Regulation (EU) n°528/2012 concerning the making
available on the market and use of biocidal products
Evaluation of active substances
Assessment Report
Benzoic acid
Product-type 03
(Veterinary hygiene)
September 2013
Germany
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Benzoic Acid: Consumer Exposure and Toxicity Studies, Study notes of Veterinary
Information on the consumer exposure to benzoic acid residues in food or feed items via biocidal products and compiles various studies on the toxicity of benzoic acid, including its metabolism, absorption, and effects on animals. The studies are mostly non-GLP published reports.
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Regulation (EU) n°528/2012 concerning the making
available on the market and use of biocidal products
Evaluation of active substances
Assessment Report
Benzoic acid
Product-type 03
(Veterinary hygiene)
September 2013
Germany
Benzoic acid (PT 03)
Assessment report
Finalised in the Standing Committee on Biocidal Products at its meeting on 27 September 2013
1. STATEMENT OF SUBJECT MATTER AND PURPOSE
1.1. Principle of evaluation
This assessment report has been established as a result of the evaluation of Benzoic acid as product-type 03 (Veterinary hygiene biocidal products), carried out in the context of the work programme for the review of existing active substances provided for in Article 16(2) of Directive 98/8/EC concerning the placing of biocidal products on the market1, with the original view to the possible inclusion of this substance into Annex I or IA to that Directive.
The evaluation has therefore been conducted in the view to determine whether it may be expected, in light of the common principles laid down in Annex VI to Directive 98/8/EC, that there are products in product-type 3 containing Benzoic acid that will fulfil the requirements laid down in Article 5(1) b), c) and d) of that Directive.
1.2. Purpose of the assessment
The aim of the assessment report is to support a decision on the approval of Benzoic acid for product-type 03, and should it be approved, to facilitate the authorisation of individual biocidal products in product-type 3 that contain Benzoic acid. In the evaluation of applications for product-authorisation, the provisions of Regulation (EU) No 528/2012 shall be applied, in particular the provisions of Chapter IV, as well as the common principles laid down in Annex VI.
The conclusions of this report were reached within the framework of the uses that were proposed and supported by the applicant (see Appendix II). Extension of the use pattern beyond those described will require an evaluation at product authorisation level in order to establish whether the proposed extensions of use will satisfy the requirements of Regulation (EU) No 528/2012.
For the implementation of the common principles of Annex VI, the content and conclusions of this assessment report shall be taken into account.
However, where conclusions of this assessment report are based on data protected under the provisions of Regulation (EU) No 528/2012, such conclusions may not be used to the benefit of another applicant, unless access to these data has been granted.
1.3. Procedure followed
This assessment report has been established as a result of the evaluation of Benzoic acid as product-type 03 (Veterinary hygiene biocidal products), carried out in the context of the work programme for the review of existing active substances provided for in Article 16(2) of Directive
1 Directive 98/8/EC of the European Parliament and of the Council of 16 February 1998 concerning the placing biocidal products on the market. OJ L 123, 24.4.98, p.
98/8/EC concerning the placing of biocidal products on the market^2 , with a view to the possible inclusion of this substance into Annex I or IA to the Directive.
Benzoic acid (CAS no. 65-85-0) was notified as an existing active substance, by Menno Chemie- Vertrieb GmbH, hereafter referred to as the applicant, in product-type 03.
Commission Regulation (EC) No 1451/2007 of 4 December 2007^3 lays down the detailed rules for the evaluation of dossiers and for the decision-making process in order to include or not an existing active substance into Annex I or IA to the Directive.
In accordance with the provisions of Article 7(1) of that Regulation, Germany was designated as Rapporteur Member State to carry out the assessment on the basis of the dossier submitted by the applicant. The deadline for submission of a complete dossier for Benzoic acid as an active substance in Product Type 03 was 31.07.2007, in accordance with Annex V of Regulation (EC) No 1451/2007.
On 26.07.2007, German competent authorities received a dossier from the applicant. The Rapporteur Member State accepted the dossier as complete for the purpose of the evaluation on 31.01.2008.
