dmdm hydantoin (dmdmh) product-type 13 (metalworking fluids) - public/library... · directive...

Directive 98/8/EC concerning the placing biocidal

products on the market

Inclusion of active substances in Annex I or IA to Directive 98/8/EC

Competent Authority Report This non-confidential version of the Evaluation Report for DMDMH has been produced by the

participant after evaluation of the RMS. The amendments made have not been validated by the

RMS. Therefore the confidential version is the only valid version of the report.

DMDM Hydantoin (DMDMH)

Product-type 13

(Metalworking Fluids)

Rapporteur Member State: Poland

Draft - June 2010

1. STATEMENT OF SUBJECT MATTER AND PURPOSE .................................................................................. 4

1.1 BACKGROUND OF THIS EVALUATION REPORT AND PURPOSE .................................................................................. 4

2. OVERALL SUMMARY AND CONCLUSIONS .............................................................................................. 5

2.1 PRESENTATION OF THE ACTIVE SUBSTANCE ......................................................................................................... 5

2.1.1 Identity, Physical‐Chemical Properties and Method of Analysis ..................................................... 5

2.1.1.1 Physical‐chemical properties ................................................................................................................. 5

2.1.1.2 Analytical Methods ................................................................................................................................ 6

2.1.2 Intended uses and Efficacy .............................................................................................................. 6

2.1.3 Classification and Labelling ............................................................................................................. 7

2.2 SUMMARY OF THE RISK ASSESSMENT ................................................................................................................. 8

2.2.1 Human Health Risk Assessment ...................................................................................................... 8

2.2.1.1 Hazard characterisation ........................................................................................................................ 8

2.2.1.1.1 DMDMH ........................................................................................................................................... 8

2.2.1.1.2 DMH ................................................................................................................................................. 9

2.2.1.1.3 Formaldehyde ................................................................................................................................ 10

2.2.1.1.4 Biocidal product ............................................................................................................................. 11

2.2.1.2 Professionals ....................................................................................................................................... 12

2.2.1.2.1 Risk assessment at the workplace .................................................................................................. 12

2.2.1.2.2 Risk assessment as a result of the use of the biocidal product ...................................................... 13

2.2.1.3 Non‐Professionals................................................................................................................................ 15

2.2.1.4 Indirect exposure as a result of use of the active substance in biocidal product ................................ 15

2.2.1.5 Combined exposure ............................................................................................................................ 15

2.2.2 Environmental Risk Assessment .................................................................................................... 16

2.2.2.1 Fate and Distribution in the Environment ........................................................................................... 16

2.2.2.1.1 Biodegradation ............................................................................................................................... 16

2.2.2.1.2 Abiotic Degradation ....................................................................................................................... 16

2.2.2.1.3 Distribution and Mobility ............................................................................................................... 17

2.2.2.1.4 Bioaccumulation ............................................................................................................................ 17

2.2.2.2 Effects Assessment .............................................................................................................................. 17

2.2.2.2.1 Aquatic Compartment .................................................................................................................... 17

2.2.2.2.2 Terrestrial Compartment ............................................................................................................... 18

2.2.2.3 PBT Assessment ................................................................................................................................... 18

2.2.2.4 Exposure Assessment .......................................................................................................................... 18

2.2.2.5 Risk Characterisation ........................................................................................................................... 20

2.2.2.5.1 Aquatic compartment including STP .............................................................................................. 20

2.2.2.5.2 Terrestrial Compartment ............................................................................................................... 21

2.2.3 Listing of Endpoints ....................................................................................................................... 21

3. PROPOSAL FOR THE DECISION ............................................................................................................ 22

3.1 BACKGROUND TO THE PROPOSED DECISION ...................................................................................................... 22

3.2 PROPOSED DECISION REGARDING THE INCLUSION IN ANNEX I ............................................................................... 22

Doc I - Competent Authority Report

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3.3 ELEMENTS TO BE TAKEN INTO ACCOUNT BY MEMBER STATES WHEN AUTHORIZING PRODUCTS .................................... 22

3.4 DEMAND FOR FURTHER INFORMATION ............................................................................................................. 23

3.5 UPDATING THIS ASSESSMENT REPORT .............................................................................................................. 23

APPENDIX I – LIST OF ENDPOINTS ................................................................................................................ 24

APPENDIX II ‐ LIST OF TERMS AND ABBREVIATIONS ..................................................................................... 52

APPENDIX III ‐ LIST OF ORGANISATIONS AND PUBLICATIONS ........................................................................ 59

DMDM Hydantoin (DMDMH) Product type 13 June 2010

1. STATEMENT OF SUBJECT MATTER AND PURPOSE

1.1 BACKGROUND OF THIS EVALUATION REPORT AND PURPOSE

This report has been established as a result of the evaluation of the biocidal active substance DMDMH in the frame of the Biocides Directive 98/8/EC. The aim of this report is to make available a detailed examination of the dossier of the existing active substance DMDMH and its biocidal product Dantogard (product type 13). The evaluation was performed in the context to the application for the inclusion of the biocidal active substance DMDMH into Annex I of the Directive 98/8/EC in frame of the review program of existing biocidal active substances according to the Commission Regulations (EC) No. 1896/2000 and No. 2032/2003 as amended by Commission Regulation (EC) No. 1048/2005, No. 1849/2006 and 1451/2007.

The evaluation was carried out on the basis of the provisions laid down in Article 6 of Commission Regulation (EC) No 1896/2000, Article 5 and Article 10 of Commission Regulation (EC) No. 2032/2003 and the provisions of Article 5(1) and Article 16(2) of Directive 98/8/EC. The evaluation followed the common principles laid down in Annex VI of Directive 98/8/EC and the Technical Notes for Guidance produced by the other contracts of the Commission and other applicable guidance documents.

The applicant for inclusion of DMDMH into the Annex I of Directive 98/8/EC is Lonza GmbH. DMDMH is manufactured in USA by Lonza Inc. The representative product is the product type 13 Dantogard produced by XXXXXX. The dossier was submitted within the deadline of the C priority list. The dossier was deemed as complete for the evaluation.

The information in this evaluation report is, at least partly, based on information, which are confidential and/or protected under the provisions of Directive 98/8/EC


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2. OVERALL SUMMARY AND CONCLUSIONS

2.1 PRESENTATION OF THE ACTIVE SUBSTANCE

2.1.1 Identity, Physical-Chemical Properties and Method of Analysis

Dimethylol Dimethyl Hydantoin (DMDMH, CAS 6440-58-0) is a formaldehyde releasing preservative agent (PT13) of Dantogard biocidal “dummy” product of Lonza GmbH company. It is manufactured through the reaction of Dimethyl Hydantoin (DMH) with formaldehyde. Dantogard is 70% aqueous solution of DMDMH as a worst case product and it is also active substance “as manufactured”. The minimum purity of solid DMDMH is 90% but active substance “as manufactured” is used for risk assessment. Detailed information on the composition of DMDMH (containing impurities) is submitted in a confidential attachment.

2.1.1.1 Physical-chemical properties

The pure Dimethylol Dimethyl Hydantoin (DMDMH) is a white non-uniform odourless powder with the melting point equal to 90°C. The active substance DMDMH decomposes before boiling at 200 °C. The bulk density of the active substance is equal to 0.4g/cm3. DMDMH is very slightly volatile (its vapour pressure was measured to be 0.000012Pa at 25°C). The active substance is very soluble in polar organic solvent and slightly soluble in non-polar organic solvent. The partition coefficient n-octanol/water is equal to -2.9. The DMDMH is not surface active substance - surface tension of 0.998 g/l solution was found to be 72.4 mN/m at 20°C. It is recognised to be not highly flammable and do not have the self-ignition temperature below the melting point. Based on the structure and experience in use it is concluded that DMDMH do not possess explosive nor oxidising properties. There are no known instances where the packaging with active substance has failed as a result of the contained product.

Due to specific properties of DMDMH (releaser of the active agent - HCHO)

properties of the second degradation product DMH are needed for complete risk assessment and are presented in the table, below.

Property Method Result

Molecular Weight 128.13

Melting point: A1 (DSC) 176°C

Boiling point: A2(DSC) 313°C

Vapour Pressure: A4 (vapour pressure balance) 0.00019 Pa at 20°C 0.00038 Pa at 25°C

Henry’s Law Constant: Calculated 1.74 x 10-7 Pa*m3*mol-1 at 20°C

Solubility in water: A6 (Flask method) 140 g/l at 20.0°C


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Property Method Result Partition coefficient n-octanol /water A8 (Shake flask method) Log Pow = – 0.475 at 22°C

pH = neutral Dissociation constant ACD/I-Lab Web Service 9.19

Solubility in organic solvents MT 181 A6 (Flask method)

Toluene: 0.136 g/l at 20°C

Methanol: 134 - 161 g/l at 20°C

Surface tension A5 (ring method) 71.6 mN/m (1.00 g/l solution)

at 21.0 ± 0.5°C

Oxidizing properties A17 Predicted negative based on structure

2.1.1.2 Analytical Methods

The identification of DMDMH and its impurities MMDMH and DMH can be performed using high performance liquid chromatography (HPLC) method with UV detector.

Since the active substance is hydrolytically unstable the substance which should be controlled in soil and water is DMH. Detection of DMH in soil can be carried out by using HPLC-MS system and was developed to analysis DMH with limit of quantification equal to 0.05 mg/kg.

HPLC-MS method is developed for residue in water with the use of two procedure types:

1. procedure A (500 times enrichment) with Limit of Quantification = 0.5μg/l and,

2. procedure B (2000 times enrichment) with Limit of Quantification = 0.1μg/l.

The active substance DMDMH and degradation product DMH are not considered to be volatile (i.e. vapour pressure ≥ 0.01 Pa) and the proposed use patterns do not indicate a high level of release to air so the method for controlling of their concentration in air is not considered to be needed.

DMDMH and DMH are not classified as toxic or highly toxic, therefore a method for determination in body fluids is not applicable. Additionally the active substance used in the biocidal product in metal working fluids will not have a contact with food and feedingstuffs.

2.1.2 Intended uses and Efficacy

Efficacy tests were performed with Dantogard in a metal working fluid against the following microorganisms:

Escherichia coli Pseudomonas aeruginosa Pseudomonas fluorescens Alcaligenes faecalis Staphylococcus aureus XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX

XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX


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XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX

XXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX

XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX DMDMH have to be consider as bactericidal product only because applicant did not presented studies concerning fungicidal or yeasticidal activity.

2.1.3 Classification and Labelling

Table 2-1 Proposal 1 for classification and labeling of DMDMH

Classification As documented in tests from the Biocidal Dossier

Classification Hazard Category 2, H315, H319

Hazard Category 4, H302, H311

GHS pictogram

Signal Word Warning

Hazard statements “Causes skin irritation”, H315

“Causes serious eye irritation”, H319

“Harmful if swallowed”, H302

“Harmful in contact with skin”, H311

Table 2-2 Proposal 2 for classification and labelling of DMDMH

Classification As documented in tests from the Biocidal Dossier

Classification Hazard Category 2, H315, H319, H351i

Hazard Category 4, H302, H311

GHS pictogram

Signal Word Warning

Hazard statements “Suspected of causing cancer by inhalation”, H351i

“Causes skin irritation”, H315




Elements of classification and labelling marked in red are proposals with which

the applicant disagrees.

