Benzyl alcohol

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The metabolic pathway of benzyl alcohol is illustrated in the OECD risk assessment (OECD 2004). Human as well as animal data give evidence that systemically available benzyl alcohol is oxidized rapidly via benzyl aldehyde to benzoic acid. Regarding benzyl acetate, an esterified benzyl alcohol, rapid hydrolysation by esterases to benzyl alcohol and acetic acid has been proven for several species including man, thus resulting in the same metabolic pathway as benzyl alcohol (OECD 2004). The majority of benzyl acetate, benzyl alcohol, benzaldehyde or benzoic acid ingested is excreted renally after transformation to hippuric acid, but also amounts of other metabolization products can be found in urine.

In the following some more detailed information regarding toxicokinetics are provided.

Investigations in humans have shown that a rapid and presumably nearly quantitative resorption from the gastro-intestinal tract is followed after oral exposure to 1.5 g benzyl alcohol. The resorbed substance is metabolized and renally excreted to at least 75-85 % within 6 hours. (DFG 2006, Clayton & Clayton 1982).

In rats and rabbits as well benzyl alcohol is quantitatively oxidized to benzoic acid, subsequently conjugated and excreted as hippuric acid via urine (OECD 2004). Study data in rabbits show that, following subcutaneous injection of 1.0 g benzyl alcohol, at least 30-40 % of the given amount was excreted as metabolites in the urine within 24 hours. After an oral dose of 400 mg/kg bw to rabbits an urinary excretion rate of 65.7 % within 6 hours was reported (DFG 2006, Clayton & Clayton 1982).

Especially data from benzyl acetate provide evidence that only at very high doses (> 500 mg/kg/day by oral gavage route) some saturation of the metabolic pathways occurs, indicating a limited capacity for glycine conjugation only at extreme high dose levels (OECD 2004, WHO 1997).

Dermal resorption revealed to be high in studies with rhesus monkeys (estimated absorption = 80 %; dose 4 µg/cm², 24 h occlusive; Bronaugh et.al. 1990) and was also shown in in vitro investigations (summarized by DFG 2006).

According to the log Pow (benzyl alcohol 1.1, benzaldehyde 1.48, benzoic acid 1.88) a low potential for bioaccumulation is suggested. This is supported by the rapid biotransformation and/or excretion of these compounds in urine in mammals, which is also outlined in the OECD evaluation (OECD 2004).

The overall conclusion in the OECD risk assessment summarises the toxicokinetic properties: “These studies clearly show, that the compound is rapidly absorbed from the gastrointestinal tract of rats and mice, and about 90% of the total dose is recovered as urinary metabolites after 24h. More than 90% of the radio-label in the urine is present as hippuric acid, with minor amounts as benzyl alcohol and benzylmercapturic acid (up to 4%); no unchanged benzyl acetate was found. Only at very high doses, saturation of these pathways will occur.

This clearly shows the rapid pathway of hydrolysis to benzyl alcohol and subsequent oxidation to benzaldehyde to benzoic acid and subsequent conjugation to the hippuric acid. All supports a very rapid absorption, distribution, biotransformation, and excretion of these substances by the common pathway given above” (OECD 2004).

ECHA issued a Draft Decision for Comments by the Registrant on a compliance check for benzyl alcohol, CAS No 100-51-6 (EC No 202-859-9), registration number: 01-2119492630-38-0000 on November 5, 2013. In response to this ECHA Draft Decision a grouping of substances and read-across approach according to Regulation (EC) No 1907/2006 (REACH), Annex XI 1.5., is applied to fulfil potential data gaps identified by ECHA for genotoxicity, fertility and developmental toxicity. The substances used for the read-across were the corresponding oxidation products identified in toxicokinetik studies with benzyl alcohol, that is benzyl aldehyde (CAS 100-52-7) and benzoic acid (CAS 65-85-0). Also toxicological data of sodium and potassium benzoate (532-32-1 and 582-25-2, respectively), which are salts of benzoic acid, were regarded to be of relevance. Furthermore, the acetate ester of benzoic acid, that is benzyl acetate (CAS 140-11-4), has shown to immediately hydrolyse to benzyl alcohol and acetic acid, thus toxicological data of benzyl acetate were also taken into account.

