Regulation (EU) No 528/2012 concerning the making available on the market and use of biocidal products Evaluation of active substances Assessment Report Citric Acid Product-type 2 (Disinfectants and algaecides not intended for direct application to humans or animals) March 2016 Belgium
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Regulation (EU) No 528/2012
concerning the making available on
the market and use of biocidal
products
Evaluation of active substances
Assessment Report
Citric Acid
Product-type 2
(Disinfectants and algaecides not
intended for direct application to humans
or animals)
March 2016
Belgium
CONTENTS
1 STATEMENT OF SUBJECT MATTER AND PURPOSE ....................... 3 1.1 Procedure followed ........................................................................................................... 3 1.2 Purpose of the assessment report ................................................................................ 4
2 Overall summary and conclusions for Citric acid ......................... 4 2.1 Presentation of the active substance ........................................................................... 4
2.1.1 Identity, physico-chemical properties, and intended uses...................................... 5 2.2 Hazard identification of the active substance ........................................................ 13
2.2.1 Summary of the human health effects assessment .................................................. 13 2.2.2 Determination of toxicological hazard endpoints ..................................................... 14 2.2.3 Summary of the environmental fate and effects assessment ............................... 16 2.2.4 Determination of PNECs ...................................................................................................... 16 2.2.5 PBT and POP assessment .................................................................................................... 18 2.2.6 Assessment of endocrine disruptor properties ......................................................... 18
2.3 Assessment of use in application product type 02 ............................................... 19 2.3.1 Critical end point(s) for the formulation ...................................................................... 19 2.3.2 Risk identification for human health .............................................................................. 20 2.3.3 RISK IDENTIFICATION FOR THE ENVIRONMENT ................................................... 21
2.4 Risk characterisation ...................................................................................................... 27 2.4.1 Human Health .......................................................................................................................... 27 2.4.2 Environment ............................................................................................................................. 28 2.4.3 Physico-chemical properties ............................................................................................. 28
Appendix I : List of End Points ........................................................................ 30 Chapter 1: Identity, Physical and Chemical Properties, and Proposed Classification and Labelling ...................................................................................................... 30 Chapter 2: Methods of Analysis ......................................................................................... 32 Chapter 3: Impact on Human Health ............................................................................... 34 Chapter 4: Fate and Behaviour in the Environment .................................................. 38 Chapter 5: Effects on Non-target Species ....................................................................... 40
Appendix II: List of Intended uses .............................................................. 42
Appendix III: List of studies ............................................................................. 43
Citric acid Product-type 2 March 2016
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1 STATEMENT OF SUBJECT MATTER AND PURPOSE
1.1 PROCEDURE FOLLOWED
This assessment report has been established as a result of the evaluation of the
active substance Citric Acid as product-type 2 (Disinfectants and algaecides not
intended for direct application to humans or animals) carried out in the context of
the work programme for the review of existing active substances provided for in
Article 89 of Regulation (EU) No 528/2012, with a view to the possible approval of
this substance.
Citric Acid (EC no. 201-069-1/ CAS no. 77-92-9) was initially notified as an
existing active substance, by Kimberly-Clark Europe Ltd, hereafter referred to as
the applicant, in product-type 1.
After the Working Group on Efficacy meeting in September 2014, two issues were
raised: whether an anti-viral tissue placed on the market with the claim ‘kills 99,9
% of cold & flu viruses in the tissue’ is a biocidal product or a treated article and, if
considered a biocidal product, whether it would belong to product-type 1 (human
hygiene) or 2 (disinfectants and algaecides not intended for direct application to
humans or animals).
A request to the Commission in accordance with Article 3(3) of the BPR was
submitted by the Competent Authority (BE) to obtain a legally binding opinion on
both issues.
After a discussion at the 60th CA meeting on 21 May 2015, the Commission
adopted the decision, that “an anti-viral tissue impregnated with citric acid
and placed on the market with the claim "kills 99.9% of cold & flu viruses
in the tissue" shall be considered as a biocidal product in accordance with
Article 3(1)(a) of Regulation (EU) No 528/2012 and shall fall within product-
type 2 as defined in Annex V to that Regulation” (Article 1 of Decision No
2015/19852 )”.
