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An assessment report on the use of Copper (II) hydroxide as a wood preservative, focusing on its toxicity to target organisms (fungi and insects) and non-target organisms (aquatic and soil species), as well as its environmental risks. The report includes data on acute and chronic toxicity, resistance, and normalization of copper concentrations.
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Purpose of the assessment report
This assessment report has been developed and finalised in support of the decision to include copper (II) hydroxide in the Annex I of Directive 98/8/EC for product-type 8.
The applicant is not currently placing nano forms of copper hydroxide on the market. Therefore, the submitted dossier and the finalised assessment report don't cover potential nanoforms of this copper compound, should such forms exist.
The aim of the assessment report is to facilitate the authorisation in Member States of individual biocidal products in product-type 8 that contain copper (II) hydroxide. In their evaluation, Member States shall apply the provisions of Directive 98/8/EC, in particular the provisions of Article 5 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 at the Commission website^3 , shall be taken into account. However, where conclusions of this assessment report are based on data protected under the provisions of Directive 98/8/EC, such conclusions may not be used to the benefit of another applicant, unless access to these data has been granted.
Overall conclusion in the context of Directive 98/8/EC
The overall conclusion from the evaluation is that it may be expected that there are products containing copper hydroxide for the product-type 8, which will fulfil the requirements laid down in Article 5 of Directive 98/8/EC. This conclusion is however subject to: i. compliance with the particular requirements in the following sections of this assessment report,
ii. the implementation of the provisions of Article 5(1) of Directive 98/8/EC, and
iii. the common principles laid down in Annex VI to Directive 98/8/EC.
Furthermore, these conclusions 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 Article 5(1) and of the common principles laid down in Annex VI to Directive 98/8/EC.
(^3) http://ec.europa.eu/comm/environment/biocides/index.htm
The main identity and the physical/chemical properties of Copper hydroxide are given in Appendix 1 (Listing of endpoints). The active substance shall comply with the specification given in Appendix 1 of this report.The evaluation has established that for the active substance notified by Spiess-Urania, traces of metals of toxicological concern (arsenic, cadmium and lead) were identified among the manufacturing impurities.
The applicant is not currently placing nano forms of copper hydroxide on the market. Therefore, the submitted dossier and the finalised assessment report don't cover potential nanoforms of this copper compound, should such forms exist.
2.1.1 Identity, physico-chemical properties of the active substance
The active substance as manufactured is copper dihydroxide Cu(OH) 2 (CAS-No_._ 20427-59-2) with a minimum purity of 96.5%. It is also known as copper (II) hydroxide or copper hydroxide. The active substance is cupric ion Cu2+, released from copper hydroxide. Traces of metals of toxicological concern (arsenic, cadmium and lead) were identified among the manufacturing impurities.
The source of copper hydroxide submitted in the dossier is accepted. See the confidential part for the specifications. However, to confirm the data presented in the dossier, a new 5-batch analysis is required at the product authorization stage to check the compliance of current production to these specifications.
Copper hydroxide is a odourless light blue powder. It has a relative density of 3.98 and decomposes above 200°C before melting. It is not volatile (its vapour pressure has been theoretically assessed to be < 1.0 × 10–5^ Pa). Solubility in water is pH dependant and increases with acidic concentrations due to release of cupric ion. It does not have any flammable, explosive or oxidising properties.
An adequate analytical method is available for the determination of copper. As the method was collaborately validated and is very widely used, limited validation data were accepted. It must be highlighted that methods of analysis for the relevant impurities were not provided and must be provided before the product authorization stage.
The analyses of copper in environmental matrices and body fluids and tissues are routinely performed in many laboratories. As these methods were collaborately validated and are very widely used, they were accepted but validation data must be provided before the product authorization stage.
2.1.2 Identity, physico-chemical properties of the biocidal product
The trade name of the biocidal product is “SPU-01860-F”. It contains 15.8% of copper hydroxide (10.3% of cupric ion).
The biocidal product is a dark lilac liquid with a fishy odour. Its pH is basic (pH = 10.9). It has a density of 1.128 g/mL. It has neither explosive nor oxidising properties. It has a flash point of 43°C and an auto-ignition temperature of 385°C.