This grouping of substances is based on previous toxicological evaluations by expert panels and regulatory authorities (e.g. OECD HPV programme 2004, IPCS 2005/ 2000, SCF 2002). For the purpose of justification, these evaluations are referenced in the following text. Nonetheless, the relevant physicochemical data and data related to toxicokinetics and human health – in particular genotoxicity, fertility and developmental toxicity are provided for benzyl alcohol and its read across substances to document the rational for this grouping approach.

For the respective substances a comprehensive toxicological database is available covering and exceeding all REACH standard data including genotoxicity, fertility and developmental toxicity, because particularly benzyl alcohol and the alkali salts of benzoic acid have been used for decades in pharmaceuticals, cosmetics and/or food as preservatives and flavoring/fragrance agents.

The weight of the evidence of the in vitro and in vivo genotoxicity data indicates that these chemicals are not mutagenic or clastogenic. In the absence of a genotoxic potential in in vivo studies and negative results in carcinogenicity studies, no classification and labelling regarding mutagenicity is required.

Taking into account all available data on reproductive toxicity/fertility and on repeated dose toxicity (examinations of reproductive organs) for the benzoates group (benzyl acetate, benzyl alcohol, benzaldehyde, sodium benzoate) there is sufficient and reliable data on benzyl alcohol and other members of the category, including a reliable 4-generation reproduction study on benzoic acid, to conclude that benzyl alcohol is not toxic to fertility.

For benzyl alcohol itself two studies on developmental toxicity with mice are available. There are studies on developmental toxicity available with benzoic acid on rat and hamster and with sodium benzoate on rat, mouse, hamster and rabbit. Based on individual studies and the whole database benzyl alcohol is not toxic to development in rodents and non-rodents.

Moreover, evidence is provided for the safe use of benzyl alcohol and the read across substances, since they have been used for decades in pharmaceuticals, cosmetics and/or food as preservatives and flavoring/fragrance agents. EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) and Joint FAO/WHO Expert Committee on Food Additives (JEFCA) evaluated the available data on the benzoate group, including benzyl alcohol, and derived a group ADI of 5 mg/kg/day. The derived DNEL are consistent with this ADI and should be considered conservative.

The overall conclusion of this elaboration is that the grouping of substances and read-across approach is justified for benzyl alcohol and no additional testing required to fulfil the REACH requirements for human risk assessment.

A comprehensive document providing discussion and justification for the conclusions drawn also in this chapter is attached to this endpoint summary in the IUCLID database (Karthaus 2014). Fractions of this justification are also copied below:

Introduction:

Regulation (EC) No 1907/2006 (REACH), Annex XI 1.5., establishes, that substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group of substances. The similarity may also be based on the likelihood of common breakdown products via physical and biological processes. Given that the grouping of substances and read-across approach can be justified, data gaps may be fulfilled from data of reference substance(s) within the group. This avoids the need to test every substance for every endpoint, which is highly recommended in the context of animal welfare considerations (Directive 2010/63/EU, 2010).

Particularly for benzyl alcohol data gaps are filled by data with a read across from a group of toxicologically similar substances.

Benzyl alcohol occurs naturally in some foods (US EPA 1989), for instance in rasperries and tea (EMEA 1997). It is an approved food additive for animals and humans inside and outside the EU, see e.g.

 Commission Implementing Regulation (EU) No 872/2012 adopting the list of flavouring substances

 EU Register of Feed Additives persuant to Regulation (EC) No 1831/2003

 US FDA Code of Federal Regulations (CFR) Title 21 § 172.515, Synthetic flavoring substances and adjuvants

The same applies to benzaldehyde and benzoic acid. Especially benzoic acid and its sodium salt are listed in US FDA CFR 21 § 184 as “Direct food substances affirmed as generally recognized as safe” (GRAS) due to their approved non-toxicity. Indeed, benzyl alcohol, benzoic acid and its sodium and potassium salts have been used for decades in pharmaceuticals, cosmetics and/or food as preservatives and flavoring/fragrance agents (OECD 2004).

In the OECD risk assessment on benzoates category (Benzoic acid, Sodium benzoate, Potassium benzoate, Benzyl alcohol) it is stated with respect to their use that “Consumer exposure in these specific applications are controlled by the fact that, for all these applications, specific regulatory frameworks (regional and/or national) with authorization/approval procedures and specific advisory bodies exist (inter alia: the US FDA, WHO JECFA, EU SCF, etc), including, on a regular basis, reevaluation of approvals, hazardous properties and factual exposures.” (OECD 2004).