Commission Regulation (EC) No 1451/2007 of 4 December 20071 lays down the
detailed rules for the evaluation of dossiers and for the decision-making process.
In accordance with the provisions of Article 7(1) of that Regulation, Belgium 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 Citric Acid as an active substance in Product Type 1 was 30
March 2006, in accordance with Annex V of Regulation (EC) No 1451/2007.
1 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
2 Commission Implementing Decision (EU) 2015/1985 of 4 November 2015 pursuant to Article 3(3) of
Regulation (EU) No 528/2012 of the European Parliament and of the Council on an anti-viral tissue
impregnated with citric acid.
Citric acid Product-type 2 March 2016
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On 28 February 2006, the Belgian competent authorities received a dossier from
the applicant. The Rapporteur Member State accepted the dossier as complete for
the purpose of the evaluation on 30 June 2006.
On 23 August 2013, the Rapporteur Member State submitted to the Commission
and the applicant a copy of the evaluation report, hereafter referred to as the
competent authority report.
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 Agency. Revisions agreed upon were presented at the Biocidal
Products Committee and its Working Groups meetings and the competent
authority report was amended accordingly.
1.2 PURPOSE OF THE ASSESSMENT REPORT
The aim of the assessment report is to support the opinion of the Biocidal Products
Committee and a decision on the approval of Citric Acid for product-type 2 and,
should it be approved, to facilitate the authorisation of individual biocidal products.
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.
For the implementation of the common principles of Annex VI, the content and
conclusions of this assessment report, which is available from the Agency web site
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 for that
purpose has been granted to that applicant.
2 OVERALL SUMMARY AND CONCLUSIONS FOR CITRIC ACID
2.1 PRESENTATION OF THE ACTIVE SUBSTANCE
The evaluation has established that for the active substance notified by Kimberly-
Clark Europe Ltd, no substances of concern among the manufacturing impurities
were identified.
EPA registered the first citric acid-containing products in the early 1970’s. The
currently registered products are used as fungicides and bactericides sanitizers,
virucides, and algicides. Citric acid is Generally Recognized As Safe (GRAS) by the
U.S. Food and Drug Administration for use in food.
Citric acid is also approved by the Joint FAO/WHO Expert Committee on Food
Additives for use in foods without limitation.
Citric acid occurs naturally in plant and animal tissues and fluids. It may be
produced on an industrial scale by mycological fermentation of carbohydrates such
Citric acid Product-type 2 March 2016
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as corn starch and crude sugar solutions (molasses). Strains of mold used include
Aspergillus niger and Candida lypolytica. Citric acid is a well-known intermediate in
carbohydrate metabolism (Krebs cycle) and ingested citrate is considered to be
completely metabolized.
Citric acid from living organisms is found naturally in soil and water. Citrates
leached from rotting vegetation and produced by micro-organisms have been
detected at low levels throughout the ecosystem. Citric acid degrades rapidly when
in contact with a variety of micro-organisms that are found in soil, natural waters
or sewage treatment systems (background concentration in Atlantic coast
Lowest relevant dermal NOAEL / LOAEL None available
Lowest relevant inhalation NOAEL /
LOAEL
None available
Genotoxicity (Annex IIA, point 6.6)
The active substance is not mutagenic in
vitro with and without metabolic activation.
The active substance is not clastogenic in
vitro without metabolic activation.
Citric acid did not induce mutagenic potential
in two in vivo studies (rat bone marrow and
rat dominant lethal assay)
Carcinogenicity (Annex IIA, point 6.4)
Species/type of tumour Rat/ Citric acid does not induce a
Citric acid Product-type 2 March 2016
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carcinogenic effect or any signs of toxicity at
the dose level tested
lowest dose with tumours Not applicable
Reproductive toxicity (Annex IIA, point 6.8)
Species/ Reproduction target / critical
effect
Rat/oral, 1-gen study, in-utero to 200 days
after birth/ F1 males decrease in bodyweight,
wet weights of fibula and tibia, haemocrit
and haemoglobin levels
Rat/oral, 2-gen/ no adverse effects observed
Lowest relevant reproductive NOAEL /
LOAEL 5 % citric acid in diet
Species/Developmental target / critical
effect
Rat/oral, 1-gen study, in-utero to 200 days
after birth/ F1 males decrease in bodyweight,
wet weights of fibula and tibia, haemocrit
and haemoglobin levels
Rat/6-15 day of gestation/no adverse effects
Mouse/oral, pre-,during and post-mating/no
adverse teratogenic effects
Rabbit/oral, 6-18 days of pregnancy/no
effects
Lowest relevant developmental NOAEL /
LOAEL 5% citric acid in diet
Neurotoxicity / Delayed neurotoxicity (Annex IIIA, point VI.1)
Species/ target/critical effect No data necessary. Data waiver in place.
