vinyl acetate is provided below. The data are organized by the conventional absorption, distribution, metabolism and elimination scheme, followed by a section on the integration of the toxicokinetic data within PBPK models.

Absorption During exposure of rats by inhalation, the degree of uptake of vinyl acetate in the upper respiratory tract was found to be inversely proportional to atmospheric concentrations falling from 94% at 76ppm to about 40% at 550 ppm; uptake then remained approximately constant at concentrations up to 2000ppm (Plowchalk et al., 1997). For risk characterization of systemic effects, systemic bioavailability of intact vinyl acetate during inhalation exposure was reported to be controlled by blood flow extraction and was estimated to be <15% of total uptake (Plowchalk et al., 1997; Bogdanffy et al., 1998). A value of 15% for uptake during inhalation is recommended as a worst case scenario for risk assessment (EU RAR, 2008). At higher concentrations (>76 ppm), where upper respiratory extraction is significantly reduced, or where oral breathing may predominate, a higher fraction, up to 60% (100%-40%) of material may pass to the conducting airways and pulmonary region, possibly increasing systemic exposure. Nonetheless, to the extent that the lower respiratory tract epithelium contains carboxylesterases, only a fraction of vinyl acetate extracted from the inhaled air would pass to the systemic blood. In addition, it should be kept in mind that vinyl acetate can be degraded in the blood with half lives between < 1 min and 4.1 min, further limiting systemic exposure to vinyl acetate (Fedtke and Wiegand, 1990). Value used for CSA: Respiratory uptake (%): 15

After oral administration of 297 mg/kg/body weight [14C] vinyl acetate, 63 % of the applied radioactivity was excreted as metabolites in exhaled air (61.2%), and urine (1.8%). The carcass contained 5.4% of the administered radioactivity 96 hours after the last dose. The authors believed that the remaining 30% of the administered radioactivity not retrieved in the mass balance was eliminated as [14]CO2 in exhaled air, but lost during the opening and closing of the chambers during the repeated dosing exercise (Hazleton, 1980a). A significant loss to exhaled air is consistent with the time course for elimination in exhaled air following oral dosing, since elimination was found to be rapid and greatest during the 6 hour dosing period. In addition, the authors reported finding only [14C] as CO2, indicating that the [14C] in exhaled air was solely derived from absorbed, metabolized vinyl acetate. Summing the measured amount eliminated in exhaled air, the amount eliminated in urine, and the amount in the carcass gives a lower bound on the percent absorbed of 68.4%. By adding the 30% which was likely eliminated in exhaled air but lost to analysis in opening the chambers, an approximate upper bound on vinyl acetate absorption of 98.5% can be estimated for the oral route. The amount in faeces (1.4%) is not included because this material may not have been absorbed. The oral dosing studies provided no information on the chemical identity of radiolabeled material(s) absorbed. Thus, though 68.4-98.5% of the orally administered, radiolabeled carbon was absorbed, no firm conclusions can be made regarding whether the material was vinyl acetate or one of its metabolites. However, systemic exposure to vinyl acetate itself following oral exposure would likely be considerably less than the high fraction of radiolabelled material absorbed. Vinyl acetate can be metabolized in the upper GI tract epithelium, it can therefore be assumed that a considerable amount of metabolism takes place presystemically, limiting systemic exposure to vinyl acetate.

There are no valid quantitative data on the systemic bioavailability of vinyl acetate and its metabolites following dermal exposure. Dermal uptake would depend on the balance between absorption, metabolism in the skin, and loss to volatilization, which would likely be extensive for vinyl acetate, which has a high vapour pressure (12000 Pa, EU RAR, 2008). Acute toxicity observed in rabbits following dermal exposure to 4-16 mL/kg of vinyl acetate (Mellon-Institute 1969) is an indication that systemic exposure occurs following dermal exposure, but the extent of exposure cannot be determined. A default or worst case assumption of 90% absorption during risk assessment was recommended (EU RAR, 2008).

DISTRIBUTION

Exposure of rodents by either inhalation or oral administration to vinyl acetate labelled with [14C] in the vinyl group resulted in a wide distribution of radioactivity throughout the tissues (Hazleton, 1980). This is to be expected for highly absorbed water soluble compounds and their metabolites, particularly when major metabolites (acetaldehyde, acetate) enter the two-carbon metabolic cycle (e.g. acetaldehyde, acetate). Following inhalation by rats, vinyl acetate derived radioactivity is widely distributed with high levels (relative to the total amount detected in the body) in the liver, kidney, lung, brain, stomach, colon, ovaries, harderian gland, ileum, submaxillary salivary gland and the GI tract contents (Hazleton, 1980a). Similarly, following oral exposure to rats, high concentrations were found in the harderian gland, submaxillary salivary gland, liver, kidney stomach, ileum, colon and gastrointestinal tract contents (Hazleton, 1980a).

