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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Expert statement
Adequacy of study:
key study
Study period:
2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An extensive Assessment of the toxicological behaviour of 4-phenylbutenone was performed, taking into account the chemical structure, the available physico-chemical-data and the available (eco-)toxicological data.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
An extensive assessment of the toxicological behaviour of 4-phenylbutenone was performed, taking into account the chemical structure, the available physico-chemical-data and the available (eco-)toxicological data.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
not applicable
Radiolabelling:
other: not applicable in this expert statement

Test animals

Species:
other: not applicable
Strain:
other: not applicable
Details on test animals and environmental conditions:
not applicable

Administration / exposure

Route of administration:
other: all routes of administration are discussed in the expert statement
Vehicle:
other: not applicable
Details on exposure:
all routes of administration are discussed in the expert statement
Details on study design:
not applicable
Details on dosing and sampling:
not applicable

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
4-phenylbutenone is favourable for absorption, due to its molecular weight (ca. 146.19 g/mol) and its water solubility (1890 mg/l), which eases absorption. The value of the LogPow of 2.04 demonstrates that the substance has a better solubility in octanol than in water (positive LogPow for lipophilic substances, negative LogPow for hydrophilic substances). Considering its LogPow above 0 and below 4, the absorption into the body is assumed to be favoured. Further enhancement of absorption might be applicable, as 4-phenylbutenone is irritating to the skin (Brulos, 1977, Opdyke, 1973, Schreiter, 1999).
The above mentioned properties determine the absorption of 4-phenylbutenone to be well based on the absorption-favouring properties (molecular weight, water solubility and positive LogPow).
The available data show that orally administered 4-phenylbutenone will be absorbed well, due to its low molecular weight, its optimal LogPow and its solubility in water. This thesis is supported by the results found for trans-methyl styryl ketone, for which was shown that the majority of the dose administered orally was absorbed readily (Sauer, 1997). However, the LD50 value of 2030 mg/kg bw available for 4-phenylbutenone, shows that the substance is despite this readily absorption not acutely toxic after oral exposure.
4-phenylbutenone has a low vapour pressure, which indicates only marginal availability for inhalation. Due to its optimal LogPow for absorption, the amount available will be absorbed, possibly through the respiratory epithelium or through aqueous pores, which is likely as the substance has a molecular weight below 200. Based on this data, it can be expected that 4-phenylbutenone is marginally available in the air for inhalation and inhaled substance is expected to be absorbed, due to its low vapour pressure and its molecular weight.
In case of 4-phenylbutenone, the molecular weight is above 100 and below 500, which indicates already a lower potential to penetrate the skin. This is accompanied by an optimal hydrophilicity of the substance (water solubility of 1890 mg/L and a LogPow of 2.04) and even though the stratum corneum is very resistant against penetration by highly hydrophilic substances, 4-phenylbutenone will be absorbed via the skin. As the substance is irritating to the skin, this might enhance dermal absorption, however, the systemic toxicity of 4-phenylbutenone via the skin has been shown to be very low, (acute dermal toxicity, LD50 value of 3000 mg/kg bw for rats).
This thesis is supported by the findings for methyl trans styryl ketone, which has been shown to be absorbed to about 50-60 % through the skin, following topical administration (Sauer, 1997).
In conclusion, the evaluation of all the available indicators and the results of toxicity studies allow the allocation of the chemical in question into the group of chemicals with a low dermal absorption.
Details on distribution in tissues:
In case of 4-phenylbutenone, no data is available for distribution patterns. The distribution is expected to be into the intravasal compartment, due to its better solubility in octanol than in water (LogPow 2.04). This is supported by the findings for methyl trans styryl ketone, which has been reported to be distributed mainly into the intravasal compartment, without reaching significantly the tissues (Sauer, 1997). This was also due to a fast and nearly complete metabolism i.e. in the blood itself. The apparent distributon volume was determined to be 0.89 liters/kg.
Details on excretion:
For 4-phenylbutenone no data is available concerning its elimination. Concerning the above mentioned behaviour predicted for its metabolic fate, its chemicals structure and its molecular weight, it is very likely that the parent substance will be excreted metabolised mainly via the urine. This is supported by the findings for methyl trans styryl ketone, which has been found to be eliminated to a large extent via the urine (after oral administration 96.6% of the dosed radioactivity was recovered in the urine and 4.8% in the faeces within 48 hr, Sauer, 1997).