Identity, physical and chemical properties (additional information is available in the attached evaluation Karthaus 2014):

Benzaldehyde and benzoic acid are oxidation products of benzyl alcohol.

Depending on the nature of the functional group (alcohol-, aldehyde-, carboxyl-) the physicochemical data like aggregate state, melting point, vapour pressure, and dissociation constant differ substantially for the substances.

The alcohol and the aldehyde are liquids at normal ambient conditions. They have no dissociable proton under normal conditions (pka: approx. 15.4 and 14.9, respectively). Benzaldehyde has a high vapour pressure and can therefore vaporise into the atmosphere, whereas benzyl alcohol will only vaporise very slightly at normal ambient conditions. Benzoic acid, on the other hand, is a solid with practically no volatility. As a carboxylic acid it has a dissociable proton, but with a pka of 4.19 its acidity is only weak. It has a moderate water solubility of approx. 3 g/L, which is increased for the alkali salts (556 g/L for sodium- or potassium benzoate). The benzaldehyde has a comparable moderate water solubility comparable to the free acid (approx. 3 g/L), whereas the water solubility for the alcohol is good (40 g/L).

Physicochemical data do not support read across for local toxicological endpoints. Local effects for instance might be very different according to the chemical nature of the functional groups, i.e. aromatic alcohol versus aromatic aldehyde versus aromatic carboxylic acid. In fact, experimental toxicological data do not show considerable differences for endpoints like skin/eye irritation/corrosion or respiratory irritation. With regard to the carboxylic acid, the acidity is only weak (pKa = 4.19), which might explain the low irritant properties observed in animal assays.

There are comprehensive and sufficient data on all local toxicity endpoints available for benyl alcohol including skin- and eye irritation studies, acute toxicity studies and a repeated dose toxicity study after inhalation exposure and no read across is performed for local endpoints.

However for systemic effects, the justification for the read across is based on the similar metabolic pathway of the substances in vivo.

OECD (2004) concluded: “Benzyl alcohol, benzoic acid and its sodium and potassium salt can be considered as a single category regarding human health, as they are all rapidly metabolised and excreted via a common pathway within 24 hrs. Systemic toxic effects of similar nature (e.g. liver, kidney) were observed.”

ADME:

The metabolic pathway of benzyl alcohol is illustrated in the following picture (based on OECD 2004). Human as well as animal data give evidence that systemically available benzyl alcohol is oxidized rapidly via benzyl aldehyde to benzoic acid. Regarding benzyl acetate, an esterified benzyl alcohol, rapid hydrolysis by esterases to benzyl alcohol and acetic acid has been proven for several species including man, thus resulting in the same metabolic pathway as benzyl alcohol (OECD 2004). As shown in the scheme, the majority of benzyl acetate, benzyl alcohol, benzaldehyde or benzoic acid ingested is excreted renally after transformation to hippuric acid, but also measurable amounts of other metabolites, including the glucuronide, can be found in urine.

In the following some more detailed information regarding toxicokinetics are provided.

Investigations in humans have shown that a rapid and presumably nearly quantitative resorption from the gastro-intestinal tract is followed after oral exposure to 1.5 g benzyl alcohol. The resorbed substance is metabolized and renally excreted to at least 75-85 % within 6 hours. (DFG 2006, Clayton & Clayton 1982).

In rats and rabbits as well benzyl alcohol is quantitatively oxidized to benzoic acid, subsequently conjugated and excreted as hippuric acid via urine (OECD 2004). Study data in rabbits show that, following subcutaneous injection of 1.0 g benzyl alcohol, at least 30-40 % of the given amount was excreted as metabolites in the urine within 24 hours. After an oral dose of 400 mg/kg bw to rabbits an urinary excretion rate of 65.7 % within 6 hours was reported (DFG 2006, Clayton & Clayton 1982).

Especially data from benzyl acetate provide evidence that only at very high doses (> 500 mg/kg/day by oral gavage route) some saturation of the final metabolic pathway from benzoic acid to hippuric acid occurs, indicating a limited capacity for glycine conjugation only at extreme high dose levels (OECD 2004, WHO 1997).

