VANTOCIL TG
VANTOCIL TG
VANTOCIL TG Antimicrobial is a broad spectrum, fast acting bactericide for the formulation of disinfectants and sanitisers.
It is a 20 % aqueous solution of poly(hexamethylenebiguanide) hydrochloride, also known as PHMB.
VANTOCIL TG Antimicrobial is used in industrial, institutional, agricultural, food, beverage and domestic disinfection applications, primarily as a solid surface disinfectant, specifically for hospitals, veterinary establishments, dairies, milking parlors, breweries, air-conditioning units, and pasteurizers in canned food & beverage bottling plants.
Vantocil TG Antimicrobial has a non-specific mode of biocidal action which means that bacterial resistance is very unlikely to occur
Chemical Family: Biguanides
Chemical Name: Poly(hexamethylenebiguanide) Hydrochloride
Cleaning Ingredient Functions
Anti-Microbial Agent
Cleaning Ingredients
Cleaning Ingredients — Microbial Control & Preservation
Other Disinfectants & Antimicrobials
VANTOCIL TG Antimicrobial; PHMB 20% aqueous solution; Poly(hexamethylenebiguanide) hydrochloride
CAS No.: 32289-58-0,27083-27-8,133029-32-0
Use: Biocide, Disinfectant
Package: 25kg/drum
Synonyms:
Vantocil IB
Poly(hexamethylene biguanidine) hydrochloride;
polihexanide
PHMB
Product name : Poly(hexamethylene biguanidine) hydrochloride(PHMB)
Item : PHMB
Details :
1 English name：Poly(hexamethylene biguanidine) hydrochloride(PHMB)
2 Chemical name：PHMB
3 Common name：polihexanide
4 Product name：Similar Vantocil IB,Vantocil TG
5 CAS number ：27083-27-8(Europe)，32289-58-0(United States)，133029-32-0(INCI)
VANTOCIL TG Antimicrobial is a broad spectrum, fast acting bactericide for the formulation of disinfectants and sanitisers, for use in industrial, institutional, agricultural, food, beverage and domestic disinfection applications.
VANTOCIL TG Antimicrobial is a 20% aqueous solution of poly(hexamethylenebiguanide) hydrochloride, also known as PHMB.
Applications
VANTOCIL TG Antimicrobial is effective in a wide range of industrial disinfection applications, primarily as a solid surface disinfectant.
Application areas include:
– Hospitals
– Institutions
– Veterinary establishments
– Dairies
– Milking parlours
– Poultry hatcheries
– Food processing plants
– Breweries
– Pasteurisers in canned food & beverage bottling plants
– Yoghurt fermentation
– Air-conditioning units
– Cheese moulds
– Beer glass cleaners
Antimicrobial Properties
The levels of VANTOCIL TG Antimicrobial needed to prevent the growth of problem micro-organisms are listed in Table 1.
MICs do not represent effective use levels but do indicate the intrinsic broad spectrum of activity of VANTOCIL TG Antimicrobial.
VANTOCIL TG Antimicrobial has a non-specific mode of biocidal action which means that bacterial resistance is very unlikely to occur.
Detailed information on the mode of action of VANTOCIL TG Antimicrobial is available on request.
Table 1: Minimum Inhibitory Concentrations (MICs)
Micro-organism Strain No.
VANTOCIL TG Antimicrobial (ppm product)
Bacteria
Bacillus subtilis NCIB 3610 1.5
Enterobacter cloacae NCIB 8271 40
Escherichia coli 0157:H7 NCTC 12900 80
Legionella pneumophila — 5
Listeria monocytogenes ATCC 15313 30
Proteus vulgaris NCTC 4175 40
Pseudomonas aeruginosa ATCC 15442 40
Pseudomonas putida — 25
Salmonella choleraesius ATCC 13311 120
Salmonella typhimurium ATCC 14028 160
Staphylococcus aureus ATCC 6538 30
Streptococcus faecalis — 5
Streptococcus lactis NCTC 7944 20
Yeasts
Candida albicans ATCC 10231 300
Rhodotorula rubra NCYC 1659 7.5
Saccharomyces cerevisiae ATCC 9763 300
Amoeba
Acanthamoeba polyphaga — 5
Table 2: Typical Physical Properties
Composition: An aqueous solution of PHMB
Active Agent: 20% w/w
Physical Form: Slightly opalescent colourless to pale yellow liquid
Viscosity at 25°C: 5 mPa s.
pH at 25°C: 5.0-6.0
Boiling Point: 102°C
Storage Stability Stable under normal conditions of storage down to 0°C.