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Hydrolysis does not apply for 4-phenylbutenone and its metabolism is likely to occur also via the Cytochrome P450 group of metabolising enzymes, as it has been predicted with the TOXTREE modelling tool (Chemservice S.A., 2012). There, the chemical has been identified to bear primary, secondary and tertiary sites and more than 4 sites for metabolism by the Cytochrome P450 group of metabolising enzymes. The primary site of metabolism (carbon atom at the end of the chain) is predicted to be subject to aliphatic hydroxylation. The secondary site of metabolism is the carbon-atom of the aromatic ring (C4), which is predicted to be subject to aromatic hydroxylation and the tertiary sites of metabolism (carbon atoms 2 and 6 of the aromatic ring and the carbonatom with the double bond of the chain) are predicted to be either subject to aromatic hydroxylation or epoxidation).
To identify all possible sites for phase I and II reactions, the molecular structure of 4-phenylbutenone was investigated in detail.
In a first step, it is possible that the double bond is reduced by addition of two hydrogen atoms (aromatic hydroxylation). Moreover, this double bond might be subject to epoxidation by cytochrome P450s. This, however, is a step backwards, but might lead in the end to the formation of 2 hydroxyl groups (R-COHCOH-C=OCH3, where R is the aromatic ring). The other carbon atoms of the ring can be subject to aromatic hydroxylations by cytochrome P450, leading to the formation of a hydroxyl group, which facilitate elimination. The carbonatoms of the chain can be subject to aliphatic hydroxylation i.e. by by cytochrome P450s.
The existing or newly introduced functional groups will react in phase II of the biotransformation with different molecules, leading to the formation of conjugations. For the hydroxyl-groups it is most likely that they could be conjugated to glucuronic acid or activated sulphate. This however, might not even be necessary as the substance / metabolite is / are already very water soluble and of low molecular weight. However, it has to be kept in mind, that metabolites conjugated to glucuronic acid, can be subject to entero-hepatic recycling, and therefore re-enter to system.
In conclusion, it is likely that the substance of interest will be subject to extensive metabolism i.e. by cytochrome P450 enzymes and subsequent glucuronidation.
Concerning the possibility of protein binding, this cannot be ruled out, without adequate experimental data.
These theses are supported by the findings for methyl trans styryl ketone, which has been reported to be extensively metabolised, leading to the formation of N-phenylacetyl-L-glycine, N-benzyl-L-glycine, N-acetyl-S-(4-phenyl-2-butan-one)-L-cystein and N-acetyl-S-(4-phenyl-2-butanol)-L-cysteine (Sauer, 1997).

Any other information on results incl. tables

Assessment of toxicological behaviour

Background

There is data available on the physico-chemical properties of 4-phenylbutenone. The substance is a yellowish to greenish crystalline solid with a characteristic odour (MW ca. 146.19 g/mol, Raschig, 2011), its melting point is 39.7 °C (Raschig, 2012) and its calculated boiling point is 234.4 °C (Chemservice, 2011). The substance is predicted to be soluble in water (1890 mg/l at 25°C, Chemservice S.A., 2012A) and a LogPow of 2.04 was predicted (Chemservice S.A., 2012B). Hydrolysis (as a function of pH) has been determined experimentally and the substance was found to be hydrolytically stable at pH 4, 7 and 9 with a half-life at 25 °C greater than 1 year (Tarran, 2012). The vapour pressure was predicted as 1.34 Pa (Chemservice S.A., 2012C) and is considered to be low.