For the clarification please see Doc.IIA Chapter 1.5


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2.2 SUMMARY OF THE RISK ASSESSMENT

2.2.1 Human Health Risk Assessment

2.2.1.1 Hazard characterisation

The active substance, DMDMH hydrolyses to DMH and formaldehyde. Long-term toxicity is therefore due to exposure to the degradant DMH (Document I Appendix XIX Justification for long-term testing on DMH).

2.2.1.1.1 DMDMH

DMDMH is harmful by acute oral (LD50 = 1572mg/kg bw) and dermal (LD50 > 1052mg a.i./kg bw) routes.

On the basis of the in vivo eye irritation and 28-day and 90-day dermal studies it can be assumed that DMDMH in the higher concentration is at least irritating to eye. The in vitro eye irritation study (Bovine Corneal Opacity and Permeability Assay – BCOP) that was used could determine the severe irritant or corrosive properties of the substance. This in vitro study can not be used to determine the medium or light irritant properties. Under the condition of this study it could be concluded that DMDMH is not severe irritating or corrosive to the eye. In the light of acute and 28-day and 90-day dermal study there is a probability that DMDMH in the concentration of > 90% could be irritating to eye and skin.

DMDMH is not sensitising to skin. From an experimental perspective, it is not possible to directly address the in

vitro mutagenic potential of DMDMH since the compound hydrolyses to free formaldehyde and DMH in dilute solutions. Accordingly, at the low concentrations in the mutagenicity assays DMDMH is likely to exist as formaldehyde and DMH.

The Ames Test performed on the pure active substance gave a negative result. DMDMH (~50% aqueous solution) was positive in the Ames Test, Cytogenicity Study – Chinese Hamster Ovaries, mouse lymphoma assay and chromosome aberration studies both with and without metabolic activation. However, the positive results are attributed to free formaldehyde formed in the test medium and not to the parent compound itself. The basis for this conclusion is that formaldehyde produces positive results in the same assays (Formaldehyde Releasers Dossier Document IIIA). The other principal hydrolysis product, dimethylhydantoin (DMH), is not mutagenic in either of these assays.

A mouse micronucleus assay and an alkaline elution assay in the rat indicated that the active substance, DMDMH, did not induce mutagenic effects in two different tissues in vivo.

After repeated dose oral toxicity (90 days) study, statistically significant increase in the absolute and relative adrenal weight in high dose males was noted. The NOAEL was assigned as 110mg/kg bw.

Repeated dermal exposure (28 and 90-days) results in no systemic adverse effects but local effects were noted (epidermal inflammation, epidermal necrosis and


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ulceration). The lowest NOAEL local = 4.4mg a.i./kg bw/day. The lowest NOAEL systemic = 440mg a.i./kg bw. These studies have a lot of discrepancies and can not be used for the risk assessment (Reliability 3).

There are no indications of DMDMH neurotoxicity.

2.2.1.1.2 DMH

DMH is not harmful by acute oral exposure (LD50 > 10000mg/kg) or dermal exposure (LD50 > 20000mg/kg bw/day).

DMH is not irritating to skin or eye of rabbits. DMH is not a skin sensitiser (Buehler Test 0/10 responders). DMH was considered as the relevant metabolite available for absorption,

distribution, metabolism and excretion. Up to 97% of the radiolabelled DMH applied via the oral or i.v. routes was excreted in urine and faeces. Approximately 2.6% of the applied dose was not excreted within the observation period.

In the absence of a dermal absorption study a first tier of 100% absorption will be used as a default value.

In the subchronic oral study in rat (13 weeks), at the highest dose (1000mg DMH/kg/day) there was an equivocal decrease in body weight, liver weight and food consumption. The NOAEL was assigned as 1000mg DMH/kg bw/day.

In the sub-chronic dermal study in rat NOAEL was assigned as 390mg/kg bw/day.

In a 2 year chronic study in rat, an equivocal decrease in body weight and

survival was observed at the highest dose (1000mg DMH/kg bw/day). The NOAEL was assigned as 300mg DMH/kg bw/day.

In a 1 year chronic dog study, the highest dose (1000mg DMH/kg bw/day) resulted in small decreases in body weight, increase in adrenal weights and mild hypertrophy in adrenal cortex for males and small decreases in bodyweight for females. The NOAEL was assigned as 300mg DMH/kg bw/day.

Teratogenicity studies in the rat and rabbit on DMH dosed by oral gavage did not produce an overall indication of teratogenicity. The results of all the developmental toxicity studies conducted with DMH and EMH suggest that significant developmental toxicity was limited to the digit defects in the rabbit and not in the rat. The finding in question was only seen at a dose level that was toxic to the adult and the finding was only seen at low incidence.

Lowest NOAEL EMH ADULT 375mg/kg DMH ADULT 500mg/kg

Offspring 500mg/kg Exposure to DMH in the diet for two generations did not result in parental

toxicity or adverse effects on reproductive performance or reproductive tissues at dietary concentrations as high as 20000ppm. However, there were effects (decreased weight gain) in offspring during lactation. Small increases in parental food consumption and body weight and transient decreases in offspring body weight during lactation were observed at the 20000ppm dose level. The NOAEL from the study is for F0 = 1395mg/kg bw/day, with the NOAEL of 379mg/kg bw/day for F1 and F2.

DMH was not mutagenic or clastogenic with and without metabolic activation in a full series of in vitro mutagenicity tests (bacterial and mammalian cell lines).


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DMH did not produce any indication of carcinogenicity in the rat (104 weeks) or the mouse (78 weeks) at up to 1000mg/kg bw/day via oral feed.

There are no indications of DMH neurotoxicity.

2.2.1.1.3 Formaldehyde

Formaldehyde is harmful if swallowed (640mg/kg bw) and toxic in contact with the skin (270mg/kg bw) and by inhalation (about 100mg/kg bw).

Single and unoccluded administration of 1mL/kg bw formaldehyde in water was reported to cause erosion of rat skin during a one week observation period. Upon exposure to formaldehyde in the air, the highly water soluble gas dissolves in epithelial fluids cause local irritation of eyes, nose, throat and lung.

Formaldehyde is a known primary skin sensitiser inducing Type IV allergic contact dermatitis (WHO, 1989; ATSDR, 1999; OECD, 2002). These properties of formaldehyde are confirmed by a large number of tests in laboratory animals.

Oral repeated toxicity has been studied in rats with exposure through the drinking water for 28 days. Local effects in the forestomach and the glandular stomach and decreased plasma levels of albumin and total protein were seen.

Local effects on the epithelia of the respiratory tract were the main findings in rats, mice and cynomolgus monkeys after inhalation repeated exposure. The type of the lesions, squamous metaplasia and hyperplasia, was identical in these three species, indicating comparability of the mechanisms involved.

Positive results in Ames tests in S. typhimurium strains TA97, 98, 100, 102 and 104 suggest that formaldehyde may induce mutations by various mechanisms and independent of metabolic activation. TK and HPRT gene mutation analysis in mammalian cells confirmed this activity. A mechanistic study suggested that mutagenesis by formaldehyde in mammalian cells involves base pair substitutions as well as deletions. This is in accordance with induction of single strand breaks and DNA crosslinks and sister chromatid exchange, micronuclei formations and DNA crosslinks. In these studies, time-dependent repair of the lesions was also reported.

Systemic and local genotoxicity of formaldehyde was evaluated in rodents, monkeys and occupationally exposed humans. It is well established, that DPX can be repaired, but if it is present during DNA replication, clastogenic effects may result. A human cohort study on workers of a plywood factory chronically exposed to concentrations between 0.1 and 0.6µg/L revealed corresponding evidence for clastogenicity in the nasal epithelium in coincidence with histologic abnormalities. Pre- and post-exposure further analysis showed clastogenic (but not aneugenic) effects in students exposed during an embalming course. These effects were more obvious in buccal cells than in cells of the nasal epithelium and high peak exposures of 0.95 to 3.4µg/L were reported (Titenko-Holland et al. 1996). Overall, there is convincing evidence, that formaldehyde exposure can induce local genotoxic effects at the site of contact.

Currently, there is no convincing evidence for carcinogenicity of formaldehyde when administered via the oral route. An acceptable study with exposure of rats through the drinking noted local effects in the forestomach and the glandular stomach. A long-term oral NOAEL of 15mg/kg bw/d (0.026% in drinking water) can thus be derived from the 2-year study in rats. Reconsidering the NOAEL of 25mg/kg bw/d from the 28-days oral rat study and the effects observed at 125mg/kg bw/d, it seems reasonable to assume that the threshold dose for local lesions remains practically constant with time, while the nature of the lesions reflects the progressing


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pathology. Hence, it is proposed to use the long-term NOAEL of 15mg/kg bw/d as an overall value for subacute, subchronic and chronic oral exposure.

In a study over 60 weeks formaldehyde was applied to the back of hairless mice induced a slight hyperplasia of the epidermis and possibly some small skin ulcers at the higher dose level. No treatment-related tumours were detected in the skin or any other organ.

Experimental evidence in rats and mice demonstrates that long-term formaldehyde inhalation causes tumours in the upper respiratory tract from exposure concentrations of 7.2µg/L. The relevance of this effect for human health was recently confirmed by an independent assessment within the IPCS Human Framework for Analysing the Relevance of the Cancer Mode of Action for Humans.

Taking into account the dose-response after subacute, subchronic and chronic inhalation exposure, it can be further concluded that the threshold dose for local lesions remains practically constant with increasing time, while the nature of the lesions reflects the progressing pathology. Hence, an overall inhalation NOAEC of 1.2mg/m3 for local effects based on the 6-months studies in rats and monkeys is derived.

There is no concern for developmental and reproductive toxicity of formaldehyde.

2.2.1.1.4 Biocidal product

The product is specified in the risk assessment as having a 70% concentration of the active substance DMDMH as manufactured. In practice this 70% DMDMH solution will not be ‘stable’ once manufactured. As indicated in Document IIA DMDMH in aqueous solution will undergo an equilibrium reaction releasing free formaldehyde and DMH, the rate of generation of the degradation products being dependent upon thermodynamic forces driving the reaction to the equilibrium. During the product manufacturing process further amounts of DMH have to be added in order to lower the free formaldehyde below the 0.1% as specified.

Due to the equilibrium state of substances in the solution any commercial products will not be formally identified as being a 70% solution of DMDMH. The free formaldehyde concentration in any product is always at a level of < 0.1% in solution with the efficacy of the product based on the biocidal activity of the whole equilibrium solution.

The product specified in Document IIIB has been characterised as a ‘dummy product’ due to the above issue with stability but, for purposes of the evaluation and the Annex I inclusion for the active substance, use of a product containing 70% DMDMH does present a ‘worst case’ scenario with the appropriate highest possible concentrations of DMH and formaldehyde formed during the degradation being considered for human health and environmental risk assessment.