If frozen, allow to thaw at room temperature and stir thoroughly before use.
Active agent is heat-stable and non-volatile.
Flash Point: Boils without flashing
Density at 25°C: 1.04
Odour: No strong odour
Foaming/Surface Tension Has significantly less tendency to tension foam than quaternary ammonium compounds.
PHMB is not surface active.
Compatibility
Effective and stable over pH range 1-11.
Compatible with nonionic surfactants, glycols, glycol ethers, most strong acids and common chelating agents such as EDTA, NTA, IDS.
Limited compatibility with anionic surfactants, strong alkalis, complex phosphates and strong oxidisers.
Amount to Use
VANTOCIL TG Antimicrobial can be used alone or in combination with other biocides to create products for a wide range of disinfection applications.
Considerable data exists which provides a measure of the intrinsic antimicrobial activity of VANTOCIL TG Antimicrobial, generated via European suspension test protocols relevant to application in Food, Industrial,
Domestic and Institutional Hygiene.
Its activity has been further demonstrated under conditions representative of practical use, and a range of use concentrations is provided in Table 3.
However, it is recommended that field tests under practical conditions be undertaken to determine the most cost-effective dose for your application.
This data and information on the compatibility of VANTOCIL TG with a range of formulating chemicals is available on request.
Table 3: Applications
Application Area % VANTOCIL TG Antimicrobial (w/w) in sanitiser use solution
Disinfection of pre-cleaned solid surfaces:
Hospitals
Food Processing
Veterinary establishments
Poultry hatcheries 0.1-0.2
Water treatment applications:
Air conditioning 0.01-0.1
Fermentation equipment:
Yoghurt
Cheese moulds 0.3-0.5
Acid descaler sanitiser:
Milking parlours
Breweries 0.4-0.7
Tunnel pasteurisation:
Canning and bottling plants 0.005-0.01
Vantocil IB and Vantocil TG are aqueous solutions of the powerful antibacterial preservative poly(hexamethylene biguanide) hydrochloride [PHMB], an active offering broad pH tolerance, low foam and good heat stability.
Applications are varied, and include surface care, fabric care and automotive care.
These single use and alcohol free impregnated wet wipes provide an antibacterial action, along with other performance features such as cleansing, deodorising, conditioning,moisturising.
Poly (hexamethylene biguanide) hydrochloride (PHMB), the active ingredient in our VANTOCIL antimicrobial range is a fast-acting and broad spectrum bactericide with a wide formulation latitude.
Consequently, by careful selection of appropriate co-formulants, a wide range of professional and domestic products can be formulated which meet the stringent demands of today’s disinfection and hygiene industries.
VANTOCIL antimicrobials can be used to formulate a wide variety of applications including:
• Professional disinfection
– Liquid hard surface disinfectants for surfaces and floors
– Solid disinfection tablets (slow release and effervescent)
– Water cooling towers
– Tunnel pasteurisers
– Room fogging
– Disinfectants for medical devices and equipment
• Household products
– Antimicrobial surface disinfectants
– Antimicrobial fabric conditioners
• Sanitizing wet wipes (for surfaces and hands)
• Antimicrobial hand soaps
The primary performance benefits of PHMB include:
• Fast-acting and broad spectrum antimicrobial activity
• No cross-resistance with therapeutic antibiotics
• High level of retained biocidal activity in both soft and hard water conditions, and in the presence
of organic load (BSA, yeast extract, milk and sucrose)
• Stable and effective performance over a pH range of 1-11
• Low surface activity and consequently can be readily water rinsed from surfaces and provide very
low foaming products for Clean-In-Place applications
Through its longstanding familiarity with PHMB, Arch Biocides is well placed to offer formulation guidance and application advice in selecting the most appropriate co-formulants to ensure that your antimicrobial products offer the performance you would expect.
ChEBI Name: polyhexamethylene biguanide hydrochloride
Definition: A hydrochloride salt of polyhexamethylene biguanide.
It is a broad spectrum and fast acting bactericide which is used for the formulation of disinfectants and sanitisers.
Formula (ClH)x.(C8H17N5)n
Net Charge 0
Roles Classification
Biological Role(s): disinfectant
An antimicrobial agent that is applied to non-living objects to destroy harmful microorganisms or to inhibit their activity.
antifungal agent
An antimicrobial agent that destroys fungi by suppressing their ability to grow or reproduce.
antibacterial agent
A substance (or active part thereof) that kills or slows the growth of bacteria.