2.1.3 Intended use and efficacy
Field of use / Function/ Mode of action
o Field of use
Product type 8 (PT): wood preservative
Copper hydroxide is intended to be used as a preventive wood preservative for wood in Use class 1, 2,
3 4-1 as defined in the EN 335^4
The active substance is restricted to industrial use only, in timber treatment plants operated by trained personnel. The representative biocidal product presented in this dossier (SPU-01860-F) is supplied as a liquid, water-miscible wood preservative concentrate and is applied by vacuum pressure or by dipping.
The representative biocidal product in this dossier (SPU-01860-F) is an amine copper product; copper hydroxide for wood preservatives is used solely in combination with other active substances. Therefore, no efficacy data with copper hydroxide as sole exist. The formulated concentrated wood preservative SPU-01860-F contains 10.3% copper and some QAV’s.
The use concentration for vacuum pressure treatment proposed in the dossier is from 1% up to max. 4 % of the product SPU-01860-F in aqueous solution, and for dipping treatment from 5% up to max. 15% of the product SPU- 01860 - F in aqueous solution.
o Function
The active substance Copper (II) hydroxide acts as a fungicide and as an insecticide use for preventive wood preservation (product type 8).
o Mode of action
As the active substance is the Cu2+^ ion, copper hydroxide is therefore described as the precursor to release of the cupric ion. As a consequence, most copper-containing formulations are described in terms of total copper.
Fungi: It is considered that the fungicidal properties of copper compounds are dependent on the affinity of the copper ion (Cu2+) for different chemical groups within cells, particularly thiol groups, resulting in the non-specific denaturation of proteins and enzymes. In addition, it is thought that the ion can interfere with the activity of the pyruvate dehydrogenase system inhibiting the conversion of pyruvate to acetyl CoA within mitochondria. Copper reacts with most essential elements within a cell. It also reacts with ligands on the cell surface and this can interfere with membrane function. Copper may also act extra- cellulary in the case of fungi and inhibit the production of fungal extracellular enzymes.
Insects: Copper in toxic doses acts as a stomach poison.
Objects to be protected, target organism
The fact is that no single active substance based wood preservative formulations are placed on the market because of the range of organisms to be controlled. As the exact composition of a formulation
(^4) Since 2007 and the revision of the EN335-1, use classes had replaced hazard classes.
depends on the end use of the treated timber, a reading across of data had to be done in assessing the efficacy of the active substance.
Copper efficacy was examined for the following target organisms:
Application mode Target organism Active substances rate
Vacuum pressure timber impregnation and dipping
Fungi:
Wood rotting basidiomycetes and soft rot fungi
Insects:
Wood boring beetles
Although the request of the applicant for a target concentration at 0.5 kg Cu2+/m^3 (claimed in the dossier), the evaluation based on the trials produced showed a minimum target concentration at 1.29 kg Cu2+/m^3 sapwood loading (12.5 kg SPU- 01860 - F per m^3 wood) (EN113+EN84).
Please note that these data do not take into account the expected service life of wooden elements treated with copper based product and should be considered as an indicator only.
Resistance
According to the data submitted, no development of resistance from the target fungi has been reported, knowing that there are strains of some species of wood destroying fungi that exhibit tolerance to copper. Additional biocides are used where necessary to control copper-tolerant strains of fungi.
According to the data submitted, the applicant, no formation of resistance has to be expected regarding target insects. There is no evidence of insects being naturally tolerant or being able to develop resistance to copper at the level of copper used for biocidal purposes in wood preservation.