Trade name: Dantogard Ingredient of preparation: Function: Content:

DMDMH Biocide for metal working fluids 70%

Ingredient of preparation: Function: Content:

Water Solvent 30%

Ingredient of preparation: Function:

Formaldehyde Chemically equivalent by-product


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Trade name: Dantogard Content <0.1% Physical state: Liquid Nature of preparation: Aqueous solution Table 2-3 Identification of the product

Product type Field of use envisaged

Concentration of Dantogard

(%)

Likely conc. at which a.i will be used

Conc. of DMH

Conc. of formaldehyde

13 Water-based

metal working fluids

XXX XXX XXX XXX

2.2.1.2 Professionals

2.2.1.2.1 Risk assessment at the workplace

Risk assessment during manufacture and formulation The active substance is manufactured in the USA and the formulation of the

70% DMDMH solution (Dantogard) is formulated at a single site in Germany and is an intrinsic part of the manufacture and therefore is regarded as manufacture rather than formulation. Dantogard is the end product of a process which includes the reaction stage, and is carried out in an enclosed system.

The active substance, DMDMH is produced in a closed system. However, there is potential exposure to DMH dust while filling the reactor with the DMH powder.

Table 2-4 Summary of exposure estimates to professionals during manufacture of DMDMH (Dantogard)

Exposure DMH mg/kg/day Formaldehyde

Dermal negligible not applicable (close system)

Inhalation 0.0313 not applicable (close system)

Table 2-5 Risk characterisation for inhalation exposure during manufacture of DMDMH (Dantogard)

Task Exposure

(mg/kg bw/d)

AEL (mg/kg bw/d)

%AEL

(exposure/AEL x 100%)

MOE (NOEL/Exposure)

Filling DMH powder into the reactor system 0.0313 3.0 1.04 9854



At the conclusion there is no concern for industrial workers during the Dantogard formulation process with respect to inhalation, dermal or oral exposure to DMH. There is no concern from inhalation dermal or oral exposure to formaldehyde.

2.2.1.2.2 Risk assessment as a result of the use of the biocidal product

Professional operators will undertake dilution of the Dantogard into the metal working fluid as well as all application and maintenance tasks relating to use of metal working fluid.

The most relevant routes are the dermal and inhalation routes as workers will be exposed during dilution of the product and during use of the metal working fluid.

Table 2-6 Summary of exposures from PT13 professional use

Exposure DMH mg/kg bw/day Formaldehyde

Diluting Dantogard into the metal working fluid with full PPE (47% DMH, 15min)

inhalation 1.16 × 10-2 3.9 × 10-3mg/m3

dermal 1.4 × 10-2 3.0 × 10-5mg/kg bw/day

Daily exposure from use in the metal working facility (0.17% DMH, 120min)

inhalation 1.34 × 10-5 1.3 × 10-3mg/m3


Maintenance of the metal working fluid machinery (0.17% DMH, 240min)

inhalation 2.68 × 10-4 1.3 × 10-3mg/m3


The AELlong–term are used for risk characterisation. There is no concern if

exposure is ≤ 100% of the AEL. An exposure level of 0.1ppm (AEC = 0.12mg/m3) is supposed to be a “safe

level” for human inhalation exposure to formaldehyde and is recommended to protect the whole population and is therefore used for risk characterisation to formaldehyde inhalation exposure.

Table 2-7 Risk characterisation to DMH

Task Exposure

(mg/kg bw/d) AEL

(mg/kg bw/d)

%AEL


MOE (NOEL/exposure)

Dermal exposure Diluting Dantogard into the metal working fluid with full PPE (47% DMH, 15min)

1.4 × 10-2 3.0 0.48 2.1 × 104


1.3 × 10-1 3.0 4.3 2.3 × 103


2.6 × 10-1 3.0 8.5 1.1 × 103


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Inhalation exposure Diluting Dantogard into the metal working fluid with full PPE (47% DMH, 15min)

1.16 × 10-2 3.0 Effectively 0 2.6 × 104


1.34 × 10-5 3.0 Effectively 0 2.2 × 107


2.68 × 10-4 3.0 Effectively 0 1.1 × 106

There is no concern for professionals from inhalation exposure to DMH whilst working with a metalworking machine and during dilution of the product into the metal working fluid. The very low vapour pressure of DMH means that the levels of active substance in the atmosphere will always be low. Additionally, the machines should have good extraction to remove any mist formed (effectively this is risk mitigation in place).There is no need to perform a tier 2 assessment as the %AELs are considered negligible. It is, however, still advisable to wear appropriate PPE to further minimise exposure. Also if the ventilation is deemed inadequate this should be reported to the Health and Safety Manager.) Table 2-8 Risk characterisation of dermal exposure to formaldehyde

Task Exposure

(mg/kg bw/d) AEL

(mg/kg bw/d)

%AEL


MOE (NOEL/exposure)

Dermal exposure Diluting Dantogard into the metal working fluid with full PPE (0.1%)

3.0 × 10-5 0.15 Effectively 0 5.0 × 105

Daily exposure from use in the metal working facility (120min) 6.1 × 10-2 0.15 40.6 2.5 × 102

Maintenance of the metal working fluid machinery (240min)

1.2 × 10-1 0.15 80.4 1.2 × 102

Table 2-9 Risk characterisation of inhalation exposure to formaldehyde

Task Exposure (mg/m3)

AEC (mg/m3)

%AEC (exposure/AEC x

100%)

MOE (NOEL/exposure)

Diluting Dantogard into the metal working fluid (0.1%) 3.9 × 10-3 0.12 3.25 3.1 × 102

Exposure from use in the metal working facility 1.3 × 10-3 0.12 1.05 9.5 × 102

There is no concern for the professional worker with respect to dermal

exposure to formaldehyde when using the machine or when diluting Dantogard into the tank as the %AEL ≤ 100% for all scenarios.

There is no risk to workers during dilution of Dantogard (70% solution) into metal working fluids. There is no concern for the professional workers in the metal working facility area as the formaldehyde concentration is predicted to be comfortably below the “safe level” for human inhalation exposure (0.12mg/m3).


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However, it is still recommended that care is always taken to ensure that the extraction systems are working correctly on metalworking machines and that if necessary any problem is reported to the Health and Safety Manager.

2.2.1.3 Non-Professionals

The Dantogard in PT13 is recommended to use only by the professional users.

2.2.1.4 Indirect exposure as a result of use of the active substance in biocidal

product

The TNsG give the secondary exposure scenario as adult dermal chronic, whilst doing home laundry of work clothes.

Formaldehyde is very volatile. It is not expected to be present on the work clothes by the time they reach home. For this reasons the dermal risk characterization was done.

Table 2-10 Risk characterisation for indirect exposure to DMH

Exposure Exposure

(mg/m3) AEL

%AEL


MOE (NOEL/exposure)

Chronic dermal Adult doing laundry of work clothes 1.4 × 10-2 3.0 0.46 2.1 × 104

For the purposes of risk assessment a worst case exposure has been considered

for workers exposed for 240min during maintenance tasks for both DMH and formaldehyde. As cleaners will not have this level of exposure it is not considered necessary to include the exposure scenarios for indirect exposure to cleaners via dermal and inhalation routes.

There will be no concern for indirect exposure to cleaners to DMH or formaldehyde.

2.2.1.5 Combined exposure

For determination of combined human exposure estimates a common-sense approach would be to determine exposure for the following scenario:

The professional worker performing the maintenance tasks (longest exposure) and washing clothes at the end of the day. Combined exposure to DMH is considered.


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Table 2-11 Combined exposure to DMH

Combined exposure Exposure

(mg/kg bw/d) AEL

%AEL


MOE (NOEL/exposure)

Inhalation and dermal routes 2.7 × 10-1 3.0 9.1 1.1 × 103

2.2.2 Environmental Risk Assessment

2.2.2.1 Fate and Distribution in the Environment

2.2.2.1.1 Biodegradation

DMDMH is readily biodegradable. However due to the rapid hydrolysis of DMDMH degradants: DMH and formaldehyde are considered to be the substances of interest.

DMH is readily biodegradable and is quite fast degraded in a water/sediment degradation study with t½ = 17.45 – 19.95 days, (t½ = 33.1-37.9 days after conversion to average EU outdoor temperature 12°C).

Formaldehyde is readily biodegradable failing 10-days window.

2.2.2.1.2 Abiotic Degradation

DMDMH is hydrolytically unstable at pH 7 and pH 9 at 25°C. It is hydrolytically stable at pH 4 at 25°C. In an aqueous environment it is expected to hydrolyse to DMH and formaldehyde. DMH is extremely stable to hydrolysis in pH 5, 7 and 9. Hydrolysis of formaldehyde can be excluded because of the absence of a hydrolysable group in the molecule.

Because DMDMH hydrolyses rapidly in aqueous solutions leaving DMH and formaldehyde, the photolysis of degradation products is considered to be less relevant for evaluation and use in risk assessment. DMH is considered to be stable in water at pH 7 at 25°C on the basis of conducted test. There are no tests on photolysis of formaldehyde in aqueous solutions available which would allow deriving a reaction rate for surface waters. In aqueous solutions formaldehyde hydrate is formed which has no chromophore that is capable of absorbing sunlight and thus should not decompose by direct photolysis. Hence photolysis in surface waters is expected to be of minor importance in abiotic degradation processes of DMDMH.


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2.2.2.1.3 Distribution and Mobility

The degradant DMH was considered relevant for soil adsorption studies due to the rapid hydrolysis of DMDMH. Based on the range of Koc values, DMH can be described as highly mobile to moderately mobile1 in all soil types used in study. The mean Koc value of 80.15 L/kg has been used for risk assessment. There is no study available on adsorption of formaldehyde in soils and sediments. The KOC was estimated using a QSAR model described in EU Technical Guidance Document on Risk Assessment (EC 2003). Based on a log KOW of 0.35 and the QSAR for non-hydrophobics, the KOC is calculated to be 15.9 L/kg. Hence formaldehyde can be described as highly mobile in soil.

2.2.2.1.4 Bioaccumulation

Because of rapid hydrolysis of DMDMH under environmental conditions, possibility of bioaccumulation of degradation products DMH and formaldehyde was investigated.

The log KOW (an indicator of the likelihood of a substance for dissolving in fatty tissue) for DMH was found to be -0.48 indicating low potential bioaccumulation in the food chain. An experimental bioaccumulation factor of <1.79 in fish also indicates it has a low bioaccumulation potential at least in the aquatic compartment.

Formaldehyde does not bioaccumulate taking into consideration log KOW (0.35) and estimated according to TGD bioconcentration factor (BCFfish = 0.4).

2.2.2.2 Effects Assessment

2.2.2.2.1 Aquatic Compartment

At a test concentration of 82.3 mg/l DMDMH did not show any acute toxic effects to fish. DMDMH is acutely harmful to Daphnia with LC50 of 29.1 mg/l and algae with ErC50 = 11 mg/l.

The degradants are considered more relevant for ecotoxicological studies. DMH is not acutely toxic to fish in concentration 972.2 mg/l. No acceptable acute test for Daphnia was provided. However chronic test is available with NOEC =70.9 mg/l. Chronic tests of DMH toxicity to fish and algae were also provided. NOEC of 14 mg/l in relation to toxic effects on the weight and growth of fish from an early life-stage study was selected for aquatic effect assessment.

Formaldehyde is acutely toxic to fish with 96h-LC50 of 5.7 mg/l. Formaldehyde is also acutely harmful for other aquatic species, obtained LC50 values are similar. LD50 for fish was used in risk assessment. No acceptable log-term toxicity study for formaldehyde was provided.