Application(s): dermatologic drug
A drug used to treat or prevent skin disorders or for the routine care of skin.
ophthalmology drug
Any compound used for the treatment of eye conditions or eye diseases.
antiseptic drug
A substance used locally on humans and other animals to destroy harmful microorganisms or to inhibit their activity (cf. disinfectants, which destroy microorganisms found on non-living objects, and antibiotics, which can be transported through the lymphatic system to destroy bacteria within the body).
Outgoing polyhexamethylene biguanide hydrochloride has part polyhexamethylene biguanide(2+)
polyhexamethylene biguanide hydrochloride has role antibacterial agent
polyhexamethylene biguanide hydrochloride has role antifungal agent
polyhexamethylene biguanide hydrochloride has role antiseptic drug
polyhexamethylene biguanide hydrochloride has role dermatologic drug
polyhexamethylene biguanide hydrochloride has role disinfectant
polyhexamethylene biguanide hydrochloride has role ophthalmology drug
polyhexamethylene biguanide hydrochloride is a hydrochloride
Synonyms
hexamethylenediamine polymer hydrochloride
PHMB hydrochloride
PHMB-HCl
polihexanide HCl
polihexanide hydrochloride
poly(hexamethylenebiguanide) hydrochloride
poly(iminoimidocarbonyl-iminoimidocarbonyl-iminohexamethylene) hydrochloride
Brand Names
Cosmocil
Cosmoquil CQ
poly(hexamethylene) biguanide hydrochloride
Prontoderm
Prontosan
Reputex 20
TriGene
Vantocil 1B
Vantocil TG
Vantosan
CAS-No. CAS-No : 27083-27-8 and 32289-58-0
It must be noted that CAS number 27083-27-8 is not based on characterisation data.
In case of a different PHMB (for example with a weigh distribution outside of the specification of the PHMB assessed in this report) the CAS number will not be able to differentiate the PHMB
EINECS-No. Not listed on the EU (EINECS) inventory because PHMB is a polymer.
Polymers are exempt from listing on EINECS if the monomers are listed.
Other No.(CIPAC, ELINCS None.
IUPAC Name CoPoly(bisiminoimidocarbonyl,hexamethylenehydrochloride),(iminoimidocarbonyl, hexamethylène hydrochloride) or Copoly(5-imino-7-imino-4,6,8-triazaundecamethylene hydrochloride) (5-imino4,6-diazanonamethylenehydrochloride)
Common name,synonym
PHMB (1600; 1.8) i.e. polyhexamethylene biguanide with a mean numberaverage molecular weight (Mn) of 1600 and a mean polydispersity (PDI) of 1.8;Polyhexamethylene biguanide; Poly(hexamethylene) biguanide hydrochloride;
polymeric biguanide hydrochloride;“PHMB”;
Polyhexanide (International non-proprietary name);
Polyaminopropyl Biguanide (INCI)
Molecular formula
Terminal function- (CH2)6- [C8H18N5Cl]n [C7H16N3Cl]m – terminal function
Possible terminal functions:
– NH2 (amine)
– C2H3N4 ( cyanoguanide)
– CH5N3Cl (guanidine)
range average
The active ingredient (a.i.) Poly Hexa Methylene Biguanide (PHMB) is a small size polymer obtained by the polycondensation of two monomers (1,6-hexanemethylenediamine and N,N”’-1,6-hexanediylbis[N’-cyanoguanidine] (ie. HMBDA)).
As PHMB is a small size polymer, some side reactions that occurred during the manufacturing process could modify significatively the structure of the polymer.
The side reaction to obtain the unit guanidine occurred up to 10% in the process.
Therefore, it can be considered that the structure of PHMB is not only composed by repetitive unit of guanidine but it is composed by repetitive unit of guanidine and biguanide.
The active substance as manufactured (TK3) is a 20% w/w aqueous solution of PHMB.
“Purity” is a difficult concept to apply to PHMB which is a mixture of polymers and related substances.
Instead the applicant refers to the “strength” of the polymer which is defined as “% total solids” or “dried material”.
The typical PHMB strength is 20 %.
However, eCA considers more appropriate to use the term “% of active substance (% a.s.)“ or “active substance content“ instead of “strength“.
The active substance content being defined as the sum of PHMB and its impurities contents, it can be considered identical to the % total solids and thus to the strength.