On 03.02.2011, the Rapporteur Member State submitted, in accordance with the provisions of Article 14(4) and (6) of Regulation (EC) No 1451/2007, to the Commission and the applicant a copy of the evaluation report, hereafter referred to as the competent authority report. The Commission made the report available to all Member States by electronic means on 14.02.2011. The competent authority report included a recommendation for the inclusion of Benzoic acid in Annex I to the Directive for product-type 03.
In accordance with Article 16 of Regulation (EC) No 1451/2007, the Commission made the competent authority report publicly available by electronic means on 10.03.2011. This report did not include such information that was to be treated as confidential in accordance with Article 19 of Directive 98/8/EC.
In order to review the competent authority report and the comments received on it, consultations of technical experts from all Member States (peer review) were organised by the Commission. Revisions agreed upon were presented at technical and competent authority meetings and the competent authority report was amended accordingly.
In accordance with Article 15(4) of Regulation (EC) No 1451/2007, the present assessment report contains the conclusions of the Standing Committee on Biocidal Products, as finalised during its meeting held on 27 September 2013.
2 Directive 98/8/EC of the European Parliament and of the Council of 16 February 1998 concerning the placing biocidal products on the market. OJ L 123, 24.4.98, p. 3 Commission Regulation (EC) No 1451/2007 of 4 December 2007 on the second phase of the 10-year work programme referred to in Article 16(2) of Directive 98/8/EC of the European Parliament and of the Council concerning the placing of biocidal products on the market. OJ L 325, 11.12.2007, p. 3
Identity, Physico-chemical Properties and Method of Analysis of the biocidal product Menno Florades
The product Menno Florades is a soluble concentrate of the active substance benzoic acid. The product is a clear slightly amber liquid with no intense odour. The product has a flash point of 28.5°C, so it has to be classified (labelled) as “flammable” (R10).
Analytical methods for detection and Identification
No residues are expected in soil, air, drinking and surface water, as well as in food and feeding stuffs and in animal and human body fluids and tissues.
No methods for the determination of non-active ingredients were submitted. They were not considered necessary as no relevant residues of non-active ingredients are expected.
2.1.2. Intended Uses and Efficacy
Benzoic acid is a bactericide, fungicide and virucide which is intended to be used in animal premises in order to prevent growth of microorganisms.
The intended use of the biocidal product “Menno Florades” is the treatment of surfaces in animal premises in order to prevent growth of microorganisms. potentially harmful organisms.
The performed tests provide reliable results for basic efficacy assessment. The following results could be derived from the studies:
-The product Menno Florades shows a basic bactericidal effectiveness on samples of the target organisms (Staphylococcus aureus and Pseudomonas aeruginosa) under clean conditions by a 1% solution (corresponds to 0.9 g/L benzoic acid) after a contact time of 60 min.
-The product shows a basic fungicidal effectiveness on samples of the target organisms under clean conditions by a 2% solution (contains 1.8 g/L benzoic acid) againstfor Candida albicans and byafter a 4% solution (contains 3.6 g/L benzoic acid) against Aspergillus brasiliensiscontact time of 60 min.
- The product shows a basic virucidal effectiveness on the model organism for the genus picornavirus Bovine enterovirus Type 1 (Enteric Cytopathogenic Bovine Orphan Virus – ECBO) by a 2% solution (corresponds to 1.8 g/L benzoic acid) at conditions without organic soiling after a contact time of 60 min.
Although the test criteria of DIN EN 1040 and DIN EN 1275 were not fulfilled, the tests are accepted in the frame of Annex I-inclusion of the active substance, because it may be possible that the efficacy achieved is sufficient for the in use situations.
The information provided is only sufficient to show a basic efficacy of benzoic acid. This is accepted in the frame of Annex-I-inclusion. Within the frame of product authorisation, essentially more information has to be provided: To support the full label claim virucidal,
bactericidal and fungicidal, further laboratory tests would be necessary. Additionally, further tests in the field of use have to be provided.
At least the tests listed in EN 14885 for the respective field of use or comparable tests have to be provided in the frame of product authorisation. As not for all possible label claims an EN norm exists, further test will then be necessary depending on the specific label claim.