At a test concentration of 100 mg/l DMDMH did not show any effects to

microbial activity in STP. DMH is not harmful for microbial activity at concentration 1000 mg/l. Formaldehyde is harmful to STP microorganisms with LC50 = 20.4 mg/l

Sediment


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No test of DMDMH or product of hydrolysis toxicity to sediment dwelling organisms were provided. However taking into consideration behaviour of these substances in the environment no accumulation in sediment is expected.

2.2.2.2.2 Terrestrial Compartment

No tests of DMDMH toxicity to terrestrial organism were provided. However the degradation products are considered more relevant for risk assessment. DMH is not harmful to earthworms and microbial activity in soil in concentration 1000 mg/kg. The lowest NOEC = 160 mg/kg used was obtained from test on terrestrial plants. No tests of formaldehyde toxicity to terrestrial organism were provided. PNECsoil for formaldehyde was calculated using the equilibrium partitioning method from PNECwater

2.2.2.3 PBT Assessment

According to the TGD, ‘The Persistent, Bioaccumulative and Toxic (PBT) assessment is considered to be different from the local and regional assessments approaches, as it seeks to protect ecosystems where risks are more difficult to estimate’. Any substance which is found to be either a PBT or very Persistent very Bioaccumulative (vPvB) substance shall not be allowed on Annex I unless releases to the environment can be effectively prevented.

Provided tests of biodegrability shows that neither DMDMH nor product of hydrolysis are persistent according to TGD criteria of persistency. DMDMH and DMH are readily biodegradable. Formaldehyde is readily biodegradable failing 10-days window.

A substance is considered to have the potential to fulfill the criterion of

bioaccumulation when the log KOW exceeds 4.5. Values of n-octanol/water partition coefficient are lover that trigger value for DMDMH and product of hydrolysis. Additionally test of DMH bioaccumulation in fish was provided. Results of the test supported position that substance is not bioaccumulative.

There are no chronic toxicity test on DMDMH available. However product of

hydrolysis are more relevant for the effect assessment. The lowest NOEC for DMH is 14 mg/l. This means that the trigger of < 0.01 mg l-1 given in the TGD is not exceeded. There are no chronic toxicity test on formaldehyde available. However long-term exposure can be anticipated only for persistent and bioaccumulative substances. Since formaldehyde do not fulfill persistence and bioaccumulation criteria DMDMH and their degradation products are not PBT substances.

2.2.2.4 Exposure Assessment

The environmental exposure assessment for products of DMDMH hydrolysis has been done using all available information. This has been taken from submitted studies and the harmonized ESD for biocides.


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Information and guidance was also taken from part II of the Technical Guidance Document on risk assessment (TGD; EC, 2003).

The product is specified in the risk assessment as having a 70% concentration

of the active substance DMDMH as manufactured. In practice this 70% DMDMH solution will not be ‘stable’ once manufactured. As indicated in Document IIA section 1.2 DMDMH in aqueous solution will undergo an equilibrium reaction releasing free formaldehyde and DMH, the rate of generation of the degradation products being dependent upon thermodynamic forces driving the reaction to the equilibrium. During the product manufacturing process further amounts of DMH have to be added in order to lower the free formaldehyde below the 0.1% specified.

Due to the equilibrium state of substances in the solution any commercial

products will not be formally identified as being a 70% solution of DMDMH. The free formaldehyde concentration in any product is always at a level of <0.1% in solution with the efficacy of the product based on the biocidal activity of the whole equilibrium solution.

The product specified in Document IIIB has been characterised as a ‘dummy

product’ due to the above issue with stability but, for purposes of the evaluation and the Annex I inclusion for the active substance, use of a product containing 70% DMDMH does present a ‘worst case’ scenario with the appropriate highest possible concentrations of DMH and formaldehyde formed during the degradation being considered for environmental risk assessment.

All calculations within the exposure scenario apply to products of DMDMH hydrolysis: DMH and formaldehyde. 2-12 Identification of the product (PT 13)


Concentration of Dantogard

(%)

Likely conc. at which a.i will

be used

Conc. of DMH

Conc. of formaldehyde

13 Water-based metal working fluids

XXX XXXX XXX XXX

Predicted environmental concentrations resulted from the use of Dantogard

in PT 13 PEC in aquatic compartment

2-13 Local PECs for DMH and formaldehyde in STP

Substance Local PECs mg/l

DMH 0.171 Formaldehyde 0.208


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2-14 Local PECs for DMH and formaldehyde in surface water

Substance Local PECs mg/l

DMH 0.0171 Formaldehyde 0.0208

PEC in terrestrial compartment

2-15 Local PECs for DMH and formaldehyde in soil

Substance Local PECs DMH 0.027 Formaldehyde 3.25E-03

PEC in air

2-16 Local PECs for DMH and formaldehyde in air

Substance Local PECs DMH 4.17E-13 Formaldehyde 1.13E-08

2.2.2.5 Risk Characterisation

PEC/PNEC values have been determined for products of DMDMH hydrolysis:

DMH and formaldehyde.

2.2.2.5.1 Aquatic compartment including STP

Table 2-17 PEC/PNEC ratios (DMH) for the aquatic compartment

Compartment Local PECs PNEC PEC/PNEC ratio Use Surface water 0.0171 1. 4 0.0122 STP 0.171 100 0.00171

Table 2-18 PEC/PNEC ratios (Formaldehyde) for the aquatic compartment

Compartment Local PECs PNEC PEC/PNEC ratio Use Surface water 0.0208 0.0057 3.65 STP 0.208 0.2 1.04

Use of DMDMH as an active substance in Dantogard, according to the

proposed use pattern for products in PT 13, pose an unacceptable risk to STP micro-organisms and aquatic organisms. Risk is caused by formaldehyde released from DMDMH.


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2.2.2.5.2 Terrestrial Compartment

Table 2-19 PEC/PNEC ratios (DMH) for the terrestrial compartment

Scenario Local PECs mg/kgwwt

PNEC mg/kgwwt PEC/PNEC ratio

Use Soil 0.027 0.99 0.027

Table 2-20 PEC/PNEC ratios (Formaldehyde) for the terrestrial compartment

Scenario Local PECs mg/kgwwt

PNEC mg/kgwwt PEC/PNEC ratio

Use Soil 3.25E-03 0.0023 1.41

Use of DMDMH as an active substance in Dantogard, according to the

proposed use pattern for products in PT 13, poses an unacceptable risk to soil organisms. Risk is caused by formaldehyde released from DMDMH.

2.2.3 Listing of Endpoints

In order to facilitate the work of Member States in granting or reviewing

authorisations, and to apply adequately the provisions of Article 5(1) of Directive

98/8/EC and the common principles laid down in Annex VI of that Directive, the most

important endpoints, as identified during the evaluation process, are listed in

Appendix I.


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3. PROPOSAL FOR THE DECISION

3.1 BACKGROUND TO THE PROPOSED DECISION

The overall conclusion from the evaluation of 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione (DMDMH) for use in product type 13 (metalworking fluids) for the category of users industrial is that it is possible for the MS to issue authorisations on biocidal products containing DMDMH in accordance with the conditions laid down in article 5 (1) (b), (c), (d) of the directive 98/8EC.

The data on the active substance and biocidal product have demonstrated

sufficient efficacy in preservation of metalworking fluids by the control of microbial deterioration. For the proposed area and manner of use biocidal product does not cause unacceptable risk to human health and cause unacceptable risk to environment.

3.2 PROPOSED DECISION REGARDING THE INCLUSION IN ANNEX I

The 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione (DMDMH) shall be included in Annex I to Directive 98/8/EC as an active substance for use in product-types 13 (metalworking fluids).

The information outlined below will be included in the entry for Annex I inclusion:

Identity IUPAC Name: 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione CAS No: 6440-58-0 EINECS No: 229-222-8 Purity The active substance as manufactured, shall have a minimum purity of 90%

w/w Proposed product type 13 (metalworking fluids)

Justification for the Provisions regarding the Inclusion on to Annex I

-

3.3 ELEMENTS TO BE TAKEN INTO ACCOUNT BY MEMBER STATES WHEN AUTHORIZING PRODUCTS

Release of formaldehyde from the active substance and the concentration of formaldehyde should be taken into account during the biocidal product authorisation


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stage. During manufacture and formulation as the system should be completely enclosed and formaldehyde should be added to the reactor via pipes.

The release of biocides used as metalworking fluids has to be considered by the relevant national authorities when issuing permits for recovery plants (according to agreement at Technical Meeting IV09 - required when an environmental risk for metalworking fluids has been identified).

3.4 DEMAND FOR FURTHER INFORMATION

It is considered that the evaluation has shown that sufficient data have been provided to verify the outcome and conclusions, and permit the proposal for the inclusion of 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione in Annex I to Directive 98/8/EC.

In the situation when the biocidal product will be authorized with higher

concentration of DMDMH than 55% the new in vivo eye and skin irritation study should be provided.

3.5 UPDATING THIS ASSESSMENT REPORT

This assessment report may need to be updated periodically in order to take account of scientific developments and results from the examination of any of the information referred to in Articles 7, 10.4 and 14 of Directive 98/8/EC. Such adaptations will be examined and finalised in connection with any amendment of the conditions for the inclusion of DMDMH in Annex I to the Directive.


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APPENDIX I – LIST OF ENDPOINTS

Chapter 1: Identity, Physical and Chemical Properties, Details of Uses,

Further Information, and Proposed Classification and Labelling

Active substance (ISO Common Name) Dimethyloldimethylhydantoin (DMDMH)

Function (e.g. fungicide) Preservative – acts as a bactericide

Rapporteur Member State Poland

Identity (Annex IIA, point II.)

Chemical name (IUPAC) 1,3-bis(hydroxymethyl)-5,5-

dimethylimidazolidine-2,4-dione

Chemical name (CA) Dimethylol Dimethyl Hydantoin

CAS No 6440-58-0

EC No 229-222-8

Minimum purity of the active substance as

manufactured (g/kg or g/l)

900g/kg

Identity of relevant impurities and

additives (substances of concern) in the

active substance as manufactured (% w/w)

None

Molecular formula C7H12N2O4

Molecular mass 188

Structural formula

N N

O

O

CH2OHHOCH2


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Identity of Degradant

DMH has been considered as the substance of relevance long-term toxicity,

ecotoxicity and environmental fate studies (Document I Appendix XIV: Justification

for performance of long-term studies on DMH). Therefore this document also

contains information (where applicable) for DMH

Chemical name (IUPAC) 5,5 dimethylimidazolidine-2,4-dione

Chemical name (CA)

Dimethylhydantoin (DMH)

CAS No 77-71-4

EC No 201-051-3

Minimum purity of the active substance as

manufactured (g/kg or g/l)

Not applicable

Identity of relevant impurities and

additives (substances of concern) in the

active substance as manufactured (% w/w)

DMH: >90% w/w

Water : 9% (max)

Ammonia: 1% (max)

Molecular formula C5H8N2O2

Molecular mass 128.13

Structural formula

Physical and chemical properties (Annex IIA, point III., unless otherwise indicated)

Physical and chemical properties (where applicable) have also been stated for the

degradant DMH.