However, the terms strength or dried PHMB are also used in identity and physico chemical sections and refer to the same thing.
As the technical material is the 20 % PHMB solution obtained directly from the manufacturing process (active substance as manufactured or TK), characterisation data were generated from the dried technical material (TC4) using the technique of freeze drying.
The content of PHMB can be calculated by subtracting the total content of impurities in the dried technical material (without residual water) to 100.
This value cannot be considered as a real purity but is the closest available data.
The minimum content of PHMB TC was demonstrated > 95.6%.
Since the active substance is a copolymer, identity characterisation criteria (based on % solid, content of PHMB in dried material, Mw, Mn and the biguanide/guanide ratio) as well as limits or range for each criterion are proposed by eCA in the confidential document IIA to characterise the source of PHMB in order to set reference specifications in case of approval of the active substance and future technical equivalence checks.
eCA proposes to rename PHMB considered for approval in this dossier as “PHMB with a mean number-average molecular weight (Mn) of 1600 and a mean polydispersity (PDI) of 1.8” i.e. “PHMB (1600; 1.8)”.
For convenience, PHMB (1600; 1.8) is referred to hereafter as “PHMB” or “a.s.”.
There is one relevant impurity, Hexamethylenediamine with a maximal content of 0.4%.
All potential impurities have not been looked for and/or quantified.
Additional data about impurities and specifications for the active substance and the impurities should be submitted prior to approval.
Quality control data on structural characteristics (2003-2011) are reported in this confidential document to demonstrate that production of TK (liquid form) remained stable during this period of time from a structural point of view.
It can be concluded that submitted characterisation data (2011) are representative of current production but also of older production and of active substance material used to perform the toxicological and ecotoxicological studies used to perform the risk assessment (See confidential doc IIA).
This statement is only valid for structural data and not for evolution of impurity content in PHMB as no data was submitted to cover this point.
The applicant also manufactures PHMB as a solid material (”Solid PHMB”).
Initially the applicant submitted both sources in the dossier.
Comparison between liquid and Solid
PHMB is discussed in confidential document IIA-02 “Comparison of liquid and solid PHMB”.
eCA considers that liquid PHMB (VANTOCIL TG) and Solid PHMB are 2 different substances, based on structural considerations.
Additional information to demonstrate technical equivalence will be required at product authorisation stage if Applicant claims solid PHMB as a new source.
The active substance considered for approval in this dossier is the active substance as manufactured (TK): 20 % w/w aqueous solution of PHMB (VANTOCIL TG) also called liquid PHMB.
Table 2.1-2: Specifications of PHMB (1600; 1.8) from Lonza
Characterisation specification
Strength 18-22%
PHMB in dried material ≥ 95.6%
molecular weight by number (Mn) 1449-1771
molecular weight by mass (Mw) 2687-3285
Polydispersity 1.80-1.91
The biguanide / guanide ratio in chain 90/10 to 92/8
Total fraction <1000 Da 16.6-24.5 %
Impurities
HMD (relevant impurity) ≤ 0.4%
Other impurities confidential
Polyhexamethylene biguanide
(Mn = 1600; PDI =1.8) (PHMB)
(eco)tox batches: Liquid PHMB used to perform (eco)toxicological key studies and efficacy studies is of the same structure than liquid PHMB characterised in this dossier, However, no data on (eco)toxicity of impurities was provided by the applicant.
Additional data about (eco)toxicity of impurities should be submitted for finalisation of specification.
– Criterion data to be used to differentiate PHMB from different origins: All of presented characterisation data are important to differentiate PHMB assessed in this dossier and other PHMB.
However, some of those criterion data could be found difficult for control (biguanide / guanide ratio quantified by NMR) or not selective (strength).
eCA is of the opinion that Mn and polydipersity would be the most convenient property for the control of the identity of PHMB used in biocidal products.
Physico-chemical properties
TC (dried PHMB) is a dusty solid/powder, off white with a strong ammonia smell.
It has a glass transition temperature of 90-91°C (non crystalline polymer) and decomposes at 205-210°C before boiling.
The TK (PHMB as manufactured, 20% in water) has a boiling point of 100.2°C.
The relative density of TC is 1.20 at 20°C and the relative density of the TK is 1.04 at 20°C.
As a polymer, PHMB is not considered to be volatile.
Henry’s Law Constant is not applicable as PHMB is not considered to be volatile and is present in ionic form at neutral pH.
It is assumed that PHMB has only slight possibility to go from water to air.