Biocidal product
Directive 67/548/EEC Class of danger: (^) Xn - Harmful, N - Dangerous to the environment Risk phrases: (^) R10: Flammable R20/21/22: Harmful by inhalation, in contact with skin and if swallowed R37/38: Irritating to respiratory system and to skin R41: Risk of serious damage to eyes R50/53: Very toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment Safety phrases: S22: Do not breathe in dust S25: Avoid contact with eyes S 26: In case of contact with eyes, rinse immediately with plenty of water and seek medical advice S37/38: Wear suitable gloves and eye/face protection S45: In case of accident or if you feel unwell, seek medical advice immediately (show the label where possible) S57: Use appropriate container to avoid environmental contamination S60: This material and its container must be disposed of as hazardous waste S61: Avoid release to the environment. Refer to special instructions/safety data sheets Regulation 1272/ Classification and hazard statements (^) Flam; Liq. 3/H226 - Flammable liquid and vapour Acute Tox. 4/H302/312/332 - Harmful if swallowed / in contact with skin / if inhaled STOT Single 3/H335 - May cause respiratory irritation Skin Irrit. 2/H315 - Causes skin irritation Eye Dam. 1/H318 - Causes serious eye damage Aquatic chronic/H410 - Very toxic to aquatic life with long lasting effects
2.2.1 Human health risk assessment
2.2.1.1 Hazard identification and effects assessment
Foreword
Copper is an essential metal for life and is employed in all human cells. The main daily dietary intake for copper in adults ranges between 1.5 and 3 mg/person/day of copper. Most human diets naturally include between 1 and 2 mg/person/day of copper, with some containing up to 4 mg/person/day
Copper is regulated by a homeostatic mechanism. Homeostasis can be described as the maintenance of a constant internal environment in response to changes in internal and external environments. Homeostatic maintenance requires the tightly coordinated control of copper uptake, distribution and efflux in cells and the organism as a whole. The ability of the body to control the uptake and excretion of copper makes this an important factor in considering the exposure and effects of essential elements like copper.
Copper is involved in the reactions and functions of many enzymes, including angiogenesis, neurohormone release, oxygen transport and regulation of genetic expression. In this scope, copper hydroxide can be considered as a precursor, releasing cupric ion, which is the actual active substance. This explains that, while several endpoints were documented by studies directly performed with copper hydroxide (acute toxicity, skin and eye irritation, sensitisation), other endpoints were documented by other copper salts (mainly copper sulphate).
In mammalian toxicity, it is also considered that the most toxic moiety of any copper salt is the Cu2+ ion. This can be shown through the comparison of the most soluble salt (copper sulphate) with other relatively insoluble copper salts, where the solubility, bioavailability and hence toxicity of these salts can vary – with copper sulphate representing the worst-case scenario. When the acute oral toxicity of this salt is compared with copper hydroxide, the data indicate that copper sulphate is more toxic and thus more bioavailable. Therefore all the properties described below for copper will also be applicable to copper hydroxide.
This has also been confirmed in comparative bioavailability studies where copper sulphate was shown to be more or equally bioavailable in relation to the copper carbonate in poultry and swine. Moreover, as presented in the table below ( Table 2.2.1.1-1 ) the Copper sulphate is more toxic than the other copper compounds, and then using studies performed with copper sulphate could be considered as a worst-case.
Table 2.2.1.1-1: Comparative toxicity of the different Copper Salts
Copper salts Solubility^
Acute toxicity (LD 50 ) Irritation oral dermal
CuSO 4 317 g/L 482 mg/kg >1000mg/kg R36/
CuCO 3 1,5 mg/L 1400 mg/kg >2000mg/kg NC*
CuO 0,3 mg/L >2000 mg/kg >2000mg/kg NC*
Cu(OH) 2 6.6μ/L 763 mg/kg >2000mg/kg R
*NC: No Classification
Consequently, it is considered appropriate to adopt a conservative approach and read-across from copper sulphate to basic copper carbonate, recognising that this may result in over-estimation of effects of less bioavailable soluble substances.
Toxicokinetics
Absorption
Oral absorption of copper has been investigated in human volunteer studies. Absorption of copper occurs primarily in the small intestine. Oral absorption rates have been shown to vary between 12.4 % for subjects with high copper diet and 55.6 % for subjects with a low-copper diet. Absorption rate for subjects with adequate diet is 36 %. Rats have been shown to absorb 30 to 50 %, although studies in rats have also shown that absorption can be reduced to 10 % at high dietary intakes, as in humans (A6.2/01). Based on these studies, an oral absorption factor of 36 % is used in risk characterisation for humans and 25 % for animals. These values were agreed at the TMIII08.