Melting point (state purity) DMDMDH: 90°C (purity 97.1%)

DMH: 176°C (purity: 99.82%)

Boiling point (state purity) DMDMH: decompose before boiling at 200 °C


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(purity 96.8%)

The calculated value of the boiling point is

equal to 412°C.

DMH: 313°C (purity: 99.82%)

Appearance (state purity) DMDMH: White non-uniform odourless powder

(purity 96.8%) DMH: not relevant

Specific gravity DMDMH: 0.4g/cm3 at 21°C

DMH: not relevant

Surface tension DMDMH: 72.4 mN/m (0.998 g/l solution) at 20.0 ± 0.5°C

DMH: 71.6 mN/m(1.00 g/l solution) at 21.0 ±

0.5°C

Vapour pressure (in Pa, state temperature) DMDMH: 0.000012 Pa at 25°C.

DMH: 0.00019 Pa at 20°C 0.00038 Pa at 25°C

Henry’s law constant DMDMH: not possible to determination due to

properties of the substance DMH: 1.74 x 10-7 Pa*m3*mol-1 at 20°C

Solubility in water (g/l or mg/l, state

temperature)

DMDMH: not possible to determination due to

properties of the substance DMH: 140 g/l at 20.0°C

Solubility in organic solvents (in g/l or

mg/l, state temperature) (Annex IIIA, point

III.1)

DMDMH:

Tolulene:

0.141 g/l @10 °C

0.214 g/l @20°C

0.279 g/l @30°C

Methanol

>252 g/l @ 10 °C

>250 g/l @20°C

>252 g/l @ 30°C DMH:

Toluene: 0.136 g/l at 20°C


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Methanol: 134 - 161 g/l at 20°C

Stability in organic solvents used in

biocidal products including relevant

breakdown products (IIIA, point III.2)

Not applicable

Partition coefficient (log POW) DMDMH: -2.9 at 20°C (pH=2.1) DMH: – 0.475 at 22°C (pH=neutral)

Storage stability (DT50) (state pH and

temperature) (point VII.7.6.2.1)

DMDMH hydrolyses in water with half-life ca

< 1 day at pH 7 and pH 9. DMDMH is

hydrolytically stable at pH4 with half life > 1

year..

Dissociation constant (not stated in Annex

IIA or IIIA; additional data requirement

from TNsG)

DMDMH: not possible to determination due to

properties of the substance

DMH: 9.19

UV/VIS absorption (max.) (if absorption >

290 nm state ε at wavelength)

DMDMH: Significant absorbance maxima at

wavelength equal to 206nm (molar absorption

coefficient 3.19 x 10 3)

Photostability (DT50) (aqueous, sunlight,

state pH)

(point VII.7.6.2.2)

As DMDMH hydrolyses in aqueous solutions,

leaving DMH, the photolysis of DMH is considered

to be more relevant to this endpoint. DMH is

photolytically stable DT50 =878 days (pH 7.0)

Quantum yield of direct

phototransformation in water at Σ > 290

nm (point VII.7.6.2.2)

As DMDMH hydrolyses in aqueous solutions,

leaving DMH, the photolysis of DMH is

considered to be more relevant to this endpoint.

There is no absorbance of DMH >290 nm.

Flammability DMDMH is not highly flammable

DMH: not relevant

Explosive properties DMDMH is not explosive based upon structure

and experience in use

DMH: not relevant

Summary of intended uses


(Hazard class)

Likely conc. at which a.s. will be

used

PT 13

Metalworking fluids

0.245%

Classification and proposed labelling (Annex IIA, point IX.)

with regard to physical/chemical data None

with regard to toxicological data

Elements of classification and labelling

marked in red are proposals with which

the applicant disagrees.

Proposal 1





Proposal 2





“Suspected of causing cancer by inhalation”,

H351i

with regard to fate and behaviour data None

with regard to ecotoxicological data None



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Chapter 2: Methods of Analysis

Analytical methods for the active substance

Technical active substance (principle of

method) (Annex IIA, point 4.1)

Method validation of the active ingredient

content by HPLC

Impurities in technical active substance

(principle of method) (Annex IIA, point

4.1)

Method validation of MMDMH and DMH

content by HPLC

Analytical methods for residues

Soil (principle of method and LOQ)

(Annex IIA, point 4.2)

Study on DMH:

The residues were determined by HPLC-MS.

The LOQ nominal was 0.05 mg/kg.

Air (principle of method and LOQ) (Annex

IIA, point 4.2)

Not applicable

Water (principle of method and LOQ)

(Annex IIA, point 4.2)

Study on DMH:

The residues were determined by HPLC-MS

with the use of:

1.procedure A (500 times enrichment) with

LOQ = 0.5μg/l and,

2. procedure B (2000 times enrichment) with

LOQ = 0.1μg/l.

Body fluids and tissues (principle of

method and LOQ) (Annex IIA, point 4.2)

Not applicable

Food/feed of plant origin (principle of

method and LOQ for methods for

monitoring purposes) (Annex IIIA, point

IV.1)

Not applicable

Food/feed of animal origin (principle of

method and LOQ for methods for

monitoring purposes) (Annex IIIA, point

IV.1)

Not applicable



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Chapter 3: Impact on Human Health

Absorption, distribution, metabolism and excretion in mammals (Annex IIA, point 6.2)

Rate and extent of oral absorption: Performed on the relevant degradation product

DMH

The majority of DMH is absorbed via the oral

and iv routes with elimination without

metabolism in the urine (up to 96%). A small

percentage (less than 1.37%) was eliminated in

faeces and can therefore be said not to have

been absorbed through the GI tract. Only 2.6%

of the oral dose was not recovered within the

test period and therefore, this percentage is

considered to be retained. The study identifies

hair and possibly fat as having the highest

residue levels but not at levels indicative of

bioaccumulation.

Formaldehyde:

100% uptake, rapid (based on 14C in exhaled

air, urine and carcass), low systemic

bioavailability (first-pass metabolism)

Rate and extent of dermal absorption: DMH

Study not performed. 100% default used in risk

assessment

Formaldehyde

100% uptake (based on 14C in excreta, organs

and carcass, and on in vitro data on human

skin), low systemic bioavailability (first-pass

metabolism)

Rate and extent of inhalative absorption Formaldehyde

100% uptake (based on 14C ) (rodents/primates

at rest: ~ 90 and 70% in nasal passages,

man/oronasal breathing: up to ~ 45% tracheo-

bronchially), systemic bioavailability below



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10% (first-pass metabolism)

Distribution: DMH

The majority of DMH was excreted in the urine

Formaldehyde 14C label widely distributed (introduction into

C1-pool)

Metabolism DMH

The majority of DMH is absorbed via the oral

and iv routes with elimination without

metabolism in the urine (up to 96%).

Formaldehyde

1) Reaction with GSH followed by enzymatic

conversion to formate and utilisation for C1-

transfer or oxidation to CO2

2) Direct enzymatic conversion to formate and

utilisation for C1-transfer or oxidation to CO2

3) Reaction with THF followed by conversion

to 5-methyl or 5-formyl THF and utilisation for

C1-transfer or transformation to 10-formyl

THF and release of formate or oxidation to CO2

4) Adduct formation with cysteine, urea,

proteins and nucleic acids

Pronounced first-pass metabolism at site of

entry

Rate and extent of excretion DMH

Elimination without metabolism in the urine

(up to 96%). A small percentage (less than

1.37%) was eliminated in faeces. Most of the

radioactivity recovered in the urine was

excreted within the first 12 hours. Urinary half

lives (obtained graphically from the data in the

reports by Σ-plots) were superimposable, with

values of 3.0 - 3.25h (males) and 2.4 - 2.8h



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(females).

Formaldehyde

Metabolic elimination, high, but variable rate

and extent of metabolite excretion (based on 14C) mainly with air and urine (initial plasma

t1/2 12h, terminal t1/2 50h, 10 - 40% 14C residues

after 3-4d)

Potential for accumulation: No evidence for accumulation for both

substances

Toxicologically significant metabolite None. DMDMH is rapidly hydrolyzed to DMH

which was considered relevant for ADME

studies.

Toxicity of metabolites of formaldehyde not

assessed separately

Urine: formate, hydroxymethylurea

Acute toxicity (Annex IIA, point 6.1)

Rat LD50 oral DMDMH: 1572mg a.i./kg bw

DMH: >10000mg/kg bw

Formaldehyde: 640mg/kg bw

Rat LD50 dermal DMDMH: >1052mg a.i./kg.bw

DMH: >20000mg/kg bw

Formaldehyde: 270mg/kg bw

Rat LC50 inhalation DMH, DMDMH Not available – not required

Formaldehyde: 0.6mg/Lx4h (~100mg/kg bw)

Skin irritation DMDMH: not irritating (53% aqueous

solution)

DMH: not irritating

Formaldehyde: Corrosive

Eye irritation DMDMH in vivo mildly irritating (53%

aqueous solution)

in vitro not corrosive

DMH not irritating

Formaldehyde: Corrosive



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Skin sensitization (test method used and

result)

DMDMH: Buehler and GPMT test not

sensitising

DMH: Buehler method not sensitising

Formaldehyde: Sensitising (M&K, LLNA,

human data)

Repeated dose toxicity (Annex IIA, point 6.3 - 6.5)

Species / target / critical effect The degradant DMH was considered relevant

for repeated dose toxicity

DMDMH

Rat/oral/90 days

High dose: a statistically significant increases

of mean absolute and relative adrenal weights

for males in both groups.

Mid and low dose: no treatment related

changes.

Rabbit/dermal/28 days

High dose: treatment related lesion at the skin

of the test sites (multifocal to diffuse epidermal

inflammation with focal to multifocal

epidermal necrosis and ulceration).

No systemic adverse effects at both doses

Rabbit/dermal/90 days

Progression of the acute and necrotizing

inflammatory process in the skin and

subsequent separation of the necrotic focus

which produced an ulcer.



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DMH

Rat/oral/90 days

High dose: males - equivocal decrease in body

weight, liver weight and food consumption;

females - equivocal increase in body weight,

liver weight and food consumption


changes.

Rat/oral/104 weeks

High dose: equivocal decrease in body weight

and survival.


changes

Dog/oral/1 year

High dose: small decreases in body weight,

increase in adrenal weights and mild

hypertrophy in adrenal cortex for males. Small

decreases in body weight for females


changes

Rat/dermal/90 days

No effects

Formaldehyde

Rat (oral): bw ↓; stomach: hyperkeratosis,

ulcerations, atrophy, hyperplasia; kidney:

papillary necrosis

Dog (oral): bw ↓

Mouse (dermal): skin: irritation, fissuring,

papules



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Rat/monkey (inhalation): nasal epithelium:

degeneration, necrosis, exfoliation, erosion,

squamous metaplasia, hyperplasia

Short-term, subchronic and toxicity

(Annex IIA, points 6.3 & 6.4)

Relevant oral NOAEL 300mg/kg bw/day, 1-year dog (DMH)

1000mg/kg bw/day, 90-day rat (DMH)

25mg/kg bw/day, 28-day rat (Formaldehyde)

Relevant dermal NOAEL 390mg/kg bw/day, 90-day rat (DMH)

Relevant inhalation NOAEL Not available – not required for DMH

1.2µg/L x 22h/day, 6-mo, rat, monkey

(Formaldehyde)

Chronic toxicity (Annex IIA, point 6.5)

Relevant chronic oral NOAEL 300mg/kg bw/day, 2-year combined chronic

toxicity/carcinogenicity study in rats (DMH)

15mg/kg bw/d, 24-mo rat (Formaldehyde)

Genotoxicity (Annex IIA, point 6.6)

In vitro tests performed on DMDMH and DMH

DMDMH: Ames test, chromosome aberration,

Cytogenicity Study – Chinese Hamster Ovaries

and mouse lymphoma assay gave a positive

result with 55% aqueous solution. Positive

results are attributed to free formaldehyde in

aqueous solution. Ames test with 100% pure

active substance gave a negative result.