METABOLISM

Vinyl acetate is hydrolysed by carboxylesterases to acetic acid and acetaldehyde, producing protons in the process. Acetaldehyde is oxidised to acetic acid (acetate) by aldehyde dehydrogenases. The resulting acetate enters the citric acid cycle as acetyl-coenzyme A (Bogdanffy et al., 1998). The tissue distribution and activity of the major enzymes responsible for the metabolism of vinyl acetate, acetaldehyde and acetate are important factors in the disposition and toxicity of vinyl acetate.

The presence of carboxylesterases capable of hydrolysing vinyl acetate with high efficiency has been demonstrated in the epithelial tissues of the nose, oral cavity, and respiratory tract, as well as the skin, blood and liver of several species including man (Hazleton, 1980a; Simon et al., 1985; Bogdanffy and Taylor, 1993; Bogdanffy et al., 1998; Morris et al., 2002). Carboxylesterases present in tissues lining the major portals of entry following inhalation, oral and dermal exposure, lead to pre-systemic hydrolysis of vinyl acetate at these sites, reducing systemic exposure to intact vinyl acetate to a degree in proportion with enzyme activity, i.e. where enzyme activity is highest, systemic exposure will be lowest and visa-versa. Conversely, the presence of carboxylesterases at a portal of entry can increase local concentrations of vinyl acetate metabolites by increasing the air-tissue flux of vinyl acetate.

Aldehyde dehydrogenase (ALDH) is widely distributed and can be found in many tissues of experimental animals including mice, rats, hamsters and guinea pigs. In all species except guinea pig, data supports the presence of two isozymes characterised by high and low affinity forms (Morris, 1997). Similar enzyme activity has been obtained for human nasal and oral cavity tissues; additionally, ALDH activity has been demonstrated in tissue from the human oesophagus and stomach and in saliva (Dong et al., 1996; Yin et al., 1997; Bogdanffy et al., 1998). ALDH activity is present at major sites of inhalation, oral and dermal exposure to vinyl acetate. At exposure levels that do not exceed the capacity of ALDH to oxidise acetaldehyde to acetic acid, there will be proportionally lower local exposure to acetaldehyde, but higher production of acetic acid. Local elevations of acetic acid may cause modest, transient reductions in intracellular pH, but the toxicological significance of this effect is unresolved (EU RAR, 2008). Systemically available acetate is incorporated into the citric acid cycle, ultimately being incorporated into endogenous substances or eliminated as CO2. At higher exposures, the capacity and protective action of ALDH will be exceeded and intracellular accumulation of acetaldehyde will occur, raising tissue levels above a threshold for local toxicity above which tumour formation may occur.

Human variability in ALDH capacity, related to polymorphisms in the high affinity form of the enzyme has been reported. The contribution of this enzyme to total acetaldehyde metabolism is believed to be relatively small (Teeguarden et al., 2008). Nonetheless, where polymorphisms were shown to increase tissue acetaldehyde following vinyl acetate exposure, a pharmacokinetic case for higher risks in this population could be made. The converse is also true. If ALDH polymorphisms reduce acetaldehyde metabolism and subsequently reduce acetic acid levels, the polymorphism could be protective. At this time, an intraspecies adjustment factor of 10 is recommended due to uncertainties in the mode of action for vinyl acetate toxicity.

More specifically, local metabolism was studied in human and rat nasal respiratory and olfactory tissue with whole turbinates in vitro (Bogdanffy et al., 1998). The studies indicated species differences of nasal respiratory carboxylesterase activities between rats and humans. Comparing enzyme activity on a per epithelial cell volume basis, rat respiratory carboxylesterase and ALDH activities were about three and two times higher than those of humans, respectively. Activities of the rat olfactory enzymes (carboxylesterase and ALDH) were about equivalent to those of humans. The Km values for both enzymes are not different between the two species. These species differences in metabolism are reflected in the vinyl acetate physiologically based pharmacokinetic model (Hinderliter et al., 2005). ALDH activities determined in whole nasal tissue homogenates from mouse, rat, hamster and guinea pig showed significantly different ratios of Vmax/Km (intrinsic clearance) for the various species indicating the existence of species differences (Morris, 1997)

Vinyl acetate hydrolysis has been studied in vitro in the oral mucosal tissues from the oral cavity of rats and mice. The hydrolysis activity of the oral tissues is at least 100-fold lower than that of the nasal tissues.