Dermal resorption revealed to be high in studies with rhesus monkeys (estimated absorption = 80 %; dose 4 µg/cm², 24 h occlusive; Bronaugh et.al. 1990) and was also shown in in vitro investigations (summarized by DFG 2006).

According to the log Pow (benzyl alcohol 1.1, benzaldehyde 1.48, benzoic acid 1.88) a low potential for bioaccumulation is suggested. This is supported by the rapid biotransformation and/or excretion of these compounds in urine in mammals, which is also outlined in the OECD evaluation (OECD 2004).

The overall conclusion in the OECD risk assessment summarises the toxicokinetic properties:

“Benzyl alcohol, benzoic acid and its sodium and potassium salt can be considered as a single category regarding human health, as they are all rapidly metabolised and excreted via a common pathway within 24 hrs. Systemic toxic effects of similar nature (e.g. liver, kidney) were observed.”

“These studies clearly show, that the compound is rapidly absorbed from the gastrointestinal tract of rats and mice, and about 90% of the total dose is recovered as urinary metabolites after 24h. More than 90% of the radio-label in the urine is present as hippuric acid, with minor amounts as benzyl alcohol and benzylmercapturic acid (up to 4%); no unchanged benzyl acetate was found. Only at very high doses, saturation of these pathways will occur.

This clearly shows the rapid pathway of hydrolysis to benzyl alcohol and subsequent oxidation to benzaldehyde to benzoic acid and subsequent conjugation to the hippuric acid.

All supports a very rapid absorption, distribution, biotransformation, and excretion of these substances by the common pathway given above” (OECD 2004).

The metabolic pathway as outlined above is widely accepted by expert panels and within regulatory authorities and scientific expert initiatives, as it could be seen from the list below:

Toxicologic programme/Commission	Reference	Statement on category	Conclusion for further action/work
MAK Commission (Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area)	DFG (Deutsche Forschungs-gemeinschaft/German Research Foundation) (2006)MAK value documentation on benzyl alcohol;The MAK Collection for Occupational Health and Safety, Wiley Online Library See also MAK value documentation on Benzaldehyde (2002, 1999) and Benzoic acid (1995, 1986)The MAK Collection for Occupational Health and Safety, Wiley Online Library	“Ältere Untersuchungen am Menschen zeigen, dass resorbierter Benzylalkohol im Organismus schnell über Benzaldehyd zu Benzoesäure oxidiert und diese nach Konjugation mit Glycin als Hippursäure über die Niere ausgeschieden wird. Von einer oral aufgenommenen Dosis von 1,5 g Benzylalkohol wurden 75–85 % mit dem Urin als Hippursäure eliminiert (Clayton und Clayton 1982; OECD 2004). Auch bei Ratten und Kaninchen wird Benzylalkohol vollständig zu Benzoesäure oxidiert, anschließend konjugiert und als Hippursäure mit dem Urin ausgeschieden (OECD 2004). Nach Gabe einer oralen Dosis von 0,25 g Benzylalkohol/kg KG an Kaninchen wurden im Urin 2% Benzylalkohol, 74% Hippursäure und 8% Kupfer-reduzierende Metaboliten (wie Glucuronsäure, k.w. A.) nachgewiesen. In einer weiteren Studie wurde nach oraler Gabe von 400 mg/kg KG bei Kaninchen von einer 65,7%igen Ausscheidung als Hippursäure berichtet. Kaninchen, denen 1000 mg Benzylalkohol subkutan verabreicht wurde, schieden 30–40% der gegebenen Menge als Hippursäure aus (Clayton und Clayton 1982).”	No MAK-value (maximum concentration at the workplace) proposed at present, since it predominantly focusses on repeated inhalation toxicity data, which were not available for benzyl alcohol at time of last evaluation.
OECD HPV (High production volume) programme	OECD (Organisation for Economic Co-operation and Development) (2004)SIDS Initial Assessment Report for 13th SIAM (Bern, 7th – 9th November 2001) on Benzoates: Benzoic acid, Sodium benzoate, Potassium benzoate, Benzyl alcohol, CAS Nos. 65-85-0, 532-32-1, 582-25-2, and 100-51-6	Summary conclusion of the SIAR:“Benzyl alcohol, benzoic acid and its sodium and potassium salt can be considered as a single category regarding human health, as they are all rapidly metabolised and excreted via a common pathway within 24hrs. Systemic toxic effects of similar nature (e.g. liver, kidney) were observed. However with benzoic acid and its salts at higher doses than with benzyl alcohol. For environmental effects the category is less clear, however all are readily biodegradable, non-bioaccumulative and acute toxicity values are similar.”	“The chemicals are currently of low priority for further work.”
IPCS (International Programme on Chemical Safety)	CICAD 26 (Concise International Chemical Assessment Document 26) (corrigendum 2005/ 2000) on benzoic acid and sodium benzoate, published under Joint Sponsorship of United Nations Environment Programme, International Labour Organization, and World Health Organization, Wissenschaftliche Verlagsgesellschaft mbH, D-70009 Stuttgart 10	“Benzyl acetate, its hydrolysis product, benzyl alcohol, and the oxidation product of this alcohol, benzaldehyde, are extensively metabolized to benzoic acid in experimental animals and humans. Therefore, toxicological data on these precursors were also utilized in the assessment of the potential health effects of benzoic acid.”„After oral uptake, benzoic acid and sodium benzoate are rapidly absorbed from the gastrointestinal tract and metabolized in the liver by conjugation with glycine,resulting in the formation of hippuric acid, which is rapidly excreted via the urine. To a lesser extent, benzoates applied dermally can penetrate through the skin. Owing to rapid metabolism and excretion, an accumulation of the benzoates or their metabolites is not to be expected.”	./.