DMH: Ames test, chromosome aberration and

mouse lymphoma assay were all negative.

In vivo performed on DMDMH

The in vivo micronucleus assay and alkaline

elution assay indicated no potential for



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mutagenicity.

Formaldehyde

Clastogenic locally in vivo (secondary to DNA-

protein crosslinks)

Carcinogenicity (Annex IIA, point 6.4)

Species / type of tumour The degradant DMH was considered relevant

for carcinogenicity

Performed on rat: The test substance did not

induce tumour formation or any other

carcinogenic effects.

Rat, Mouse (inhalative):

Nasal epithelium: squamous cell carcinoma

Lowest dose with tumours Formaldehyde:

Rat (24-mo): 7.2µg/L x 6h/d

Mouse (24-mo): 18µg/L x 6h/d

Reproductive toxicity (Annex IIA, point 6.8)

Species / Reproduction target / critical

effect

Performed on DMH, the substance of relevance

for long-term toxicity.

Rat/Oral/2-gen

No parental toxicity or adverse effects on

reproduction or reproductive tissues. Body

weight ↓ in F1 and F2 generations at high dose

level.

Results from a 2-generation reproductive toxicity study in rats showed that DMH is not selectively toxic to the fertility or the developing offspring. Exposure to DMH in the diet did not result in parental toxicity or adverse effects on reproductive performance or reproductive tissues at dietary concentrations as high as 20000ppm (~1395mg/kg bw/day). However, there were effects (decreased weight gain) in offspring during lactation. Small increases in parental food consumption and



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body weight and transient decreases in offspring body weight during lactation were observed at the 20000ppm dose level.

Lowest relevant reproductive NOAEL /

LOAEL

NOAEL parental = 1395mg/kg bw/day NOAEL offspring = 379mg/kg bw/day

Species/Developmental target / critical

effect

DMH, EMH:

In general, the administration of DMH or EMH

to pregnant rats or rabbits does not result in

profound toxicity to either species. High dose

levels are required to induce some toxic effects.

It is apparent that there was no significant

developmental toxicity to rat offspring.

Findings were limited, in this case to rib effects

which are most likely a consequence of toxicity

to the adult. The overall opinion must be that

DMH and EMH do not induce developmental

effects in the rat at non toxic dose levels and

the effects with DMH are not significant

enough to suggest it is a developmental

toxicant.

In the case of the rabbit, the findings are less

conclusive. At dose levels of EMH and DMH

that were toxic to the adult there was some

evidence of a specific developmental effect.

With DMH this was absence of a digit on the

forepaws. With EMH it was an increase in the

incidence of foetuses with unossified bones in

the forepaws. It is of note that these findings

were not seen in a second study (Hoar R.M.

(1986)) at a dose level of 1000mg/kg:

considered a limit dose (for developmental

toxicity studies). The effects seen were limited

in their incidence. It is also important to note



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that the effect with EMH was not considered to

be significant proof of developmental toxicity

by the author of the study (Beyer B.K. (1992)).

Most importantly, these findings are only seen

at dose levels that are toxic to the adult and are

therefore of limited significance.

In one developmental toxicity study in the

rabbit (Nemec M.D. (1992)), a further finding

seen at dose levels of 500 and 1000mg/kg was

considered to be an effect on foetal

development. The increase in incidence of

foetuses with 27 presacral vertebrae and 13 rib

pairs. At the time of the study this may have

been considered possible indicators of

developmental toxicity. However, subsequent

evidence (Drain M.R. and Wilby O.K. (1994))

do indicate that other factors influence these

findings and their toxicological significance is

highly questionable. It should be noted that

these findings were not seen in a second

developmental toxicity study in the rabbit. It is

the opinion of this study author that the true

NOAEL for developmental toxicity for the

study in question should be 500mg/kg and not

100mg/kg.

The results of all the developmental toxicity

studies conducted with DMH and EMH suggest

that significant developmental toxicity was

limited to the digit defects in the rabbit and not

in the rat. The finding in question was only

seen at a dose level that was toxic to the adult

and the finding was only seen at low incidence.

Formaldehyde:



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Rat, Mouse:

No teratogenic effects

Lowest relevant developmental NOAEL

EMH ADULT 375mg/kg

DMH ADULT 500mg/kg

Offspring 500mg/kg

It is considered, based on the weight of

evidence and the type of effects observed that

the lowest NOAEL applicable for the Risk

Assessment is 375mg/kg bw/day and that

further investigation is not warranted.

Neither DMH nor EMH should be considered

to be developmental toxins based on the results

of the available studies

Maternal:

Rat:1000mg/kg bw/day (DMH)

Rabbit: 1000mg/kg bw/day (DMH, EMH)

375mg/kg bw/day (EMH)

Developmental:

Rat:1000mg/kg bw/day (DMH)

Rabbit: 1000mg/kg bw/day (DMH, EMH)

375mg/kg bw/day (EMH, comparable

to DMH)

Formaldehyde:

Maternal:

Rat (inhalation): 24µg/L x 6h/day

Mouse: 148mg/kg bw/day

Developmental:

Rat: 24µg/L x 6h/day

Mouse: 148mg/kg bw/day



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Neurotoxicity / Delayed neurotoxicity (Annex IIIA, point VI.1)

Species / target / critical effect Not considered necessary

Lowest relevant developmental NOAEL /

LOAEL.

N/A

Other toxicological studies (Annex IIIA, VI/XI)

Ocular and respiratory irritation, human Formaldehyde:

Eye irritation:

≥ 0.36µg/L x 4h with peaks of

0.72µg/L,

Nasal irritation:

≥ 0.6µg/L x 4h with peaks of 1.2µg/L;

NOAEC: 0.36µg/L

population NOAEC: 0.12µg/L

Medical data (Annex IIA, point 6.9)

Cohort study

Formaldehyde:

Evidence for association of occupational

inhalative exposure with increase in

standardised mortality ratio for upper

respiratory tract cancer (NPC); increase in

relative risk with peak exposure and average

intensity

Patch test DMDMH:

12 formaldehyde-allergic patients applied a

cream containing 1% DMDMH and 4

formaldehyde-allergic patients applied cream

containing 0.25% DMDMH.

It concludes that an increase in the use of

DMDMH in cosmetic products will also

inevitably increase the risk of cosmetic

dermatitis in consumers allergic to



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formaldehyde.

1808 animals applied 2% aq. solution pet –

0.3% positive.

34321 human applied 2% aq. solution – 0.5%

positive.

The frequency of sensitisation was

comparatively low.

Summary (Annex IIA, point 6.10)

DMDMH Value Study Safety factor

AEL acute 3.75mg/kg

bw/d

Teratogenicity

study in rabbit

for EMH

100

AEL medium-term 3.0mg/kg

bw/d

1-year chronic

study in dog

100

Drinking water limit N/A N/A N/A

AEL long-term 3.0mg/kg

bw/d

1-year chronic

study in dog

100

ADI (if residues in food or feed) Not allocated

ARfD (if residues in food or feed) Not allocated

Formaldehyde

Value Study Safety factor

AELacute

AELmedium-term

AELlong-term

0.15mg/kg

bw/d

Rat, overall

(28-d, 90-d, 2-

yr)

100

AECacute, inhalative

AECmedium-term, inhalative

AEClong-term, inhalative

0.12µg/L Human, eye

irritation

3

Human,

overall

1



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ocular/respirat

ory irritation

Rat, Monkey,

6-mo

10

Drinking water limit Not allocated

ADI (if residues in food or feed) Not allocated

ARfD (if residues in food or feed) Not allocated

Acceptable exposure scenarios (including method of calculation)

Professional users PT13

Scenario 1: Professionals diluting product into

metal working fluids sump. 70% active

substance in product equivalent to 47.7% DMH

and 0.1% formaldehyde.

Model: TNsG exposure model for pouring and

pumping liquids into systems (Mixing and

Loading; Model 7) used for dermal and

inhalation exposure.

Exposure: Once a day, 15 minutes exposure.

Exposure to formaldehyde and DMH

considered.

Scenario 2: Professional users undertaking

metal working and maintenance tasks. 0.245%

active substance in product equivalent to 0.17%

DMH and 0.08% formaldehyde.

Model 1: Inhalation exposure, TNsG part 2

p.189 MWF.

Model 2: BEAT calculation for PT13 with

input value recommended by HEEG (TM III

08).

Exposure: Once a month maintenance for

240min, daily exposure during metal working

for 120min. Exposure to formaldehyde and



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DMH considered.

Non-professional users Non-professional use is not envisaged

Indirect exposure as a result of use Scenario: Deposits of metal working fluid on

clothes whilst doing laundry.

Model: CONSEXPO

Exposure: Dermal exposure to DMH ~ 1

minute.



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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)

DMDMH: DT50 pH4 = > 1 year, pH 7= < 1

day, pH 9 = < 1 day at 25°C

DMDMH: DT50 pH 7.5 at 35°C dirty water

and tap water = < 1 hour

Hydrolyses to DMH and formaldehyde

DMH and formaldehyde stable in water

Photolytic / photo-oxidative degradation of

active substance and resulting relevant

metabolites

DMH: no photolytic degradation

Formaldehyde: no photolytic degradation

Readily biodegradable (yes/no) DMDMH: Yes, readily biodegradable

DMH: Yes, readily biodegradable

Formaldehyde: Yes, readily biodegradable

(failing 10-days window)

Biodegradation in seawater Not applicable

Non-extractable residues

Distribution in water / sediment systems

(active substance)

DMDMH undergoes rapid hydrolyses to DMH.

Distribution of the degradant considered below.

Distribution in water / sediment systems

(metabolites)

Performed on DMH the substance of relevance

for environmental fate studies

DMH was steadily degraded with whole

systems and aqueous phase DT50 values of

17.45 to 19.95 days (33.1-37.9 days after

conversion to average EU outdoor temperature

12°C). The unextractable radioactivity (bound

residue) increased from 0.5% to a maximum of

9.8% of the initial radioactivity after 84 days

incubation then decreased to 7.7% at the end

of the test. The predominant degradation

product was CO2 which accounted for 55 to



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65% of the applied radioactivity at the end of

the incubation phase

Route and rate of degradation in soil (Annex IIIA, point VII.4, XII.1.1, XII.1.4; Annex VI,

para. 85)

Mineralization (aerobic) Not performed

Laboratory studies (range or median, with

number of measurements, with regression

coefficient)

Not performed

Field studies (state location, range or

median with number of measurements)

Not performed

Anaerobic degradation Not performed

Soil photolysis Not performed

Non-extractable residues Not performed

Relevant metabolites - name and/or code,

% of applied a.i. (range and maximum)

Not performed

Soil accumulation and plateau

concentration

Not performed



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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)

Performed on DMH

DMH: Kd = 0.593 Koc = 80.15 (mean

values)

No

Formaldehyde (calculation)

Koc = 15.9

Fate and behaviour in air (Annex IIIA, point VII.3, VII.5)

Direct photolysis in air DMDMH will convert readily to DMH and

formaldehyde in the environment and therefore

the latter two molecules were considered.