Mode of action
In solution, benzoic acid exists in a pH-dependent equilibrium between the undissociated and dissociated form. Only in its undissociated state, the acid is able to pass the cells membrane. At a relatively low pH, the uncharged acid enters the cell. Inside the cell, the benzoic acid dissociates due to the higher pH. The molecules remain inside the cell, because the resulting ions cannot pass the membrane. The pH inside the cell is lowered and metabolic reactions are inhibited. Further effects are also reported: Decrease of the membrane permeability for amino acids, organic acids, phosphates resulting in uncoupling of both substrate transport and oxidative phosphorylation from the electron transport system. Furthermore, an inhibition of the citric acid cycle is observed.
The intended uses of the substance, as identified during the evaluation process, are listed in Appendix II.
Development of resistance
Many publications are available that report about resistance of micro-organisms against benzoic acid, mainly in the context of food spoilage (Davidson, PM and Harrison, MA, 2002; Brul, S and Coote, P, 1999). A number of yeasts are known to be resistant to benzoates. It is suggested that the mechanism by which yeasts develop resistance to weak acidic antimicrobials, including benzoic acids, is related to membrane permeability and the ability of the cells to continuously pump antimicrobials out of the cell. Some micro-organisms on the other hand have innate resistance to benzoates because they metabolize the compounds. These bacteria and moulds degrade benzoic acid through either the ortho or the meta cleavage pathway. Few studies examine the potential for acquired resistance to benzoic acid in yeasts previously exposed to sub-inhibitory concentrations of benzoic acid. Pre-exposure to benzoic acid caused a 1.4 to 2. fold increase in MIC. The proposed resistance mechanism was increased cellular efflux (Warth, AD, 1988). There was neither any evidence of indicating increased resistance due to mutation nor any evidence that the resistance was stable. Further, there is little or no evidence in the literature of acquired bacterial resistance to benzoic acid.
Considering the length of time that benzoic acid has been applied to food products as a food additive it would seem, however, that the development of acquired resistance by spoilage and pathogenic micro-organisms is very rare or non-existent.
2.1.3. Classification and Labelling
Benzoic acid is not yet listed in Annex VI of Regulation (EC) No 1272/2008 (2nd ATP; former Annex I of Directive 67/548/EEC (up to 31st ATP)).
Remark:
The proposed classification on the basis of toxicological properties regarding H318 (Causes serious eye damage) is in accordance with the proposal under Directive 91/414 EEC (SANCO/1396/2001-Final, Monograph on Benzoic Acid, EU, 2003). The classification “Eye Dam. 1; H318” is warranted due to non-reversible corneal lesions caused by benzoic acid instilled in rabbits’ eyes.
Non-immunogenic contact urticaria (transient intense erythema and oedema, also termed pseudoallergy) is evoked by benzoic acid when applied to human skin of sensitive persons as reported in several studies and case reports or to the ear lobes of guinea pigs. While not proven in a narrow sense, there is mechanistic evidence, that these skin reactions are mediated by release of vasoactive substances. An immunological T-cell mediated mechanism is ruled out, because no sensitisation (induction phase) is required for the reaction. In comparison to sorbic acid for which classification with H315 was proposed based on the same effect, the reaction provoked by benzoic acid is stronger, of longer duration and higher frequency.
Thus, the data are regarded sufficient to justify classification of benzoic acid “Skin Irrit. 2; H315” (Causes skin irritation).In addition to the proposal by the RMS, the RAC Opinion of 25th November 2012 considers that there is evidence for pulmonary toxicity after repeated exposure to benzoic acid dust via inhalation and proposes a classification with STOT RE H372 (lungs, inhalation).
The active substance is readily biodegradable and is not considered toxic to aquatic organisms. Consequently, no environmental classification of the active substance benzoic acid is required.
Table 3 Proposed labelling of Benzoic Acid based on Directive 67/548/EEC
Labelling Wording Hazard Symbols, Indications of danger
T* Toxic
R-phrases R R R48/23*
Irritating to skin Risk of serious damage to eyes Toxic, Danger of serious damage to health by prolonged exposure through inhalation S-phrases S1/ 2
S
S37/
S 45
Keep locked up and out of the reach of children In case of contact with eyes, rinse immediately with plenty of water and seek medical advice Wear suitable gloves and eye/face protection. In case of accident or if you feel unwell, seek medical advice immediately (show the label where possible)
*** According to RAC Opinion from 25th November 2012, in addition to the proposal by the RMS**
Remark:
S26 and S39 are obligatory because of R41. S25 is usually dispensable for substances which are not likely to be used by the general public.