FEMA (Expert Panel of the Flavor and Extract ManufacturersAssociation)	The FEMA GRAS assessment of benzyl derivatives used as flavor ingredients (2005), Food and Chemical Toxicology 43, 1207–1240	“Based on these studies, benzyl derivatives are expected to be rapidly absorbed, and rapidly metabolized to benzoic acid. The acid is then conjugated with glycine and excreted mainly in the urine. At high dose levels, the glycine conjugation pathway may be saturated; in which case, free benzoic acid is excreted unchanged.”“Benzyl esters and acetals are hydrolyzed to benzyl alcohol and benzaldehyde,respectively (see Fig. 1). The alcohol and aldehyde are rapidly oxidized to benzoic acid while benzoate esters are hydrolyzed to benzoic acid. The benzoic acid derivatives are excreted primarily as the glycine conjugate. Benzoic acid is readily conjugated with glycine in liver (321 nmol/min/g) and kidney homogenate (254 nmol/min/g) (Temellini,1993 ). At high dose levels formation of the glycine conjugate is glycine limited. When glycine is depleted, free benzoic acid may be excreted unchanged or as the glucuronic acid conjugate (Bray et al.,1951; Diack and Lewis,1928; Williams,1959).”	./.
SCF (Scientific Committee on Food)	European Commission, Health & Consumer Protection Directorate-General (2002),Opinion of the Scientific Committee on Food on Benzyl alcohol; SCF/CS/ADD/FLAV/78 Final	Conclusions“The metabolism of benzyl alcohol to benzoic acid by man is well established. In special studies, biochemical effects have been investigated. The toxicity has been studied extensively, including acute, short-term and long-term toxicity, carcinogenicity, genotoxicity and developmental toxicity.”“Taking account the toxicity data and the fact that benzyl alcohol is metabolised via benzaldehyde to benzoic acid, the Committee confirms the inclusion of benzyl alcohol in the group ADI of 0-5 mg/kg bw for benzoic acid and benzoates, as agreed in the SCF opinion of 1981.”	./.
EFSA, Panel on Food Contact Materials, Enzymes,Flavourings and Processing Aids (CEF	SCIENTIFIC OPINIONFlavouring Group Evaluation 54, Revision 1 (FGE.54Rev1) (2009):Consideration of benzyl derivatives evaluated by JECFA (57th meeting)structurally related to benzyl alcohols, benzaldehydes, a related acetal, benzoicacids and related esters evaluated by EFSA in FGE.20Rev1 (2009) 1Scientific Opinion of the Panel on Food Contact Materials, Enzymes,Flavourings and Processing Aids (CEF). The EFSA Journal (2009) 1025, 1-73	“The Panel concluded that the 37 substances in the JECFA flavouring group of benzyl derivatives are structurally related to the group of benzyl alcohols, benzaldehydes, a related acetal, benzoic acids and related esters evaluated by the Panel in the FGE.20Rev1.”“The Panel agrees with the way the application of the Procedure has been performed by the JECFAfor all 37 substances in the group of benzyl derivatives.”	./.
JEFCA (Joint FAO/WHO Expert Committee on Food Additives)	WHO (World Health Organization) (2002) Evaluation of Certain Food Additives and Contaminants, Fifty-seventh report of the Joint FAO/WHO Expert Committee on FoodAdditives; WHO technical report series 909(http://whqlibdoc.who.int/trs/WHO_TRS_909.pdf)	Chapter on Benzyl derivatives:“All the benzyl and benzoate esters and acetals of benzaldehyde (or acetaldehyde) are anticipated to be hydrolysed readily under acidic conditions to yield benzyl alcohol (and carboxylic acids) and to benzaldehyde (and alcohols), respectively, followed by oxidation to yield benzoic acid. Benzoate esters are hydrolysed to benzoic acid (and alcohols).”
JEFCA (Joint FAO/WHO Expert Committee on Food Additives)	WHO (World Health Organization) (1997) Evaluation of Certain Food Additives and Contaminants, Forty-sixth report of the Joint FAO/WHO Expert Committee on FoodAdditives; WHO technical report series 868	Chapter on Benzyl acetate, benzyl alcohol, benzaldehyde, benzoic acid and the benzoate salts: “Since they are all metabolized to benzoic acid, it was considered reasonable to assume that the results of studies on one member of the group would apply to all the others.The results of a number of studies in humans and experimental animals indicated that the formation of hippuric acid from benzoic acid is a saturable process in which the availability of glycine is the rate-limiting step. This observation is particularly relevant to the interpretation of the toxic effects of these compounds in experimental animals, since supplementation of the diet with glycine was shown to alleviate the toxic effects of high doses of benzyl acetate and benzoic acid, including reductions in body-weight gain and neurotoxicity. However, even with saturation of hippuric acid formation, clearance of compounds in the benzyl group is relatively rapid in both experimental animals and humans. “.	