Lowest relevant developmental NOAEL /
LOAEL.
Other toxicological studies (Annex IIIA, VI/XI)
Not applicable
Medical data (Annex IIA, point 6.9)
Not applicable
Summary (Annex IIA, point 6.10)
Value Study
Safety
factor
ADI (if residues in food or feed) Not specified
Citric acid Product-type 2 March 2016
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AEL MRTD value
of 100
mg/kgbw/d
is used
instead
MRTD
(Maximum
Recommended
Therapeutic
Dose) of FDA
list (US Food
and Drugs
Admnistration)
n.a.
Drinking water limit Not specified
ARfD (acute reference dose) Not specified
Acceptable exposure scenarios (including method of calculation)
Professional users There is no professional use
Non-professional users Consumers using the biocidal product, i.e.
the tissue, will be potentially exposed by the
dermal and inhalation routes to 100% of the
active substance in each tissue.
Each consumer on average uses 326 tissues
per year. Therefore, based on the worst case
scenario, the consumer will be exposed to 87
g of the active substance per year.
The worst-case scenario is for use of the
tissue by children, therefore the systemic
dose is based upon a child (weight = 15 kg).
The systemic dose is therefore 15.89
mg/kg/day.
Lowest MoE for adults : 1598
Lowest MoE for children : 1220
Lowest MoE for toddlers: 380
Lowest MoE for infants : 418
Indirect exposure as a result of use Secondary exposure may occur via disposal
of the used tissues. However, this exposure
will be minimal in comparison to exposure to
citric acid from other sources, such as food.
Citric acid Product-type 2 March 2016
38
CHAPTER 4: FATE AND BEHAVIOUR IN THE ENVIRONMENT
Route and rate of degradation in water (Annex IIA, point 7.6, IIIA, point
XII.2.1, 2.2)
Hydrolysis of active substance and
relevant metabolites (DT50) (state pH
and temperature)
DT50 > 1 year, +25°C, pH 4,7 and 9
Photolytic / photo-oxidative degradation
of active substance and resulting
relevant metabolites
Half-life 72.9 years.
Indirect Photolysis: t½ = 2.3 days
Readily biodegradable (yes/no) Yes
Biodegradation in seawater Not applicable
Non-extractable residues Not applicable
Distribution in water / sediment systems
(active substance)
The active substance is highly water soluble
and has a low Pow. However, studies on
absorption/desorption to soil show high Koc.
The substance ionises in the terrestrial
environment which will cause it to strongly
adhere to soil or sediment.
Background concentrations of < 0.04 – 0.2
mg/l in river surface water and 0.025 –
0.145 mg/l in Atlantic coast seawater.
Distribution in water / sediment systems
(metabolites)
The active substance is readily
biodegradable.
Citric acid Product-type 2 March 2016
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Route and rate of degradation in soil (Annex IIIA, point VII.4, XII.1.1, XII.1.4;
Annex VI, para. 85)
Mineralization (aerobic) Studies on absorption/desorption to soil
show high Koc. The substance ionises in the
terrestrial environment which will cause it to
strongly adhere to soil, where it will be
rapidly biodegraded.
Laboratory studies (range or median,
with number of measurements, with
regression coefficient)
No studies available
Field studies (state location, range or
median with number of measurements) No studies available
Anaerobic degradation No studies available
Soil photolysis No studies available
Non-extractable residues No studies available
Relevant metabolites - name and/or
code, % of applied a.i. (range and
maximum)
No studies available
Soil accumulation and plateau
concentration
In a radio-labelled study, there was
substantial disappearance from soil in seven
days.