The substance is not acutely toxic, when administered to rats orally (LD50 2030 mg/kg bw, GESTIS, 2011) or dermally (LD50 3000 mg/kg bw, Opdyke, 1973). It is a skin but not an eye irritant (Brulos, 1977, Opdyke, 1973, Schreiter, 1999), and was shown to bear a potential to cause allergic reactions (sensitising via Magnusson and Kligman Method, Opdyke, 1973, sensitising in LLNA, Gerberik, 2005). Repeated oral exposures to methyl trans-styryl ketone (CAS 1896-62-4, 0.025, 0.05, 0.1, 0.2 and 0.4 % in diet) for 14 weeks did not cause mortalities in rats or mice (NTP report TR 572, 2011). However, clinical signs were noted (diarrhoea and hyperactivity) and in addition the final mean body weights of rats were reduced at the highest dose administered. A NOAEL of 145 mg/kg bw/day for female and 150 mg/kg bw/day for male rats and a NOAEL of 350 and 400 mg/kg bw/day for female and male mice was derived. Repeated dermal exposures to methyl trans-styryl ketone (CAS 1896-62-4, 22, 44, 87.5, 175 and 350 mg/kg bw/day) for 14 weeks did not cause mortalities in rats (NTP report TR 572, 2011). However, clinical signs were noted (dermal irritation, thickened skin and ulceration at the site of application) and in addition the final mean body weights of rats were reduced at 175 and 350 mg/kg bw. A NOAEL of 87.5 mg/kg bw was derived for rats. Mice received 0, 87.5, 175, 350, 700, or 1,400 mg, clinical findings included dermal irritation (350 mg/kg bw) and crust formation at the application site (700 and 1,400 mg/kg bw) and the mice of the two highest dose groups had to be sacrificed moribund before the end of the study (NTP report TR 572, 2011). Mean body weights were significantly reduced in the dose group 175 mg/kg bw. A LOAEL of 87.5 mg/kg bw was derived for mice. Additionally, the substance was reported to bear genotoxic potential in an AMES-test (mutagenic with and without metabolic activation, Seifried, 2006). Moreover, it was shown to be positive in the non activated mouse lymphoma test (Seifried, 2006). However, the substance was tested negative in the micronucleus test (Roth, 2012) and was also reported negative in the micronucleus test by the National toxicology program (NTP, 2012). Concerning the carcinogenic potential methyl trans-styryl ketone was not reported bear carcinogenic potential after dermal application to rats or mice (NTP report TR 572, 2011). Administration of methyl trans-styryl ketone resulted in nonneoplastic lesions of the skin at the site of application in male and female rats and mice.

Assessment of toxicological behaviour

The available physico-chemical and toxicological information of the substance has been evaluated and used to assess the toxicological behaviour. The results of this analysis will address the question on how the chemical will react in the body.

The EU Technical Guidance Document on Risk Assessment (EU TGD, Part I, Appendix VI) provides guidance, which physico-chemical properties commonly determine oral, inhalatory and dermal absorption, distribution, metabolism and elimination of substances (LINK to Guidance Document: http://ecb.jrc.ec.europa.eu/tgd/).

Absorption

In general, absorption of a chemical is possible, if a substance crosses biological membranes. This process requires a substance to be soluble, both in lipid and in water, and is also dependent on its molecular weight (substances with molecular weights below 500 are favourable for absorption). Generally, the absorption of chemicals which are surfactants or irritants may be enhanced, because of damage to cell membranes.

4-phenylbutenoneis favourable for absorption, due to its molecular weight (ca. 146.19 g/mol) and its water solubility (1890 mg/l), which eases absorption. The value of the LogPow of 2.04 demonstrates that the substance has a better solubility in octanol than in water (positive LogPow for lipophilic substances, negative LogPow for hydrophilic substances). Considering its LogPow above 0 and below 4, the absorption into the body is assumed to be favoured (LogPow between 0 and 4 are favourable for absorption). Further enhancement of absorption might be applicable, as 4-phenylbutenone is irritating to the skin (Brulos, 1977, Opdyke, 1973, Schreiter, 1999).

The above mentioned properties determine the absorption of 4-phenylbutenone to be well based on the absorption-favouring properties (molecular weight, water solubility and positive LogPow).

Absorption from the gastrointestinal tract

Regarding oral absorption, in the stomach, a substance will most likely be hydrolysed, because this is a favoured reaction in the acidic environment of the stomach. For 4-phenylbutenone, its potential to hydrolyse was experimentally determined (Taran, 2012). However, the substance was found not to hydrolyse but to be hydrolytically stable with a half-life greater than 1 year. In accordance with the above mentioned principles, it is very unlikely for4-phenylbutenoneto be hydrolysed in the stomach.