It is very soluble in water (426 g/L).
It is also soluble in methanol (41%), in ethanol (0.5%) and sparingly soluble in organic solvents (10-3 g/L).
The pKa is calculated as approximately 4.4 at 25°C. Log Pow is –
2.3 at pH=7.4 and 25°C. TC is not highly flammable, and does not have oxidizing and explosive properties.
A surface tension study should be performed but PHMB is not expected to be surface active based on structural considerations.
Methods of analysis
It is impossible to determine directly PHMB since it is not a single chemical entity but a polymeric mixture with a range of molecular weight.
Adequate methodology exists for the characterisation of the active ingredient and the determination of the known impurities in the TC but more validation data are required.
Justifications for non submission of analytical methods for residues of the active substance in soil, water, air and body fluids and tissues, in food or feedstuffs were submitted.
For polymeric substances it may be difficult to develop an adequate residue analytical method.
A limited residue definition in form of a marker will be required if PHMB is proposed for approval
Residue definition: a proposal of residue definition for drinking water and body fluid and tissues is required 6 months before the date of approval
Monitoring methods:
Based on the bibliography and the nature of the active ingredient, determination of PHMB in soil is currently not technically feasible.
Moreover, eCA considers that if a method could allow to quantify PHMB in soil, this method could probably not be considered as enforcement method.
The non submission is acceptable for air because occurrence in air is not probable.
The non submission is acceptable for surface water, as eCA considers that the issue is the same than in soil.
However, determination of PHMB in drinking water should be technically feasible. Therefore, a validated methods for determination of PHMB would be required
The justification for non submission submitted by the applicant is not acceptable for body fluids and tissues as PHMB is classifed as very toxic.
An analytical method for determination of PHMB in body fluids and tissues or another justification of non submission of data would be required.
The justificatification for non submission submitted by the applicant is acceptable for food and feeding stuff
VANTOCIL TG is a very pale yellow liquid without odour.
Its pH is acid (pH=5.7). It has a relative density of 1.04 at 20 °C.
The product is a free flowing mobile liquid with a low viscosity of 4.15 mPa.s.
Experience in use indicates that the product does not foam.
A study should be provided at the product authorisation stage for confirmation.
Data on the surface tension measured with VANTOCIL TG is required at the product authorisation stage.
VANTOCIL TG is stable 14 days at 54°C. Low temperature stability (7 days at 0°C) and a shelf life study (2 years at ambient temperature) including measure of PHMB adsorbed on container after storage were not submitted and should be required.
VANTOCIL TG is not flammable and has neither oxidising nor explosive properties.
Experience in use indicates no reactivity with High Density Polyethylene (PE-HD) and lacquer lined stee
Mode of action
The lethal action of PHMB is an irreversible loss of essential cellular components as a
direct consequence of cytoplasmic membrane damage.
It is concluded that cytoplasmic precipitation is a secondary event to the death of the bacterial cell.
It has been shown that the lethal sequence consists of a series of cytological and physiological changes – some of which are reversible – which culminate in the death of the cell.
The important steps are:
binding to a receptive site on the surface
leakage of low molecular weight cytoplasmic components
precipitation of cell contents
The molecular interaction between PHMB and bacterial membranes has been deduced by over laying this lethal sequence with the findings of experiments modelling the possible interactions of polymeric biguanides and membrane components – particularly phospholipids.
Objects to be protected, target organisms
The product is added to cooling fluids in closed recirculating cooling systems.
The table below presents the intended use for which efficacy data demonstrate the efficacy of PHMB (refer also to Appendix II).
The data are generated from laboratory studies and should be consolidated at the product authorisation stage with data generated with field tests. The product efficacy would have to be confirmed if the duration of preservation is higher than 28 days. For other target organisms claimed,the efficacy would have to be demonstrated.
The data presented in the dossier demonstrate the efficacy of the product at the application rate of 0.02 % v/v Vantocil TG, equivalent to 0.004 % v/v a.s for 28 days.
Even if the application dose claimed by the applicant is higher (0.025% v/v Vantocil TG (0.005% v/v a.s)) and is efficient, there is no data to determine the protection duration.
Consequently for the purpose of the efficacy assessment of the PHMB as PT11, the application rate of 0.02% v/v Vantocil TG and one application every 28 days is validated.
2.1.3.5 Resistance
The evaluation of the literature studies provided by the applicant does not show particular resistance to PHMB with bacteria.