Quantitative in-vitro measurements of human percutaneous copper absorption have been in the range 0.66 to 5.04% of the applied dose. For the purpose of risk assessment, a percutaneous absorption level
Repeated-dose toxicity
With regard to oral repeated dose toxicity, the 90-day dietary study (A6.4.1/01-02) was considered to be the pivotal study for Cu2+^ presented as copper sulphate pentahydrate. Based on kidney damages, consisting in an increase of cytoplasmic protein droplets, a NOAEL of 1000 ppm (16.3 and 17. mgCu/kg bw/day in male and female rats respectively) was determined. Other findings such as liver inflammation and lesions of the forestomach were also reported at 2000 ppm and above (corresponding to doses from 34 mgCu/kg bw/day). These NOAEL of 16.3 mg/kg bw/d was used for the risk characterisation.
There were no dermal repeated dose toxicity studies. However, these studies are not required considering the ability to read-across from the above oral study. Moreover, due to the lack of toxicity observed in the acute dermal toxicity of copper hydroxide and the weak rate of dermal penetration, a toxic effect is not expected.
For repeated-dose toxicity, it was considered that due to the low inhalation exposure during the use of copper-containing wood preservative products, no sub-acute, sub-chronic and/or chronic inhalation studies was necessary.
Mutagenicity
In vitro tests There was no evidence of mutagenic activity in Salmonella typhimurium strains in the presence or absence of the metabolic activation system when tested with copper sulphate pentahydrate (A6.6.1). Although limited, these in vitro data were deemed sufficient and no further in vitro assays were required, considering the results of the in vivo tests.
In vivo tests In vivo studies, conducted with copper sulphate pentahydrate, induced neither micronuclei in the polychromatic erythrocytes from the bone marrow of mice (A6.6.4), nor DNA damage in a rat hepatocyte UDS assay (A6.6.5). Equivocal results of additional in vivo genotoxicity studies from the public domain (Bhunya and Pati, 1987; Agarwal et al ., 1990; Tinwell and Ashby, 1990), but these studies do not meet the higher reliability criteria (1 or 2) under the BPD.
Copper is therefore considered as non genotoxic.
Carcinogenicity
No carcinogenic potential of copper sulphate was detected in rats and mice. However, all available data are of limited value to evaluate the carcinogenic potential of copper compounds. Study durations are in particular too short (<2 years) and group sizes are small for drawing formal conclusions. However, due to the lack of genotoxicity and considering that the expected level of exposure (as described in paragraph 2.2.1.2) is significantly lower than the usual dietary intake of copper (2- mg/day), there is no need to conduct new carcinogenicity studies according to OECD guideline 451/453.
Reproductive toxicity
Developmental toxicity
Copper administered as copper hydroxide was not teratogenic in rats, mice and rabbits treated during the phase of organogenesis (A6.8.1/04-05). In rabbits, a decreased food consumption and body weight loss occurred in dams receiving 9 mg Cu/kg bw/day. An increased incidence of a common skeletal variant was also observed in foetuses of dams administered with 9 mg Cu/kg bw/day. The NOAEL for
maternal and developmental effects was established at 6 mg Cu/kg bw/day for rabbits and at 30 mg/kg bw/day for rats and mice.
Fertility
According to the two-generation oral reproduction study in rats administered with copper sulphate (A6.8.2/06), the NOAEL for reproductive toxicity for parental males was 1500 ppm (the highest concentration tested corresponding to 23.6 mg/kg bw/d), The NOAEL for parental females was only 1000 ppm (15.2-35.2 mg/kg bw/d), based on the reduced spleen weight at 1500 ppm. This reduction also occurred in F1 and F2 generations at the same dose level in both males and females. However the reduced spleen weights were not considered a reproductive endpoint as it did not affect growth and fertility.
Therefore as the results of this study do not indicate specific reproductive toxicity at the highest dose level tested, it is proposed that copper sulphate and copper hydroxide should not be classified as reprotoxic compounds.