EXCRETION

In rats, radioactivity derived from inhaled [14C]-vinyl acetate was rapidly eliminated in expired air, urine and faeces. The radioactivity in expired air was present as CO2 and acetaldehyde; concentrations of acetaldehyde increased as vinyl acetate exposure was increased, suggesting saturation of acetaldehyde metabolism (Plowchalk et al., 1997). Higher concentrations of acetaldehyde are expected following inhalation, compared with oral exposure, because in the former, acetaldehyde is generated in tissues lining the respiratory tract and equilibrates with exhaled air. This explains differences in the amount of exhaled acetaldehyde reported by Hazleton (1980a), for oral exposure and Plowchalk (1997) for inhalation exposure. Radioactivity from orally administered [14C]-vinyl acetate was also rapidly eliminated predominantly as CO2 in exhaled air along with small amounts of radiolabel in both urine and faeces (Hazleton, 1980a). [13C]-Acetaldehyde has been measured in exhaled air from human volunteers exposed by inhalation to [13C]-vinyl acetate (Hinderliter et al., 2005). Overall, these data support the conclusion that the principle route of elimination for absorbed vinyl acetate is through metabolism, leading to exhalation of the metabolite acetaldehyde and metabolically derived CO2 and acetaldehyde.

PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELS

A physiologically based pharmacokinetic model was developed which describes the deposition of vinyl acetate vinyl acetate in the nasal cavity of the rat. This model predicts steady state concentrations of the metabolite acetic acid after continuing 6 h-exposure in respiratory tissue that are approximately 2.4-5.3 times greater than in olfactory tissue at concentrations between 200 and 1000 ppm, but 46 times greater at the lowest bioassay concentration of 50 ppm. In the olfactory epithelium, acetaldehyde concentrations are approximately half those of acetic acid, except at the 50 ppm exposure level where they are twice the acetic acid concentration. Acetaldehyde concentrations are approximately 10 -fold lower than acetic acid concentrations in the dorsal and ventral epithelium (Plowchalk et al., 1997). As the concentration of acids is indicative of the local metabolism to acetate and increased concentration of protons, the model predicts the greatest reduction in intracellular pH for respiratory mucosa (Plowchalk et al., 1997). Hence, pH effects should be more pronounced in this tissue as compared to other nasal or systemic tissues. This physiologically based toxicokinetic/toxicodynamic model for rat was modified for the olfactory and respiratory epithelium of humans. The change in intracellular pH is predicted to be slightly greater for human compared to rat olfactory epithelium at concentrations above 50 ppm vinyl acetate, but slightly less than the rat at 50 ppm. To provide validation data for the human vinyl acetate PBPK model, controlled human exposures at exposure levels of 1, 5 and 10 ppm to inhaled vinyl acetate were conducted (Hinderliter et al., 2005). Air was sampled by a probe inserted into the nasopharyngeal cavity of five volunteers at bi-directional breathing through the nose. Data from ion trap mass spectrometry measurements of labeled vinyl acetate and acetaldehyde were compared with data from the human nasal model simulation. For the vinyl acetate data, a good fit was demonstrated (r = 0.9). Acetaldehyde data are fitted with a somewhat lower precision. The results show that the human nasal model predicts the experimental observations with regard to vinyl acetate concentrations and the acetaldehyde washout in the airstream of human nasopharyngeal cavity in a concentration range from 1 to 10 ppm. Though there are some uncertainties in the enzyme kinetic data used to establish the model, the PBPK model currently represents the best integration of the available data on the kinetics of vinyl acetate, acetaldehyde and acetate metabolism and well as other physiological processes affecting nasal tissue dosimetry of these compounds. Thoughtful consideration of the PBPK models strengths and limitations is appropriate when the outputs are applied in risk assessment.

Use of the validated PBPK model for cross species extrapolation of nasal tissue dosimetry can replace the standard interspecies adjustment factor for pharmacokinetic differences (3), reducing the interspecies uncertainty factor from 10 to 3. Because pharmacodynamic differences between species cannot be ruled out, and since local metabolism will limit systemic absorption and metabolism, the total interspecies adjustment factor of 3 appears justified and should be applied in a risk assessment.

Due to recognized human polymorphisms in ALDH activity, an intraspecies adjustment factor of 5 or 10 (worker or general population, respectively) is recommended to account for uncertainties in ALDH activity in mode of action for vinyl acetate toxicity.

DISCUSSION ON ABSORPTION RATE

Although the absorption of vinyl acetate following dermal exposure has not been directly measured, systemic toxicity was observed in rabbits exposed dermally to very high dose levels (4-16ml/kg), suggesting some absorption of vinyl acetate or its metabolites (Mellon Institute, 1969).