Nevertheless it is not appropriate to conclude that PHMB resistance is not an issue and that a resistance management strategy is not required.
In particular, the description in the literature of:
– cross resistances;
– modifications of the expression of genes as a mechanism of tolerance to
subletal concentrations of PHMB;should be taken into account in the strategy of resistance management.
Standard methods of measuring resistance brought about by biocide use are not available and should be developed for all type of biocides (Assessment of the Antibiotic Resistance Effects of Biocides, Scenihr 2009).
SUMMARY OF HUMAN HEALTH RISK ASSESSMENTS
Hazard identification
Toxicokinetic:
Oral absorption of PHMB ranges approximately from 0.3 to 8% but the value of 4% is retained based on the oral absorption of PHMB from diet at the lower dose tested.
This value was selected as it corresponds to the closest conditions to the experimental conditions of the study in which the relevant oral NOAEL was determined.
A dermal absorption of PHMB was determined to be 4% by default based on EFSA guidance on dermal absorption (2012), corresponding to the oral absorption value.
Since no information is available on absorption of PHMB by inhalation, an absorption of 100% is retained.
Acute toxicity:
A classification for acute oral or dermal toxicity is not justified for the active substance as manufactured, PHMB 20% in water. For respiratory route, a classification Xn; R20 or Acute Tox 4 – H332 is proposed based on the RAC opinion for PHMB.
Irritation/Sensitisation:
PHMB is not irritant by dermal contact. For eye irritation, classification is not justified based on the data of the PHMB 20% w/w. PHMB is considered as a moderate to strong potency skin sensitizer based on animal data. Human studies indicate that PHMB is a skin sensitizer in humans, although with a rare frequency of sensitisation in the current conditions of consumer uses. Classification Xi; R43 (may cause sensitisation by skin contact) or Skin sens 1 – H317 for CLP, is therefore warranted.
Relatively low incidences from human data support classification as CLP Skin Sens 1B– H317 according to the 2nd ATP to CLP Regulation.
Repeated toxicity:
On the basis of the severity of the effects caused by inhalation of PHMB (mortality and to a lesser extent histopathological changes in the respiratory tract and in the thymus), the absence of reversibility of inflammation in the respiratory tract and the very low doses causing these effects, classification T; R48/23 is warranted (CLP STOT RE 1 – H 372). By inhalation the primary target organ is the respiratory tract and no effect warranting classification are identified by oral and dermal route.
The target organs are kidneys and liver via oral route. By dermal contact, local effects are expected
PHMB is not considered to be mutagenic or genotoxic, according to the results of the in vitro (Ames test and chromosomal aberration test) and in vivo studies (mouse bone marrow micronucleus test and UDS assay).
Carcinogenicity:
PHMB increases the incidence of benign and malign vascular tumours in female rats by oral route and in male and female mice by oral and dermal route.
The tumours are induced mainly in the liver, which is one of the target organ of PHMB and the increase is clearly seen at doses above the MTD.
However, it is also observed more equivocally at doses below MTD (mouse oral study at mid-dose and rat oral study at high dose).
These increases are not considered incidental when considering the clear induction of vascular tumours at higher doses and they are considered biologically significant and attributed to treatment.
A classification as carcinogenic category 3; R40 or Carc 2 – H351 for CLP, is warranted.
In absence of carcinogenicity data by inhalation, it is proposed to allocate the general hazard statement H351 without indication of the route of exposure.
Reprotoxicity:
PHMB has no teratogenic effect and has no effect on fertility or reproductive performance at dose levels up to 2000 ppm.
Determination of AEL/AEC/ADI/ARfD
Systemic effets
The lowest NOAEL from any oral studies is 13 mg/kg bw/day from the rat developmental toxicity study (Doc IIIA 6.8.1/01).
This value is based on reduced maternal food consumption and body weight (-23% of controls) seen at the next higher dose.
The choice of this value is also supported by the rabbit developmental toxicity study, in which increased mortality and reduced bodyweight with associated reduced food consumption were seen at the same level of doses.
The absorption rate following administration in the diet for females is 4%.
Hence,internal NOAEL is 0.52 mg a.s./kg bw/day
The default assessment factors are 10 for inter-species variation and 10 for intraspecies variation in the case of the systemic effects.
The inter-species factor consists
of 2.5 for toxicodynamic- and 4.0 for toxicokinetic variability, while the interindividual factor consists of 3.2 for toxicokinetic and 3.2 for toxicodynamic variability.