In addition to the proposal by the RMS, classification with T; R48/23 is proposed in the RAC Opinion from 25. November 2012.
The active substance is readily biodegradable and is not considered toxic to aquatic organisms. Consequently, no labelling according to environmental classification of the active substance benzoic acid is required.
Classification and Labelling of MENNO Florades
Table 5 Proposed classification of MENNO Florades based on Directive 1999/45/EC
Classification Wording Hazard symbols, Indications of danger
Xn Xi
Harmful Irritant R-phrases R R48/20*
R R
Flammable Danger of serious damage to health by prolonged exposure through inhalation. Risk of serious damage to eyes. Vapours may cause drowsiness and dizziness.
*** In adaptation to RAC Opinion from 25th November 2012, in addition to the proposal by the RMS**
Remark:
Beside benzoic acid (90 g/l), the biocidal product Menno Florades contains propan-1-ol and propan-2ol. Therefore, the biocidal product has to be classified with R67 (Vapours may cause drowsiness and dizziness) in addition to “Xi; R41” (Irritant; Risk of serious damage to eyes) and – in adaptation of the RAC Opinion – “Xn, R48/20 (Harmful; Danger of serious damage to health by prolonged exposure through inhalation)”.
No environmental classification of the model formulation is required.
Table 6 Proposed classification of MENNO Florades based on Regulation (EC) No 1272/ Classification Wording Hazard classes, Hazard categories
Flam. Liq. 3 Eye Dam. 1 STOT SE 3 STOT RE 2 Hazard statements H H H H
Flammable liquid and vapour Causes serious eye damage May cause drowsiness or dizziness May cause damage to lungs through prolonged or repeated inhalative exposure
*** In adaptation to RAC Opinion from 25th November 2012, in addition to the proposal by the RMS**
Remark:
Beside benzoic acid (90 g/l), the biocidal product Menno Florades contains propan-1-ol and propan-2ol. Therefore, the biocidal product has to be classified “STOT SE 3; H336 (May cause drowsiness or dizziness) in addition to “Eye Dam. 1; H318 (Causes serious eye damage)” and –
in adaptation of the RAC Opinion – “STOT RE 2; H373 (May cause damage to lungs through prolonged or repeated inhalative exposure)”.
No environmental classification of the model formulation is required.
Table 7 Proposed labelling of Menno Florades based on Directive 1999/45/EC
Labelling Wording Hazard Symbols, Indications of danger
Xn (Xi) Harmful (Irritant)
R-phrases R R R48/20*
R
Flammable Risk of serious damage to eyes. Harmful, Danger of serious damage to health by prolonged exposure through inhalation. Vapours may cause drowsiness and dizziness. S-phrases S S
S
S S
S
S
Keep out of the reach of children Keep away from food, drink and animal feedingstuffs Keep away from sources of ignition - No smoking Avoid contact with skin In case of contact with eyes, rinse immediately with plenty of water and seek medical advice. Wear eye/face protection
If swallowed, seek medical advice immediately and show this container or label
*** According to RAC Opinion from 25th November 2012, in addition to the proposal by the RMS**
Remark:
The Safety phrases S26 and S39 are mandatory because of R41 according to Annex VI of Directive 67/548/EEC. S16 is added to the labelling proposal because of R10. S24 is added because of the possible dermal effects by benzoic acid and the results of human health risk assessment. S13 is required as a general hygienic measurement and the fact that the biocidal product is used in food-producing facilities. S2 and S46 are required since the biocidal product is used in areas (farms) where access of person s equivalent to the general public cannot be excluded.
No labelling according to environmental classification of the model formulation is required.
Additional labelling of the biocidal product: Due to the pseudoallergic properties of benzoic acid to induct non-immunological contact urticaria the biocidal product Menno Florades has to be labelled with: Contains benzoic acid. May produce pseudo-allergic reactions.