“The Committee was satisfied that the data reviewed for compounds in this group were sufficient to demonstrate the lack of teratogenic, reproductive or carcinogenic potential. Consequently, the Committee concluded that further studies were not required, and the group ADI of 0-5 mg per kg of body weight as benzoic acid equivalents was maintained.”
CIR (Cosmetic Ingredient Review) by the Cosmetic Ingredient Review Expert Panel	Nair, B. (2001) Final Report on the Safety Assessment of Benzyl Alcohol, Benzoic Acid, and Sodium Benzoate; International Journal of Toxicology 20 (Suppl. 3), 23-50See also Nair, B. (2006) Final Report on the Safety Assessment of Benzaldehyde;International Journal of Toxicology 25 (Suppl. 1), 11-27	“When metabolized, Benzyl Alcohol is converted to Benzoic Acid by simple oxidation (Flavor and Extract Manufacturers’Association 1984).The relevant data, therefore, relate to Benzoic Acid and Sodium Benzoate.“	“The Cosmetic Ingredient Review (CIR) Expert Panel was satisfied that results of toxicity, mutagenicity, carcinogenicity,reproductive/developmental, and sensitization studies cited in this report support the safety of these ingredients in cosmetic formulations.”
US NTP (National Toxicology Programme)	US NIH (National Institutes of Health) (1989), NTP Technical Report 343 on the Toxicology and Carcinogenesis, Studies of Benzyl alcohol; NIH Publication No. 89-2599	Chapter on Absorption, Distribution, and Metabolism:“Benzyl alcohol is readily absorbed from the alimentary tract and rapidly oxidized to benzoic acid, which is conjugated with glycine and excreted as hippuric acid in the urine; higher doses result in excretion of the benzyl alcohol conjugated with glucuronide (Williams, 1959). Benzyl alcohol was shown to be an intermediate product in the metabolic pathway of benzyl acetate (Chidgey et al., 19861, for which the subsequent metabolism was identical to that of benzyl alcohol (Clapp and Young, 1970; Abdo et al., 1985).”	All NTP-studies on benzyl alcohol are completed; no ongoing action
Toxicological profiles by EPA/ATSDR (Agency for Toxic Substances and Disease Registry)	US EPA (Environmental Protection Agency) (1989), Environmental Criteria and Assessment Office, Office of Research and Development, EPA/600/8-90/033,Health and Environmental Effects Document for Benzyl Alcohol	“Metabolism of benzyl alcohol involves rapid oxidation to benzoic acid using benzaldehyde intermediate. Benzoic acid is further metabolized to hippuric acid, which is excreted in the urine in both animals and man (Bray et al., 1958, Diack and Lewis, 1928, Stekol, 1939, McCloskey et a., 1986, Snapper et al., 1924).””In humans, the immature liver and kidney of preterm infants appear to have a reduced capacity to metabilize benzyl alcohol by glycine conjugation (LeBel et al., 1988).”	./.
Handbook of toxicology	Patty’s Industrial Hygiene and Toxicology (1982)3rd revised Ed., Volume 2C, G.D. Clayton & F.E. Clayton (eds.), John Wiley and Sons, 4636-4641	“Benzyl alcohol is oxidized by ADH. Winer (331) reports the activity of ADH on benzyl alcohol to be slightly less than on ethanol. Von Wartburg (230) reports benzyl alcohol to be approximately one-half as active as ethanol in reaction with ADH and to have affinity to ADH roughly equal to that of isopropyl and butyl alcohols. The animal organism readily oxidizes benzyl alcohol to benzoic acid, which, after conjugating with glycine is rapidly eliminated as hippuric acid in the urine.”