Indirect phtolysis:

The half-life of photolysis of DMH is 3.495

days with an overall OH rate constant of

3.0608E-12 cm3/molecule-sec (half-life

calculated using EPIWIN v 3.12).

The half-life of photolysis of formaldehyde is

1.7 days with an overall OH rate constant of

3.0608E-12 cm3/molecule-sec (half-life

calculated using EPIWIN v 3.12).

Quantum yield of direct photolysis No data available

Photo-oxidative degradation in air Latitude: ............. Season: .................

DT50 ..............

Volatilization DMDMH is not volatile (vapour pressure

=0.00000012hPa at 25°C)



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Monitoring data, if available (Annex VI, para. 44)

Soil (indicate location and type of study) No data

Surface water (indicate location and type

of study)

No data

Ground water (indicate location and type

of study)

No data

Air (indicate location and type of study) No data



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Chapter 5: Effects on Non-target Species

Studies performed with DMDMH, DMH and formaldehyde

Toxicity data for aquatic species (most sensitive species of each group) DMDMH

(Annex IIA, point 8.2, Annex IIIA, point 10.2)

Species Time-

scale

Endpoint Toxicity

Fish

Brachydanio rerio 96 h LC50 >82.3 mg/l

Invertebrates

Daphnia magna 48h EC50 29.1 mg/l

Algae

Desmodesmus

subspicatus

72 h NOEC 5.1 mg/l

Microorganisms Activated sludge

3h EC50 > 100 mg/l

Toxicity data for aquatic species (most sensitive species of each group) DMH


Species Time-

scale

Endpoint Toxicity

Fish

Oncorhynchus mykiss 96h LC50 >972.2 mg/l

Invertebrates

Daphnia magna 48h EC50 6200 mg/l

Algae

Pseudokirchneriella

subcapitata

96h NOEC >1000 mg/l

Microorganisms

Activated sludge,

domestic

3h EC50 > 1000 mg/l



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Toxicity data for aquatic species (most sensitive species of each group)

formaldehyde


Species Time-

scale

Endpoint Toxicity

Fish

Morone saxatilis 96h LC50 5.7 mg/l

Invertebrates

Daphnia pulex 48h EC50 5.8 mg/l

Algae

Pseudokirchneriella

subcapitata

96h EC50 5.7 mg/l

Microorganisms

Activated sludge,

domestic

3h EC50 20.4 mg/l

Effects on earthworms or other soil non-target organisms

Acute toxicity to earthworms

(Annex IIIA, point XIII.3.2)

Performed on DMH

14-day LC50 > 1000 mg/kg

Reproductive toxicity to

…………………………


N/A

Effects on soil micro-organisms (Annex IIA, point 7.4)

Nitrogen mineralization Performed on DMH

EC50 (28 days) > 1000 mg/kg

NOEC (28 days) = 1000 mg/kg

Carbon mineralization N/A



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Effects on terrestrial vertebrates

Acute toxicity to mammals


N/A

Acute toxicity to birds


N/A

Dietary toxicity to birds


N/A

Reproductive toxicity to birds


N/A

Effects on honeybees (Annex IIIA, point XIII.3.1)

Acute oral toxicity N/A

Acute contact toxicity N/A

Effects on other beneficial arthropods (Annex IIIA, point XIII.3.1)

Acute oral toxicity N/A

Acute contact toxicity N/A

Acute toxicity to

…………………………………..

N/A

Bioconcentration (Annex IIA, point 7.5)

Bioconcentration factor (BCF) Performed on the relevant degradant DMH.

DMH: BCF <1.79

Formaldehyde (calculation) BCF =0.396

Depuration time (DT50) N/A



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(DT90)

Level of metabolites (%) in organisms

accounting for > 10 % of residues

None

Chapter 6: Other End Points

Acute Toxicity to Plants - DMH (Annex IIIA, XIII.3.2)

Species Endpoint Toxicity Soybean

Emergence (EC50) >1000 mg/kg

Cucumber

Emergence (EC50) 990 mg/kg

Oat

Emergence (EC50) >1000 mg/kg

Soybean)

Growth (EC50) >1000 mg/kg

Cucumber


Oat




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APPENDIX II - LIST OF TERMS AND ABBREVIATIONS

Stand. term / Abbreviation

Explanation

A ampere

ACh acetylcholine

AChE acetylcholinesterase

ADI acceptable daily intake

ADME administration distribution metabolism and excretion

ADP adenosine diphosphate

AE acid equivalent

AEL Systemic (= Internal) Acceptable Exposure Level

AECinhalative Inhalative (= External) Acceptable Exposure Concentration

AF assessment factor

AFID alkali flame-ionisation detector or detection

A/G albumin/globulin ratio

ai active ingredient

ALD50 approximate median lethal dose, 50%

ALT alanine aminotransferase (SGPT)

Ann. Annex

AMD automatic multiple development

ANOVA analysis of variance

AP alkaline phosphatase

approx approximate

ARC anticipated residue contribution

ARfD acute reference dose

as active substance

AST aspartate aminotransferase (SGOT)

ASV air saturation value

ATP adenosine triphosphate

BAF bioaccumulation factor

BCF bioconcentration factor

bfa body fluid assay


Explanation

BOD biological oxygen demand

bp boiling point

BPD Biocidal Products Directive

BSAF biota-sediment accumulation factor

BSE bovine spongiform encephalopathy

BSP bromosulfophthalein

Bt Bacillus thuringiensis

Bti Bacillus thuringiensis israelensis

Btk Bacillus thuringiensis kurstaki

Btt Bacillus thuringiensis tenebrionis

BUN blood urea nitrogen

bw body weight

c centi- (x 10 –2 )

°C degrees Celsius (centigrade)

CA controlled atmosphere

CAD computer aided design

CADDY computer aided dossier and data supply (an electronic dossier interchange and archiving format)

cd candela

CDA controlled drop(let) application

cDNA complementary DANN

CEC cation exchange capacity

cf confer, compare to

CFU colony forming units

ChE cholinesterase

CI confidence interval

CL confidence limits

cm centimetre

CNS central nervous system

COD chemical oxygen demand

CPK creatinine phosphatase



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Explanation

cv coefficient of variation

Cv ceiling value

d day(s)

DES diethylstilboestrol

DIS draft international standard (ISO)

DMSO dimethylsulfoxide

DNA deoxyribonucleic acid

dna designated national authority

DO dissolved oxygen

DOC dissolved organic carbon

dpi days post inoculation

DRP detailed review paper (OECD)

DT50(lab) period required for 50 percent dissipation (under laboratory conditions) (define method of estimation)

DT90(field) period required for 90 percent dissipation (under field conditions) (define method of estimation)

dw dry weight

DWQG drinking water quality guidelines

ε decadic molar extinction coefficient

EC50 median effective concentration

ECD electron capture detector

ED50 median effective dose

EDI estimated daily intake

EINECS European inventory of existing commercial substances

ELINCS European list of notified chemical substances

ELISA enzyme linked immunosorbent assay

e-mail electronic mail

EMDI estimated maximum daily intake

EN European norm

EPMA electron probe micro-analysis

ERL extraneous residue limit

ESPE46/51 evaluation system for pesticides


Explanation

EUSES European Union system for the evaluation of substances

F field

F0 parental generation

F1 filial generation, first

F2 filial generation, second

FBS full base set

FELS fish early-life stage

FIA fluorescence immuno-assay

FID flame ionisation detector

Fmol fractional equivalent of the metabolite´s molecular weight compared to the active substance

FOB functional observation battery

foc organic carbon factor (compartment dependent)

fp freezing point

FPD flame photometric detector

FPLC fast protein liquid chromatography

g gram(s)

GAP good agricultural practice

GC gas chromatography

GC-EC gas chromatography with electron capture detector

GC-FID gas chromatography with flame ionisation detector

GC-MS gas chromatography-mass spectrometry

GC-MSD gas chromatography with mass-selective detection

GEP good experimental practice

GFP good field practice

GGT gamma glutamyl transferase

GI gastro-intestinal

GIT gastro-intestinal tract

GL guideline level

GLC gas liquid chromatography

GLP good laboratory practice

GM geometric mean



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Explanation

GMO genetically modified organism

GMM genetically modified micro-organism

GPC gel-permeation chromatography

GPS global positioning system

GSH glutathione

GV granulosevirus

h hour(s)

H Henry’s Law constant (calculated as a unitless value)

ha hectare(s)

Hb haemoglobin

HC5 concentration which will be harmless to at least 95 % of the species present with a given level of confidence (usually 95 %)

HCG human chorionic gonadotropin

Hct haematocrit

HDT highest dose tested

hL hectolitre

HEED high energy electron diffraction

HID helium ionisation detector

HPAEC high performance anion exchange chromatography

HPLC high pressure liquid chromatography or high performance liquid chromatography

HPLC-MS high pressure liquid chromatography - mass spectrometry

HPPLC high pressure planar liquid chromatography

HPTLC high performance thin layer chromatography

HRGC high resolution gas chromatography

HS Shannon-Weaver index

Ht haematocrit

HUSS human and use safety standard

I indoor

I50 inhibitory dose, 50%

IC50 median immobilisation


Explanation

concentration or median inhibitory concentration 1

ICM integrated crop management

ID ionisation detector

IEDI international estimated daily intake

IGR insect growth regulator

im intramuscular

inh inhalation

INT 2-p-iodophenyl-3-p-nitrophenyl-5-phenyltetrazoliumchloride testing method

ip intraperitoneal

IPM integrated pest management

IR infrared

ISBN international standard book number

ISSN international standard serial number

IUCLID International Uniform Chemical Information Database

iv intravenous

IVF in vitro fertilisation

k (in combination)

kilo

k rate constant for biodegradation

K Kelvin

Ka acid dissociation constant

Kb base dissociation constant

Kads adsorption constant

Kdes apparent desorption coefficient

kg kilogram

KH Henry´s Law constant (in atmosphere per cubic metre per mole)

Koc organic carbon adsorption coefficient

Kom organic matter adsorption coefficient

Kow octanol-water partition coefficient

Kp solid-water partition coefficient

kPa kilopascal(s)

l, L litre



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Explanation

LAN local area network

LASER light amplification by stimulated emission of radiation

LBC loosely bound capacity

LC liquid chromatography

LC-MS liquid chromatography- mass spectrometry

LC50 lethal concentration, median

LCA life cycle analysis

LC-MS-MS liquid chromatography with tandem mass spectrometry

LD50 lethal dose, median; dosis letalis media

LDH lactate dehydrogenase

ln natural logarithm

LOAEC lowest observable adverse effect concentration

LOAEL lowest observable adverse effect level

LOD limit of detection

LOEC lowest observable effect concentration

LOEL lowest observable effect level

log logarithm to the base 10

LOQ limit of quantification (determination)