Table 2.2.1.2-1: Summary of exposure estimates for industrial workers during industrial dipping of wood
Industrial dipping (including mixing and loading, and post-application) Users : Trained industrial workers Frequency : 5 cycles/day, 2.5 hours/day, daily Model : TNsGs Dipping model 1
Tier - PPE
Inhalation exposure Dermal exposure Total exposure Inhaled uptake mg as/day
Systemic dose mg as/ kg bw
Deposit on skin mg as/day
Systemic dose mg as/ kg bw
Systemic dose mg as/ kg bw Tier 1 : gloves, minimal clothing, no RPE
4.83 x 10-^2 8.05 x10-^4 621.17 5.18 x10-^1 5.18 x10-^1
Tier 2 : gloves, protective clothing, no RPE
4.83 x 10-^2 8.05 x10-^4 141.64 1.18 x10-^1 1.19 x10-^1
Table 2.2.1.2-2: Summary of exposure estimates for industrial workers during vacuum-pressure impregnation of wood
Vacuum-pressure impregnation (including mixing and loading, and post-application) Users : Trained industrial workers Frequency : 3 cycles/day , 5 hours/day, daily Model : TNsGs handling model 1
Tier - PPE
Inhalation exposure Dermal exposure Total exposure Inhaled uptake mg as/day
Systemic dose mg as/ kg bw
Deposit on skin mg as/day
Systemic dose mg as/ kg bw
Systemic dose mg as/ kg bw Tier 1 : gloves, minimal clothing, no RPE
4.89 x 10-^2 8.15 x 10-^4 119.27 9.94 x 10-^2 1.00 x 10-^1
Tier 2 : gloves, protective clothing, no RPE
4.89 x 10-^2 8.15 x 10-^4 26.06 2.17 x 10-^2 2.25 x 10-^2
Secondary exposure
The secondary human exposure estimates consider the potential for the exposure of adults (workers and consumers), infants and children in which they may come into contact with copper treated timber.
Results of the exposure assessment are reported in the following table:
Table 2.2.1.2-3: Summary of estimates for indirect exposure scenarios Scenario Route Estimate * PPE Uptake mg as/day
Systemic dose mg as/ kg bw
Adults (professional) - Chronic
Handling, cutting and sanding treated timbers
inhalation
1 None RPE
dermal
2 None Gloves
TOTAL
2 None RPE +
Adults (consumers) - Acute
Handling, cutting and sanding treated timbers
inhalation 1 None 0.163 0. dermal 2 None 0.17 0. TOTAL 2 None 0.33 0. Children – Chronic Playing on playground structure outdoors
dermal 2 None 0.08 0.
Infants - Chronic Playing on playground structure outdoors and mouthing
dermal 2 None 0.08 0.
oral 2 None 0.10 0.
TOTAL 2 None 0.18 0. Infants - Acute Chewing preserved timber off-cuts
oral 2 None 0.096 0.
*: The different estimates are due to refinements used for the estimation of the dislodgeable copper concentration. Estimate 1 = 68μg/cm² (unrealistically conservative). Estimate 2 = 2μg/cm². Only the more relevant estimate for each scenario/route is reported here. The use of PPE (protective gloves and mask) is considered additionally only for professional users.
2.2.1.3 Risk characterisation for human health
The human health risk characterisation is performed using both the AEL and the MOE approaches.
AELs determination
For each exposure scenario, an appropriate AEL is determined on the basis of the exposure frequency. Accordingly, three types of AELs are classically derived: AELshort-term, AELmedium-term and AELlong-term corresponding to short-, medium- and long-term exposures respectively. AELs are usually derived by applying the following formula:
Assessment factors
In the case of copper hydroxide, all AELs (AELshort-term, AELmedium-term and AELlong-term) were derived on the basis of the NOAEL of 1000 ppm, corresponding to 16.3 mgCu/kg bw/day obtained in the 90-day oral rat study with copper sulphate (A6.4.1). An oral absorption rate of 25% was taken into account for calculating the systemic NOAEL as follows: NOAELsystemic 16. 3 x 0. 25 4. 1 mgCu / kgbw / d
Table 2.2.1.3-1: Summary of risk assessment after assessment factors refinement for professional users during long-term exposure
Exposure scenario
systemic total dose [mgCu/kg bw/day]
MOEref AEL long-term % AEL MOE
Industrial uses – Primary exposure, dipping process
All phases of exposure : Tier 1 (mixing and loading + application + post- application)
5.18 x10-^1 100 0.041 (^) 1263 7.
