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EC number: 935-783-6 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
Description of key information
No data on Toxicokinetics, metabolism and distribution for Preventol KMX (reaction mass of 6-chloro-m-cresol, 2-chloro-m-cresol and m-cresol) are available. Therefore a read-across to 4-chloro-3-methylphenol in accordance with Regulation (EC) No 1907/2006 Annex XI 1.5. (Grouping of substances and read-across approach) was assessed as data for this component of Preventol KMX is available. It is likely that Preventol KMX is absorbed after oral, dermal and inhalation exposure. Subsequently transformation via glucuronidation and sulphatation into the respective conjugates will occur. Both, the parent and the conjugated substance will be eliminated quickly via the urine. Excretion via the feces may occur as parent compound and maybe as glutathione conjugate, but to a much lesser extent. No accumulation of Preventol KMX in different tissues and organs is to be expected after absorption as excretion is almost complete.
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
Additional information
No data on Toxicokinetics, metabolism and distribution for Preventol KMX (reaction mass of 6-chloro-m-cresol, 2-chloro-m-cresol and m-cresol) are available. Therefore a read-across to 4-chloro-3-methylphenol in accordance with Regulation (EC) No 1907/2006 Annex XI 1.5. (Grouping of substances and read-across approach) was assessed as data for this component of Preventol KMX is available. According to Annex XI 1.5 a read-across approach is possible for substances, whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity. The components 2-chloro-m-cresol, 6-chloro-m-cresol and 4-chloro-3-methylphenol (= 4-chloro-m-cresol) of Preventol KMX are isomers which differ only in the position of the chlorine atom on the benzene ring what makes a read-across feasible.
A literature search and QSAR predictions were performed for 2-chloro-m-cresol, 6-chloro-m-cresol using m-cresol and 4-chloro-3-methylphenol as reference substances. Next to physico-chemical properties, environmental fate, ecotoxicity, toxicity, and metabolism of chlorocresols and chlorophenols in various databases, special emphasis was set on determining the effects of different positions of chlorine on aromatic ring structures as this is the determinant difference between the 3 chlorocresol constituents, which may influence outcome in physicochemical and toxicological behaviour. The aim was to ensure a safe and legally valid analogue approach.
Physico-chemical properties
The chlorocresols 2-chloro-m-cresol, 6-chloro-m-cresol, 4-chloro-3-methylphenol and m-cresol are found to be similar in structure and the available data shows that the substances are similar in physico-chemical properties. A summary of the physico-chemical properties is given in the text below and table 1. The vapour pressures of the single components are all within the same range. The melting points are between 12 °C and 65 °C and the boiling points are between 196 °C and 235 °C. The partition coefficient n-octanol/water is similar too (logKow: 1.96 to 3.1). Furthermore 2-chloro-m-cresol, 6-chloro-m-cresol, 4-chloro-3-methylphenol and m-cresol are soluble in water (1.2 to 22.7 g/L). With 0.14 to 38.79 Pa the single components show a low to moderate vapour pressure. The melting point of Preventol KMX is somewhat lower than the melting points of the single components. This is in accordance with the higher vapour pressure of Preventol KMX. However these effects are not prominent and may be explained by the reaction process or impurities due to the technical nature of the test item.
Table 1: Physico-chemical properties of thechlorocresols and m-cresol
Name |
Preventol KMX |
4-chloro-3-methylphenol |
m-cresol |
2-chloro-m-cresol |
6-chloro-m-cresol |
CAS No. |
EG: 935-783-6 |
59-50-7 |
108-39-4 |
608-26-4 |
615-74-7 |
Boilingpoint |
199°C |
235°C |
202°C |
230°C |
196°C |
Meltingpoint |
- 26°C |
65°C |
12°C |
56°C |
46°C |
Density (20°C) |
1.189 g/cm³ |
1.370 g/cm³ |
1.030 g/cm³ |
1.228 g/cm³ |
1.215 g/cm³ |
Log Kow |
No data |
3.1 |
1.96 |
2.7 |
2.9 |
Log Koc (pH 7, 25°C) |
No data |
2.9 |
1.5 |
2.8 |
2.8 |
Water solubility (pH 7, 25°C) |
No data |
3.83 g/L |
22.7 g/L |
1.2 g/L |
1.3 g/L |
Vapour pressure (25°C) |
100 Pa (20°C) |
0.144 – 10 Pa |
14.70Pa |
5.94 Pa |
38.79 Pa |
Toxicological data
When comparing available data of toxicological effects of the chloro-cresols and m-cresol it became obvious that the substances despite the physical and chemical similarities show also a comparable pattern of toxicological effects (see table 2). For instance, Preventol KMX and 4-chloro-3-methylphenol, met the criteria to be classified as harmful in contact with skin and if swallowed (Xn, R21/22) while m-cresol met the criteria for classification as toxic in contact with skin or if swallowed (self-classification for Preventol KMX within this dossier and data achieved from the European chemical Substances Information System for 4-chloro-3-methylphenol and m-cresol). When regarding corrosion/irritation, Preventol KMX and m-cresol caused burns while 4-chloro-3-methylphenol was not classified for skin irritation but for Risk of serious damage to eyes.