In the small intestine absorption occurs mainly via passive diffusion or lipophilic compounds may form micelles and be taken into the lymphatic system. Additionally, metabolism can occur by gut microflora or by enzymes in the gastrointestinal mucosa. However, the absorption of highly lipophilic substances (LogPow of 4 or above) may be limited by the inability of such substances to dissolve into gastrointestinal fluids and hence make contact with the mucosal surface. The absorption of such substances will be enhanced if they undergo micellular solubilisation by bile salts. Substances absorbed as micelles enter the circulation via the lymphatic system, bypassing the liver.

The available data show that orally administered 4-phenylbutenone will be absorbed well, due to its low molecular weight, its optimal LogPow and its solubility in water. This thesis is supported by the results found for trans-methyl styryl ketone, for which was shown that the majority of the dose administered orally was absorbed readily (Sauer, 1997). However, the LD50 value of 2030 mg/kg bw available for 4-phenylbutenone, shows that the substance is despite this readily absorption not acutely toxic after oral exposure.

Absorption from the respiratory tract

Concerning absorption in the respiratory tract, any gas or vapour has to be sufficiently lipophilic to cross the alveolar and capillary membranes (moderate LogPow values between 0-4 are favourable for absorption). The rate of systemic uptake of very hydrophilic gases or vapours may be limited by the rate at which they partition out of the aqueous fluids (mucus) lining the respiratory tract and into the blood. Such substances may be transported out of the lungs with the mucus and swallowed or pass across the respiratory epithelium via aqueous membrane pores. Lipophilic substances (LogPow >0) have the potential to be absorbed directly across the respiratory tract epithelium. Very hydrophilic substances can be absorbed through aqueous pores (for substances with molecular weights below and around 200) or be retained in the mucus.

4-phenylbutenone has a low vapour pressure, which indicates only marginal availability for inhalation. Due to its optimal LogPow for absorption, the amount available will be absorbed, possibly through the respiratory epithelium or through aqueous pores, which is likely as the substance has a molecular weight below 200. Based on this data, it can be expected that4-phenylbutenoneis marginally available in the air for inhalation and inhaled substance is expected to be absorbed, due to its low vapour pressure and its molecular weight.

Absorption following dermal exposure

In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the epidermis is most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight below 100 are favourable for penetration of the skin and substances above 500 are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/l, dermal uptake is likely to be low. Additionally LogPow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal; TGD, Part I, Appendix VI). Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow. Moreover vapours of substances with vapour pressures below 100 Pa are likely to be well absorbed and the amount absorbed dermally is most likely more than 10% and less than 100 % of the amount that would be absorbed by inhalation. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. During the whole absorption process into the skin, the compound can be subject to biotransformation.

In case of 4-phenylbutenone, the molecular weight is above 100 and below 500, which indicates already a lower potential to penetrate the skin. This is accompanied by an optimal hydrophilicity of the substance (water solubility of 1890 mg/L and a LogPow of 2.04) and even though the stratum corneum is very resistant against penetration by highly hydrophilic substances, 4-phenylbutenone will be absorbed via the skin. As the substance is irritating to the skin, this might enhance dermal absorption, however, the systemic toxicity of4-phenylbutenonevia the skin has been shown to be very low, (acute dermal toxicity, LD50 value of 3000 mg/kg bw for rats).

This thesis is supported by the findings for methyl trans styryl ketone, which has been shown to be absorbed to about 50-60 % through the skin, following topical administration (Sauer, 1997).

In conclusion, the evaluation of all the available indicators and the results of toxicity studies allow the allocation of the chemical in question into the group of chemicals with a low dermal absorption.

Distribution

In general, the following principle applies: the smaller the molecule, the wider the distribution. A lipophilic molecule (LogPow >0) is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. It’s not possible to foresee protein binding, which can limit the amount of a substance available for distribution. Furthermore, if a substance undergoes extensive first-pass metabolism, predictions made on the basis of the physico-chemical characteristics of the parent substance may not be applicable.