Remark:
Precautionary statements are also selected on the whole in accordance with the recommendations given in the Guidance to Regulation (EC) No 1272/2008 on Classification, Labelling and Packaging of substances and mixtures (IHCP, DG Joint Research Centre, European Commission, 2009).
Additional labelling of the biocidal product: Due to the pseudoallergic properties of benzoic acid to induct non-immunological contact urticaria the biocidal product Menno Florades has to be labelled with: Contains benzoic acid. May produce pseudo-allergic reactions.
2.2. Summary of the Risk Assessment
2.2.1. Human Health Risk Assessment
2.2.1.1. Hazard identification
Benzoic acid and its salts are natural compounds widely spread in the environment. They are generated in plant and animal metabolism and therefore, are constituents in many foodstuffs: up to ca. 40 mg/kg are found in milk products and up to 100 mg/kg in honey (IPCS, 1999; BUA Report, 1993). Benzoic acid and benzoates are used as therapeutic substances in human and veterinary medicine. Because of its antimicrobial activity, benzoic acid is commonly used as preservative in food, cosmetics and pharmaceuticals.
The worldwide industrial production volume is about 700 000 tons per year (OECD SIDS dossier, 2005).
Bridging concept
Although the application for Annex I Inclusion under Directive 98/8/EC is restricted to benzoic acid, benzoates are included in the toxicological evaluation because a considerable part of data was generated with these substances. Particularly sodium benzoate has been used in many experiments because of the low water solubility of benzoic acid at neutral pH. Furthermore, after ingestion of sodium benzoate the acidic pH of the stomach moves the equilibrium to the undissociated benzoic acid molecule (pKa: 4.19). Additionally, for some studies it was not definitely stated whether benzoic acid or benzoates were used. Regarding the great similarity of the toxicological profile (with the exception of irritancy), benzoic acid and sodium benzoate can in general be considered together.
Quality of data
The toxicological evaluation of the a.s. benzoic acid is based on literature which is very heterogeneous. In several studies – especially in short-term and long-term studies - only one or two doses and only few parameters were tested. Results were often insufficiently reported.
As stated in the OECD SIDS dossier, “several of the toxicological studies on [...] benzoic acid and its salts were carried out some years ago and do not always fulfill for 100% present-day guidelines. However, well-known research groups and/or test laboratories ran the studies according to scientific standards and/or accepted protocols at that time. They did appear to be acceptable studies for evaluation. Also, all were peer-reviewed and published in high quality scientific literature. Most of them have been reviewed and accepted by other fora like FDA, JECFA, and IPCS as acceptable studies. In addition, there is good consistency in the individual data for a substance in the group as well as between members of the group [...]. Therefore, taken as a whole, the available studies give a robust database for hazard assessment and hazard evaluation of these compounds and further studies are not indicated.”
Regarding the overall conclusions on the toxicological properties of benzoic acid/benzoates in this report, they resemble those drawn in other evaluations (see Doc II Table 3-1). The ADI derived in this monograph is in agreement with the ADI of JECFA (1983) and EU (2003,
Like in humans, benzoic acid is almost entirely excreted as hippuric acid in rabbits, rats, and pigs, whereas other species such as marmosets and ferrets excrete also considerable quantities of benzoyl glucuronide.
In neonatal and protein-deficient rats, the proportion excreted as hippuric acid appeared to be reduced, approx. 20 % of the urinary radiolabel were identified as benzoyl glucuronide.
In cats, which lack the metabolic pathway of glucuronic acid conjugation, benzoic acid will build up to toxic levels when glycine conjugation to hippuric acid is saturated.
The major sites of conversion of benzoic acid to hippuric acid and benzoyl-glucuronic acid in humans are the liver and the kidneys. While the conjugation rate was greater in the renal cortex than in the liver, the larger mass and strategic anatomical position of the liver were considered to make it quantitatively the more important organ with respect to glycine conjugation. In vitro experiments indicated that after percutaneous absorption of benzoic acid a small amount can also be converted to hippuric acid in the skin.
Dermal Absorption
Because of the immense use of benzoic acid/sodium benzoate as preservative in cosmetics and the suitability of benzoic acid as reference substance, many investigations dealt with the percutaneous absorption in several animal species in vivo, e.g. rat, rhesus monkey, dog, pig, guinea pig and in humans as well as in human and rat skin in vitro.