Comparison of toxicological endpoints

Although the metabolism pathway of benzyl alcohol, benzaldehyde and benzoic acid provides evidence, that systemic human health toxicity should be the same for the substances, a comparison of toxicological endpoints is briefly provided in the following, based on OECD risk assessment (2006).

Endpoint	Benzoic acid, sodium benzoate, potassium benzoate, benzyl alcohol(Summaries cited from OECD 2004)	Benzaldehyde(Summaries cited from DFG 2006)
Acute toxicity	“The compounds (author’s note: benzoic acid, sodium benzoate, potassium benzoate, benzyl alcohol) exhibit low acute toxicity as for the oral and dermal route. The LD50 values are > 2000 mg/kg bw except for benzyl alcohol which needs to be considered as harmful by the oral route in view of an oral LD50 of 1610 mg/kg bw. The 4 hrs inhalation exposure of benzyl alcohol or benzoic acid at 4 and 12 mg/l as aerosol/dust respectively gave no mortality, showing low acute toxicity by inhalation for these compounds.”	“The acute toxicity of benzaldehyde is low. At the lowest concentration of 500 ml/m³ in short-term inhalation studies with rats, minimal to slight goblet-cell metaplasia in the area of the nasal septum, clinical symptoms of intoxication and delays in body weight gain were observed.”
Irritation/Corrosion	“Benzoic acid and benzyl alcohol are slightly irritating to the skin, while sodium benzoate was not skin irritating. No data are available for potassium benzoate but it is also expected not to be skin irritating. Benzoic acid and benzyl alcohol are irritating to the eye and sodium benzoate was only slightly irritating to the eye. No data are available for potassium benzoate but it is expected also to be only slightly irritating to the eye.”	“Benzaldehyde causes moderate irritation on the skin and slight irritation in the eye.”
Skin Sensitisation	“The available studies for benzoic acid gave no indication for a sensitizing effect in animals, however occasionally very low positive reactions were recorded with humans (dermatological patients) in patch tests. The same occurs for sodium benzoate. It has been suggested that the very low positive reactions are a non-immunologic contact urticaria. Benzyl alcohol gave positive and negative results in animals. Benzyl alcohol also demonstrated a maximum incidence of sensitization of only 1% in human patch testing. Over several decades no sensitization with these compounds has been seen among workers.“	“Sensitizing effects on the skin can be induced in guinea pigs only after induction with intradermal injection; the findings in animals, therefore, do not indicate that the substance is a contact allergen.““Despite the relatively widespread use of the substance there is no evidence of a pronounced sensitization potential in man.“
Repeated dose toxicity	“For benzoic acid repeated dose oral toxicity studies give a NOAEL of 800 mg/kg/day. For the salts values > 1000 mg/kg/day are obtained. At higher doses increased mortality, reduced weight gain, liver and kidney effects were observed. For benzyl alcohol the long-term studies indicate a NOAEL > 400 mg/kg bw/d for rats and > 200 mg/kg bw/d for mice. At higher doses effects on bodyweights, lesions in the brains, thymus, skeletal muscle and kidney were observed. It should be taken into account that administration in these studies was by gavage route, at which saturation of metabolic pathways is likely to occur. It can be concluded that benzoic acid and its salts exhibit very low repeated dose toxicity. Benzylalcohol exhibits low repeated dose toxicity.”	“In studies with medium-term ingestion of high doses, the target organs of toxic effects are the forestomach, kidneys and brain; the NOEL (no observed effect level) was found to be 200 mg/kg body weight and day for male rats and 400 mg/kg body weight and day for female rats. In mice, the NOEL for kidney changes was 300 mg/kg body weight for male animals and 600 mg/kg body weight for females.”
Genotoxicity	“All chemicals showed no mutagenic activity in in vitro Ames tests. Various results were obtained with other in vitro genotoxicity assays.Sodium benzoate and benzyl alcohol showed no genotoxicty in vivo.While some mixed and/or equivocal in vitro chromasomal/chromatid responses have been observed, no genotoxicity was observed in the in vivo cytogenetic, micronucleus, or other assays. The weight of the evidence of the in vitro and in vivo genotoxicity data indicates that these chemicals are not mutagenic or clastogenic. They also are not carcinogenic in long-term carcinogenicity studies. In addition data from in-vivo genotoxicity studies on benzyl acetate and benzaldehyde (JECFA report, 1997) support the non-genotoxicity of benzylalcohol and benzoic acid and its salts.“	“In vitro studies with benzaldehyde yielded evidence of, at most, weak genotoxic activity; in the Drosophila test benzaldehyde is inactive.”
Carcinogenicity	“Carcinogencity studies (2-year) with sodium benzoate and benzyl alcohol showed no evidence of carcinogenic activity.”	“A carcinogenic potential of benzaldehyde cannot be deduced from the results of long-term carcinogenicity studies with mice and rats given the substance by oral administration.”
Reproductive toxicity	Fertility: “In a 4-generation study with benzoic acid no effects on reproduction were seen (NOAEL > 750 mg/kg). No compound related effects on reproductive organs (gross and histopatology examination) could be found in the (sub) chronic studies in rats and mice with benzyl acetate, benzyl alcohol, benzaldehyde, sodium benzoate and supports a non-reprotoxic potential of these compounds. In addition, data from reprotoxicity studies on benzyl acetate (NOAEL >2000 mg/kg bw/d; rats and mice) and benzaldehyde (tested only up to 5 mg/kg bw; rats) support the non-reprotoxicity of benzyl alcohol and benzoic acid and its salts.”Developmental toxicity:In rats for sodium benzoate dosed via food during the entire gestation developmental effects occurred only in the presence of marked maternal toxicity (reduced food intake and decreased body weight) (NOAEL = 1400 mg/kg bw ).. For hamster (NOEL : 300 mg/kg bw), rabbit (NOEL :250 mg/kg bw) and mice (CD-1 mice, NOEL : 175 mg/kg bw) no higher doses (all by gavage) were tested and no maternal toxicity was observed For benzyl alcohol: NOAEL= 550 mg/kg bw (gavage; CD-1 mice). LOAEL = 750 mg/kg bw (gavage mice). In this study maternal toxicity was observed e.g. increased mortality, reduced body weight and clinical toxicology. Benzyl acetate: NOEL = 500 mg/kg bw (gavage rats). No maternal toxicity was observed.	Fertility:No evidence for effects on fertility concluded from the available studies.1) Sporn et al., Igiena (Bucharest) 16: 23–24, 1967: according to DFG, 2006, study was not regarded as reliable for assessment.2) Kluwe et al., Fd Chem Toxic 21: 245–250, 1983, NTP 1990, Technical Report 378, NIH Publication No. 90-2833, US Department of Health and Human Services, National Institute of Health, Bethesda, MD, USA: “Decreased testis weights were observed, but the effective dose of 800 mg/kg body weight (dissolved in corn oil, administered by gavage) was highly toxic and led to the death of 6 of 10 animals, so that this finding cannot be regarded as evidence of an impairment in fertility. In the 400 mg/kg group, in which there were no deaths or signs of intoxication, this effect did not occur effects only seen at highly toxic doses, and no effects at a dose leading not to deaths or signs of intoxication.”