In case of 4-phenylbutenone, no data is available for distribution patterns. The distribution is expected to be into the intravasal compartment, due to its better solubility in octanol than in water (LogPow 2.04). This is supported by the findings for methyl trans styryl ketone, which has been reported to be distributed mainly into the intravasal compartment, without reaching significantly the tissues (Sauer, 1997). This was also due to a fast and nearly complete metabolism i.e. in the blood itself. The apparent distribution volume was determined to be 0.89 liters/kg.

Accumulation

It is also important to consider the potential for a substance to accumulate or to be retained within the body. Lipophilic substances have the potential to accumulate within the body (mainly in the adipose tissue), if the dosing interval is shorter than 4 times the whole body half-life. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, substances with high LogPow values tend to have longer half-lives. On this basis, there is the potential for highly lipophilic substances (LogPow >4) to accumulate in biota which are frequently exposed. Highly lipophilic substances (LogPow between 4 and 6) that come into contact with the skin can readily penetrate the lipid rich stratum corneum but are not well absorbed systemically. Although they may persist in the stratum corneum, they will eventually be cleared as the stratum corneum is sloughed off. A turnover time of 12 days has been quoted for skin epithelial cells

Accordingly, the LogPow, the water solubility, the LogPow value and the predicted behaviour concerning absorption and metabolism of4-phenylbutenonedo not indicate a potential for accumulation in the body. This is supported by the results for trans-methyl styryl ketone, which was shown not to accumulate in Fischer 344 rats (Sauer, 1997).

Metabolism:

Route specific toxicity results from several phenomena, such as hydrolysis within the gastrointestinal or respiratory tracts, also metabolism by gastrointestinal flora or within the gastrointestinal tract epithelia (mainly in the small intestine), respiratory tract epithelia (sites include the nasal cavity, tracheo-bronchial mucosa [Clara cells] and alveoli [type 2 cells]) and skin.

As specified above,hydrolysis does not apply for 4-phenylbutenone. Its metabolism is likely to occur also via the Cytochrome P450 group of metabolising enzymes, as it has been predicted with the TOXTREE modelling tool (Chemservice S.A., 2012). There, the chemical has been identified to bear primary, secondary and tertiary sites and more than 4 sites for metabolism by the Cytochrome P450 group of metabolising enzymes. The primary site of metabolism (carbon atom at the end of the chain) is predicted to be subject to aliphatic hydroxylation. The secondary site or metabolism is the carbon-atom of the aromatic ring (C4), which is predicted to be subject to aromatic hydroxylation and the tertiary sites of metabolism (carbon atoms 2 and 6 of the aromatic ring and the carbonatom with the double bond of the chain) are predicted to be either subject to aromatic hydroxylation or epoxidation).

To identify all possible sites for phase I and II reactions, the molecular structure of 4-phenylbutenone was investigated in detail.

In a first step, it is possible that the double bond is reduced by addition of two hydrogen atoms (aromatic hydroxylation). Moreover, this double bond might be subject to epoxidation by cytochrome P450s. This, however, is a step backwards, but might lead in the end to the formation of 2 hydroxyl groups (R-COHCOH-C=OCH3, where R is the aromatic ring). The other carbon atoms of the ring can be subject to aromatic hydroxylations by cytochrome P450, leading to the formation of a hydroxyl group, which facilitate elimination. The carbon atoms of the chain can be subject to aliphatic hydroxylation i.e. by by cytochrome P450s.

The existing or newly introduced functional groups will react in phase II of the biotransformation with different molecules, leading to the formation of conjugations. For the hydroxyl-groups it is most likely that they could be conjugated to glucuronic acid or activated sulphate. This however, might not even be necessary as the substance / metabolite is / are already very water soluble and of low molecular weight.However, it has to be kept in mind, that metabolites conjugated to glucuronic acid, can be subject to entero-hepatic recycling, and therefore re-enter to system.

In conclusion, it is likely that the substance of interest will be subject to extensive metabolism i.e. by cytochrome P450 enzymes and subsequent glucuronidation.

Concerning the possibility of protein binding, this cannot be ruled out, without adequate experimental data.