All phases of exposure : Tier 2 (mixing and loading + application + post- application)
1.19 x10-^1 100 0.041 290 34.
Industrial uses – Primary exposure, simple vacuum pressure impregnation process
All phases of exposure : Tier 1 (mixing and loading + application + post- application)
1.00 x 10-^1 100 0.041 244 41
All phases of exposure : Tier 2 (mixing and loading + application + post- application)
2.25 x 10-^2 100 0.041 55 182
The % of AEL in the first tier assessment during long-term exposure is >100 and the MOE is <100 for the “dipping process application scenario with handling model 1” and the “simple vacuum pressure impregnation process”. However, this tier does not take into account the Personal Protective Equipment (PPE). When PPE (protective clothing and new gloves) are worn, it can be seen that the % of AEL and MOE are acceptable for the “simple vacuum pressure impregnation process” but is still unacceptable for the “dipping process”^6.
Conclusion : the risk for industrial or professional users under the conditions specified above is not acceptable for the “dipping process” whereas the risk is acceptable for the simple-vacuum process when PPE are worn.
Non-professional users
The biocidal product is foreseen to be used by trained professionals only. Thus, a risk characterisation for non-professionals is not relevant.
Risk characterisation for secondary (indirect) Human Exposure
The %AELs and the Margins of Exposure (MOE) were calculated for secondary exposure scenarios as reported in the tables below:
(^6) Even when assuming that industrial users, wearing PPE, would be acutely exposed, the risk remains unacceptable (%AEL = 145%, MOE = 34.4).
Table 2.2.1.3-2: Summary of risk assessment for secondary exposure
**Scenario Exposurepath Estimate *** (^) mg as / kg bwSystemic dose MOEref MOE
AEL (mgCu/ kg bw/d)
Expo as % AEL
Adults (professional) - Chronic Handling, cutting and sanding treated timbers
Inhalation and dermal
2 RPE + gloves
100
1464
14636
6.
0.
Adults (consumers) – Acute Handling, cutting and sanding treated timbers
Inhalation and dermal
2 0.0028 50 1464 0.082 3.
Children - Chronic Playing on playground structure outdoors
dermal 2 0.00027 100 15185 0.041 0.
Infants – Chronic Playing on playground structure outdoors and mouthing
Dermal and oral
2 0.0040 100 1025 0.041 9.
Infants - Acute
Chewing preserved timber off- cuts
oral 2 0.0035 (^50) 1171 0.082 (^) 4.
*: The different estimates are due to refinements for the estimation of the dislodgeable copper concentration. Estimate 1 = 68μg/cm² (unrealistically conservative). Estimate 2 = 2μg/cm².Only the more relevant estimate for each scenario/route is reported here. The use of PPE (protective gloves and mask) is considered additionally only for professional users. For all these scenarios, %AEL and MOE values show that no unacceptable risk are anticipated for people secondarily exposed.
Overall assessment of the risk for the use of the active substance in biocidal products
Application of copper hydroxide as an approx. 0.4 % aqueous solution (elemental copper) in preventive wood protection (dipping/immersion and vacuum pressure process) is considered to induce an unacceptable risk for professional facility workers on Tier 1 level except for one scenario “cutting and sanding”. Higher tier (Tier 2) reflecting actual measures of occupational safety further reduce any potential hazards and result in a satisfactory protection level for workers for the “simple vacuum pressure impregnation process” but the “dipping process” still represents an unacceptable risk for workers even if PPE are worn long-term exposure.
Secondary (indirect) human exposures are considered to be devoid of unacceptable risk.