Citric acid Product-type 2 March 2016
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Adsorption/desorption (Annex IIA, point XII.7.7; Annex IIIA, point XII.1.2)
Ka , Kd
Kaoc , Kdoc
pH dependence (yes / no)
(if yes type of dependence)
Soil type Kd Log Koc
OECD soil type 2 8.97 2.67
OECD soil type 3 14.1 2.64
OECD soil type 4 10.9 2.56
OECD soil type 5 22.9 3.18
OECD soil type 7 8.68 1.88
Fate and behaviour in air (Annex IIIA, point VII.3, VII.5)
Direct photolysis in air No data available
Indirect: t½ = 2.3 days
Quantum yield of direct photolysis No data available
Photo-oxidative degradation in air DT50 t½ = 2.3 days
Volatilization No data available. However, a very low
vapour pressure would suggest that this
would be low.
Monitoring data, if available (Annex VI, para. 44)
Soil (indicate location and type of study) No data available
Surface water (indicate location and type
of study)
Background concentrations of < 0.04 – 0.2
mg/l in river surface water and 0.025 –
0.145 mg/l in Atlantic coast seawater.
Ground water (indicate location and type
of study) No data available
Air (indicate location and type of study) No data available
CHAPTER 5: EFFECTS ON NON-TARGET SPECIES
Toxicity data for aquatic species (most sensitive species of each
group) (Annex IIA, point 8.2, Annex IIIA, point 10.2)
Species Time-scale Endpoint Toxicity
Fish
Rainbow trout 96h LC50 >100 mg/l
Invertebrates
Daphnia magna 48hr EC50 34 mg/l
Algae
Scenedesmus subspicatus 72hr ECb50
ECr50
1.9 mg/l
2.0 mg/l
Microorganisms
Citric acid Product-type 2 March 2016
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Activated sewage sludge 3h EC50 370 mg/l
Effects on earthworms or other soil non-target organisms
Acute toxicity to
(Annex IIIA, point XIII.3.2) No data
Reproductive toxicity to
(Annex IIIA, point XIII.3.2) No data
Effects on soil micro-organisms (Annex IIA, point 7.4)
Nitrogen mineralization No data
Carbon mineralization /
Effects on terrestrial vertebrates
Acute toxicity to mammals
(Annex IIIA, point XIII.3.3) No data
Acute toxicity to birds
(Annex IIIA, point XIII.1.1) No data
Dietary toxicity to birds
(Annex IIIA, point XIII.1.2) No data
Reproductive toxicity to birds
(Annex IIIA, point XIII.1.3) No data
Effects on honeybees (Annex IIIA, point XIII.3.1)
Acute oral toxicity No data
Acute contact toxicity No data
Effects on other beneficial arthropods (Annex IIIA, point XIII.3.1)
Acute oral toxicity No data
Acute contact toxicity No data
Acute toxicity to No data
Bioconcentration (Annex IIA, point 7.5)
Bioconcentration factor (BCF) BCF estimated from Log Pow to be 1.27 x 10-4
Depuration time (DT50) (DT90) Not available
Level of metabolites (%) in organisms
accounting for > 10 % of residues Not available
Chapter 6: Other End Points
Citric acid Product-type 2 March 2016
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APPENDIX II: LIST OF INTENDED USES
Object
and/or
situation
Member
State or
Country
Product
name
Organisms
controlled
Formulation Application Applied amount per
treatment
Remarks
Type Conc.
of
a.s.
Method
Kind
Number
min
max
Interval
between
applications
(min)
g
a.s./L
min
max
Water
L/m2
min
max
g
a.s./m2
min
max
(m)
Active
against
viruses
– PT2
All Kleenex®
Anti-
Viral
Tissues
Respiratory
Syncytial
Virus
(RSV),
Influenza A
and
Influenza B
Facial
tissues
7.5%
w/w*
n.a. n.a. n.a. n.a. n.a. n.a. n.a.
* Please find in the confidential part of the dossier, explanation on what the dose in the tissue is.
Citric acid Product-type 2 March 2016
43
APPENDIX III: LIST OF STUDIES
Data protection is claimed by the applicant in accordance with Article 60 of
Regulation (EU) No 528/2012.