LPLC low pressure liquid chromatography

LSC liquid scintillation counting or counter

LSD least squared denominator multiple range test

LSS liquid scintillation spectrometry

LT lethal threshold

m metre

M molar

µm micrometre (micron)

MAC maximum allowable concentration

MAK maximum allowable concentration

MC moisture content

MCH mean corpuscular haemoglobin


Explanation

MCHC mean corpuscular haemoglobin concentration

MCV mean corpuscular volume

MDL method detection limit

MFO mixed function oxidase

µg microgram

mg milligram

MHC moisture holding capacity

MIC minimum inhibitory concentration

min minute(s)

MKC minimum killing concentration

mL millilitre

MLT median lethal time

MLD minimum lethal dose

mm millimetre

MMAD mass median aerodynamic diameter

mo month(s)

MOE margin of exposure

mol mole(s)

MOS margin of safety

mp melting point

MRE maximum residue expected

MRL maximum residue level or limit

mRNA messenger ribonucleic acid

MS mass spectrometry

MSDS material safety data sheet

MTD maximum tolerated dose

MT material test

MW molecular weight

n.a. not applicable

n- normal (defining isomeric configuration)

n number of observations

NAEL no adverse effect level

nd not detected

NEDI national estimated daily intake

NEL no effect level



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Explanation

NERL no effect residue level

ng nanogram

nm nanometre

NMR nuclear magnetic resonance

no, n° number

NOAEC no observed adverse effect concentration

NOAEL no observed adverse effect level

NOEC no observed effect concentration

NOED no observed effect dose

NOEL no observed effect level

NOIS notice of intent to suspend

NPD nitrogen-phosphorus detector or detection

NPV nuclear polyhedrosis virus

NR not reported

NTE neurotoxic target esterase

OC organic carbon content

OCR optical character recognition

ODP ozone-depleting potential

ODS ozone-depleting substances

OEL occupational exposure limit

OH hydroxide

OJ Official Journal

OM organic matter content

Pa pascal

PAD pulsed amperometric detection

2-PAM 2-pralidoxime

pc paper chromatography

PC personal computer

PCV haematocrit (packed corpuscular volume)

PEC predicted environmental concentration

PECA predicted environmental concentration in air

PECS predicted environmental concentration in soil

PECSW predicted environmental


Explanation

concentration in surface water

PECGW predicted environmental concentration in ground water

PED plasma-emissions-detector

pH pH-value

PHED pesticide handler’s exposure data

PIC prior informed consent

pic phage inhibitory capacity

PIXE proton induced X-ray emission

pKa negative logarithm (to the base 10) of the acid dissociation constant

pKb negative logarithm (to the base 10) of the base dissociation constant

PNEC predicted no effect concentration (compartment to be added as subscript)

po by mouth

POP persistent organic pollutants

ppb parts per billion (10 -9 )

PPE personal protective equipment

ppm parts per million (10 -6 )

PPP plant protection product

ppq parts per quadrillion (10 -24 )

ppt parts per trillion (10 -12 )

PSP phenolsulfophthalein

PrT prothrombin time

PRL practical residue limit

PT product type

PT(CEN) project team CEN

PTDI provisional tolerable daily intake

PTT partial thromboplastin time

QA quality assurance

QAU quality assurance unit

(Q)SAR quantitative structure-activity relationship

r correlation coefficient

r 2 coefficient of determination

RA risk assessment

RBC red blood cell



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Explanation

REI restricted entry interval

RENI Registry Nomenclature Information System

Rf retardation factor

RfD reference dose

RH relative humidity

RL50 median residual lifetime

RNA ribonucleic acid

RP reversed phase

rpm revolutions per minute

rRNA ribosomal ribonucleic acid

RRT relative retention time

RSD relative standard deviation

s second

S solubility

SAC strong adsorption capacity

SAP serum alkaline phosphatase

SAR structure/activity relationship

SBLC shallow bed liquid chromatography

sc subcutaneous

sce sister chromatid exchange

SCAS semi-continous activated sludge

SCTER smallest chronic toxicity exposure ratio (TER)

SD standard deviation

se standard error

SEM standard error of the mean

SEP standard evaluation procedure

SF safety factor

SFC supercritical fluid chromatography

SFE supercritical fluid extraction

SIMS secondary ion mass spectroscopy

S/L short term to long term ratio

SMEs small and medium sized enterprises

SOP standard operating procedures

sp species (only after a generic name)

SPE solid phase extraction


Explanation

SPF specific pathogen free

spp subspecies

SSD sulphur specific detector

SSMS spark source mass spectrometry

STEL short term exposure limit

STER smallest toxicity exposure ratio (TER)

STMR supervised trials median residue

STP sewage treatment plant

t tonne(s) (metric ton)

t½ half-life (define method of estimation)

T3 tri-iodothyroxine

T4 thyroxine

T25 tumorigenic dose that causes tumours in 25 % of the test animals

TADI temporary acceptable daily intake

TBC tightly bound capacity

TCD thermal conductivity detector

TG technical guideline, technical group

TGD Technical guidance document

TID thermionic detector, alkali flame detector

TDR time domain reflectrometry

TER toxicity exposure ratio

TERI toxicity exposure ratio for initial exposure

TERST toxicity exposure ratio following repeated exposure

TERLT toxicity exposure ratio following chronic exposure

tert tertiary (in a chemical name)

TEP typical end-use product

TGGE temperature gradient gel electrophoresis

TIFF tag image file format

TLC thin layer chromatography

Tlm median tolerance limit

TLV threshold limit value



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Explanation

TMDI theoretical maximum daily intake

TMRC theoretical maximum residue contribution

TMRL temporary maximum residue limit

TNsG technical notes for guidance

TOC total organic carbon

Tremcard transport emergency card

tRNA transfer ribonucleic acid

TSH thyroid stimulating hormone (thyrotropin)

TTC 2,3,5-triphenylterazoliumchloride testing method

TWA time weighted average

UDS unscheduled DNA synthesis

UF uncertainty factor (safety factor)

ULV ultra low volume

UR unit risk

UV ultraviolet

UVC unknown or variable composition,


Explanation

complex reaction products

UVCB undefined or variable composition, complex reaction products in biological material

v/v volume ratio (volume per volume)

vis visible

WBC white blood cell

wk week

wt weight

w/v weight per volume

ww wet weight

w/w weight per weight

XRFA X-ray fluorescence analysis

yr year

< less than

≤ less than or equal to

> greater than

≥ greater than or equal to

APPENDIX III - LIST OF ORGANISATIONS AND PUBLICATIONS

Abbreviation Explanation

ASTM American Society for Testing and Materials

BA Biological Abstracts (Philadelphia)

BART Beneficial Arthropod Registration Testing Group

BBA German Federal Agency of Agriculture and Forestry

CA(S) Chemical Abstracts (System)

CAB Centre for Agriculture and Biosciences International

CAC Codex Alimentarius Commission

CAS Chemical Abstracts Service

CCFAC Codex Committee on Food Additives and Contaminants

CCGP Codex Committee on General Principles

CCPR Codex Committee on Pesticide Residues

CCRVDF Codex Committee on Residues of Veterinary Drugs in Food

CE Council of Europe

CEC Commission of the European Communities

CEFIC European Chemical Industry Council

CEN European Committee for Normalisation

CEPE European Committee for Paints and Inks

CIPAC Collaborative International Pesticides Analytical Council Ltd

CMA Chemicals Manufacturers Association

COREPER Comite des Representants Permanents

COST European Co-operation in the field of Scientific and Technical Research

DG Directorate General

DIN German Institute for

Abbreviation Explanation Standardisation

EC European Commission

ECB European Chemicals Bureau

ECCO European Commission Co-ordination

ECDIN Environmental Chemicals Data and Information Network of the European Communities

ECDIS European Environmental Chemicals Data and Information System

ECE Economic Commission for Europe

ECETOC European Chemical Industry Ecology and Toxicology Centre

EDEXIM European Database on Export and Import of Dangerous Chemicals

EEC European Economic Community

EHC Environmental Health Criteria

EINECS European Inventory of Existing Commercial Chemical Substances

ELINCS European List of New Chemical Substances

EMIC Environmental Mutagens Information Centre

EPA Environmental Protection Agency

EPAS European Producers of Antimicrobial Substances

EPFP European Producers of Formulated Preservatives

EPO European Patent Office

EPPO European and Mediterranean Plant Protection Organization

ESCORT European Standard Characteristics of Beneficials Regulatory Testing

EU European Union

EUPHIDS European Pesticide Hazard Information and Decision Support System

EUROPOEM European Predictive Operator Exposure Model

EWMP European Wood Preservation



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Abbreviation Explanation Manufacturers

FAO Food and Agriculture Organization of the UN

FOCUS Forum for the Co-ordination of Pesticide Fate Models and their Use

FRAC Fungicide Resistance Action Committee

GATT General Agreement on Tariffs and Trade

GAW Global Atmosphere Watch

GIFAP Groupement International des Associations Nationales de Fabricants de Produits Agrochimiques (now known as GCPF)

GCOS Global Climate Observing System

GCPF Global Crop Protection Federation (formerly known as GIFAP)

GEDD Global Environmental Data Directory

GEMS Global Environmental Monitoring System

GRIN Germplasm Resources Information Network

IARC International Agency for Research on Cancer

IATS International Academy of Toxicological Science

ICBP International Council for Bird Preservation

ICCA International Council of Chemical Associations

ICES International Council for the Exploration of the Seas

ILO International Labour Organization

IMO International Maritime Organisation

IOBC International Organization for Biological Control of Noxious Animals and Plants

IPCS International Programme on Chemical Safety

IRAC Insecticide Resistance Action Committee

ISCO International Soil Conservation Organization


ISO International Organization for Standardisation

IUPAC International Union of Pure and Applied Chemistry

JECFA FAO/WHO

Joint Expert Committee on Food Additives

JFCMP Joint FAO/WHO Food and Animal Feed Contamination Monitoring Programme

JMP Joint Meeting on Pesticides (WHO/FAO)

JMPR Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Expert Group on Pesticide Residues (Joint Meeting on Pesticide Residues)

MITI Ministry of International Trade and Industry, Japan

NATO North Atlantic Treaty Organization

NAFTA North American Free Trade Agreement

NCI National Cancer Institute (USA)

NCTR National Center for Toxicological Research (USA)

NGO non-governmental organisation

NTP National Toxicology Program (USA)

OECD Organization for Economic Co-operation and Development

OLIS On-line Information Service of OECD

OPPTS Office of Prevention, Pesticides and Toxic Substances (US EPA)

OSPAR Oslo Paris Convention (Convention for the Protection of the Marine Environment of the North-East Atlantic)

PAN Pesticide Action Network

RIVM Netherlands National Institute of Public Health and Environmental Protection

RNN Re-registration Notification Network

RTECS Registry of Toxic Effects of Chemical Substances (USA)



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SETAC Society of Environmental Toxicology and Chemistry

SI Système International d'Unitès

SITC Standard International Trade Classification

TOXLINE Toxicology Information On-line

UBA German Environmental Protection Agency


UN United Nations

UNEP United Nations Environment Programme

WFP World Food Programme

WHO World Health Organization

WPRS West Palearctic Regional Section

WTO World Trade Organization

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