Overall, the percutaneous absorption in humans accounts for approximately 40 % in vivo (14 – 42.6 %) and 70 % (53 - 99 %) in vitro. However, in the absence of data for the biocidal product and due to the heterogeneous results in human dermal absorption studies, a dermal absorption of 100 % is assumed.
Acute Toxicity including irritancy and skin sensitisation
Benzoic acid is of low toxicity in rat, mouse, rabbit and dog, and of moderate toxicity in cat. The oral LD50 of benzoic acid in the rat is in the range of 2000 to 3040 mg/kg bw, the dermal LD50 is >10000 mg/kg bw and the inhalative LC50 > 1.2 mg/L air x 6 h (dust, highest attainable concentration).
Classification and labelling for acute toxicity according to Directive 67/548/EEC: Not required Classification and labelling for acute toxicity according to Regulation (EC) No 1272/2008: Not required
Benzoic acid is not irritating to the skin (below classification threshold) in standard animal irritation studies but highly irritating to the eyes. The effects observed on the eyes comprised corneal opacity (severe (1/3 animals) and not reversible (2/3 animals), no reaction to light up to d 21 (1/3 animals), non-reversible chemosis (2/3 animals), iridial injection and conjunctival redness as reported in the SCCP report (SCCP/0891/05-Opinion on Benzoic Acid and Sodium Benzoate, EU, 2005). Sodium benzoate is not skin-irritating.
Classification (labelling) for irritation/corrosivity according to Directive 67/548/EEC: Xi; R41 (Irritant; Risk of serious damage to eyes) Classification (labelling) for irritation/corrosivity according to Regulation (EC) No 1272/2008: Eye Dam. 1; H318 (Causes serious eye damage)
No sensitising potential of benzoic acid was observed in a guinea pig maximisation test, in a local lymph node assay, a Buehler test and a mouse ear swelling test.
Non-immunogenic contact urticaria (NICU):
Transient, but nevertheless intense erythema and oedema are evoked by benzoic acid when applied to the ear lobes of guinea pigs and human skin of sensitive persons in various parts of the body (cf. Doc II chapter 3.10 Medical data). While not proven in a narrow sense, some mechanistic evidence was presented, that these skin reactions are mediated by release of vasoactive substances. An immunological T-cell mediated mechanism is ruled out, also because no systemic reaction has been observed in the respective patients and no sensitisation (induction phase) is required for the reaction.
Together with the guinea pig data on non-immunological contact urticaria (NICU), the findings are regarded in the medical surveillance reports (cf. Doc II chapter 3.10 Medical data) sufficient to justify labelling of benzoic acid with R38 (Irritating to the skin) resp. H315 (Causes skin irritation).
Classification (labelling) for sensitisation according to Directive 67/548/EEC: Not required for sensitisation. For the induction of NICU: Xi; R38 (Irritant; Irritating to the skin) Classification (labelling) for sensitisation according to Regulation (EC) No 1272/2008: Not required for sensitisation. For the induction of non-immunological contact urticaria (NICU): Skin Irrit. 2; H315 (Causes skin irritation).
Short-term Toxicity
A large number of subacute and subchronic oral toxicity studies with benzoic acid or sodium benzoate have been performed in various mammalian species. However, in general these do not meet current standards with regard to study design and reporting. Many of these studies primarily relied on clinical observations.
Typical signs caused by benzoic acid in the rat were similar to those from acute studies and included ataxia, aggressiveness, tremor, convulsions, reduction of food consumption and bw gain, and mortality. With few exceptions, histopathological evaluation was not performed or included only few organs. A 35-d CNS toxicity study reported regional CNS necrosis from daily doses of 2250 mg/kg in the rat. The kidney weight was increased in some studies. Generally, LOAEL values for the rat were between 1200 and 2250 mg/kg bw/d for subacute and subchronic exposure without strict correlation to exposure time. A reliable NOAEL for derivation of threshold limit values may be based on a multigeneration study. In this study, no changes in bw gain (data supplied only for up to 12/8 weeks for M/F) and histopathology of key organs performed after wk 16 were reported at the top dose of 500 mg/kg bw/d benzoic acid.