Author(s)
Section No /
Reference No
Year
Title. Source (where different from company)
Company, Report No. GLP (where relevant) /
(Un)Unpublished
Data Protec
tion
Claimed
(Yes/No)
Owner
A Wiley-Interscience Publication
Supporting information
for the active
substance
1993 : Chlorocarbons and Chlorohydrocarbons to Combustion Technology, Encyclopedia of
Chemical Technology, Fourth Edition, Vol. 6 N
Abbott T.R. A6.2(10) 1983
: Changes in serum calcium fractions and citrate concentrations during massive blood transfusions and cardiopulmonary bypass, British Journal of Anaesthesia, Vol. 55, p
753-759, 1983
N
Anbar M. and Neta P. A7.3.1 1967
A Compilation of Specific Bimolecular Rate Constants for the Reactions of Hydrated Electrons, Hydrogen Atoms and Hydroxyl
Radicals with Inorganic and Organic Compounds in Aqueous Solution
N
Anderson B.G.
Supporting information for Section
7.4.1.2
1944
: The Toxicity Thresholds of Various Substances Found in Industrial Wastes as Determined by the Use of Daphnia magna, Sewage Works J., Vol. 16, No. 6, p 1156-
1165, 1944
N
Baxter, K.A B5.10.2(3) 2002
: Virucidal Efficacy of Facial Tissue for Treated and Untreated Tissue Against Influenza A, ATCC VR-1469, Hill Top Research Inc, 02-120048-106, (Un)
N
Baxter, K.A B5.10.2(5) 2002
: Virucidal Efficacy of Facial Tissue for Treated and Untreated Tissue Against
Respiratory Syncytial Virus, ATCC VR-26, Hill Top Research Inc, 02-120091-106, (Un)
N
Baxter, K.A B5.10.2(4) 2002 : Virucidal Efficacy of Facial Tissue for Treated and Untreated Tissue Against
N
Citric acid Product-type 2 March 2016
44
Influenza B, CDC ID# 2001701156, Hill Top Research Inc, 02-120088-106, (Un)
Baxter, K.A B5.10.2(1) 2002
: Virucidal Efficacy of Facial Tissue for Treated and Untreated Tissue Against Rhinovirus IA, ATCC VR-1364, Hill Top Research Inc, 02-120089-106, (Un)
N
Baxter, K.A B5.10.2(2) 2002
: Virucidal Efficacy of Facial Tissue for Treated and Untreated Tissue Against Rhinovirus 2, ATCC VR-482, Hill Top Research Inc, 02-120090-106, (Un)
N
Barros M.J et al A6.12.2(3) 1990
: Importance of Inspiratory Flow Rate in the Cough Response to Citric Acid Inhalation in Normal Subjects, Clinical Science, 78 (5), p
521-525, 1990
N
Baruch S.B. et al A6.2(13) 1975 : Renal Metabolism of Citrate, Medical Clinics of North America, Vol. 59, No. 3, p 569-582,
1975 N
BIBRA
Supporting information
for the active
substance
1993 : Toxicity Profile: Citric ac id and its common
salts, BIBRA Information Services Ltd., BIBRA
N
Bonting S.L., Jansen B.C.
A6.5(2), A6.8.2(1)
1956 : The effect of a prolonged intake of
phosphoric acid and citric acid in rats, Voeding, 17: 137-148
N
Bringmann G. and Kuhn R.
Supporting information for Section
7.4.1.4
1980
: Comparison of the Toxicity Thresholds of Water Pollutants to Bacteria, Algae and
Protozoa in the Cell Multiplication Inhibition Test, Water Research, Vol. 14, No. 3, p 231-
241, 1980
N
Bringmann G. and Kuhn R.
A7.4.1.2(2) 1982
: Results of toxic action of water pollutants on Daphnia magna strauss treated by an
improved standardised procedure, Z. Wasser Abwasser Forsch, 15:1-6
N
Brynhildsen L. and Rosswall Th.
Doc II B 3.3.3
1997
EFFECTS OF METALS ON THE MICROBIAL
MINERALIZATION OF ORGANIC ACIDS
Department of Water and Environmental
Studies, Link¨oping University, S-581 83 Link¨oping, Sweden