These theses are supported by the findings for methyl trans styryl ketone, which has been reported to be extensively metabolised, leading to the formation of N-phenylacetyl-L-glycine, N-benzyl-L-glycine, N-acetyl-S-(4-phenyl-2-butan-one)-L-cystein and N-acetyl-S-(4-phenyl-2-butanol)-L-cysteine (Sauer, 1997).

Excretion:

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the gastrointestinal mucosa). For non-polar volatile substances and metabolites exhaled air is an important route of excretion. Substances that are excreted favourable in the urine tend to be water-soluble and of low molecular weight (below 300 in the rat) and be ionized at the pH of urine. Most will have been filtered out of the blood by the kidneys though a small amount may enter the urine directly by passive diffusion and there is the potential for reabsorption into the systemic circulation across the tubular epithelium. Substances that are excreted in the bile tend to be amphipathic (containing both polar and nonpolar regions), hydrophobic/strongly polar and have higher molecular weights and pass through the intestines before they are excreted in the faeces and as a result may undergo enterohepatic recycling which will prolong their biological half-life. This is particularly a problem for conjugated molecules that are hydrolysed by gastrointestinal bacteria to form smaller more lipid soluble molecules that can then be reabsorbed from the GI tract. Those substances less likely to recirculate are substances having strong polarity and high molecular weight of their own accord. Other substances excreted in the faeces are those that have diffused out of the systemic circulation into the GIT directly, substances which have been removed from the gastrointestinal mucosa by efflux mechanisms and non-absorbed substances that have been ingested or inhaled and subsequently swallowed. Non-ionized and lipid soluble molecules may be excreted in the saliva (where they may be swallowed again) or in the sweat. Highly lipophilic substances that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with or without metabolism with skin cells.

For4-phenylbutenoneno data is available concerning its elimination. Concerning the above mentioned behaviour predicted for its metabolic fate, its chemicals structure and its molecular weight, it is very likely that the parent substance will be excreted metabolised mainlyvia the urine. This is supported by the findings for methyl trans styryl ketone, which has been found to be eliminated to a large extent via the urine (after oral administration 96.6% of the dosed radioactivity was recovered in the urine and 4.8% in the faeces within 48 hr, Sauer, 1997).

Conclusion

In order to assess the toxicological behaviour of4-phenylbutenone, the available physico-chemical and toxicological data have been evaluated. The substance is expected to be well absorbed after oral exposure, based on its water solubility and it’s LogPow of 2.04. Concerning the absorption after exposure via inhalation, as the chemical has low vapour pressure and is highly hydrophilic, it is clear, that the substance is poorly available for inhalation and will not be absorbed significantly.4-phenylbutenone however,is expected to be absorbed following dermal exposure into the stratum corneum and into the epidermis, due to its molecular weight and its LogPow. Concerning its distribution in the body4-phenylbutenoneis expected to be distributed mainly in the intravasal compartment, due to its LogPow. The substance does not indicate a significant potential for accumulation.4-phenylbutenoneis expected to be extensively metabolised and subsequently eliminated as metabolites mainly via the urine.

Applicant's summary and conclusion

Conclusions:
An extensive Assessment of the toxicological behaviour of 4-phenylbutenone was performed (expert statement), taking into account the chemical structure, the available physico-chemical-data and the available (eco-)toxicological data.
Executive summary:

In order to assess the toxicological behaviour of4-phenylbutenone, the available physico-chemical and toxicological data have been evaluated. The substance is expected to be well absorbed after oral exposure, based on its water solubility and it’s LogPow of 2.04. Concerning the absorption after exposure via inhalation, as the chemical has low vapour pressure and is highly hydrophilic, it is clear, that the substance is poorly available for inhalation and will not be absorbed significantly.4-phenylbutenone however,is expected to be absorbed following dermal exposure into the stratum corneum and into the epidermis, due to its molecular weight and its LogPow. Concerning its distribution in the body4-phenylbutenoneis expected to be distributed mainly in the intravasal compartment, due to its LogPow. The substance does not indicate a significant potential for accumulation.4-phenylbutenoneis expected to be extensively metabolised and subsequently eliminated as metabolites mainly via the urine.