Table 2: Comparison of available data on classification and labeling
Name |
Preventol KMXa) |
4-chloro-3-methylphenolb) |
m-cresolb) |
2-chloro-3-methylphenol |
6-chloro-3-methylphenol |
Classification |
Xn, R21: Harmfull in contact with skin |
Xn, R21 Harmfull in contact with skin |
T, R24: Toxic in contact with skin |
- |
- |
Xn, R22: Harmfull if swallowed |
Xn, R22: Harmfull if swallowed |
T, R25: toxic if swallowed |
Xn, R22: Harmfull if swallowedc) |
Xn, R22: Harmfull if swallowedc) |
|
- |
R43: May cause sensitisation by skin contact |
- |
Xn, R43: May cause sensitisation by skin contactc) |
Xn, R43: May cause sensitisation by skin contactc |
|
C, R34:Causes burns |
- |
C, R34: Causes burns |
- |
Xi, R38:Irritating to skinc) |
|
- |
R41: Risk of serious damage to eyes |
- |
- |
|
|
Specific concentration limits |
|||||
- |
Conc. >=10%, R21/R22 |
Conc. 1-5% Xn, R21/R22 |
- |
- |
a)According to self-classification suggested within this registration process
b)According to the European Chemical Substances Information System
c)According to the Danish Environmental Protection Agency’s advisory list for self-classification of dangerous substances
Absorbtion and Metabolism
In a study with 4-chloro-3-methylphenol (Schmidt, 1980), a single oral gavage of 300 mg/kg bw unlabeled test substance was administered to male Wistar rats. 62.7% of the total applied dose was excreted via the urine within 24 hours after application and small quantities were detected up to 72 hours after application. Two polar metabolites were also detected in the urine. These metabolites are not included in the quantification and could account for the 30% of test substance not detected within this study. The faeces represented the minor excretion route with a mean value of only 0.4% of the applied dose excreted within 24 hours after application. These results suggest that there is no accumulation of 4-chlor-3-methylphenol in fatty tissues. This suggestion was confirmed in a study, where three groups of male Wistar rats received oral doses of 150, 500 or 1500 ppm 4-chloro-3-methylphenol in diet over 13 weeks (Schmidt&Bomhard, 1981). The liver and samples of fatty tissue from the abdominal cavity were removed from 3 animals per dose group 1, 4, 8 and 13 weeks after start of treatment. No test substance was detected within samples of the liver tissue, and in samples of the fat tissue the test substance was detected only occasionally. No cumulative effect of 4-chloro-3-methylphenol was observed.
Metabolism data for other phenolic compounds like o-phenylphenol (Bartels et al., 1998) or o-benzyl-p-chlorophenol (Kao & Birnbaum, 1986) demonstrate that phenolics are metabolised predominantly by glucuronidation and sulphatation of the phenolic hydroxyl group. In analogy to the phenols, the metabolic fate is expected to be the same for all compared chloro-cresols (not being influenced by the position of the chlorine). Halogen atoms like chlorine bound to aryl groups are frequently substituted by glutathione by glutathione S-transferase isozymes (Casarett and Doull's Toxicology: The Basic Science of Poisons, 7th edition, C.D.Klaassen, McGraw-Hill). Glutathione conjugates are predominantly excreted via bile whereas sulphates and glucuronides are typical urinary metabolites. Since all chlorocresols have an appreciable solubility in water (>1.2 g/L at 25 °C, pH 7), urinary excretion of unchanged substance can also be possible in all cases independent of the position of the chlorine. The glucuronide and sulphate conjugates are likely to represent the two polar metabolites detected in the study of the Schmidt (1980). The unchanged parent compound was also identified in the urine in this study.
Due to the similar physico-chemical properties of the chloro-cresols, absorption of the substances after oral, dermal or inhalation exposure is expected to be comparable, independent of the position of the halogen substituent. Permeation of 4-chloro-3-methylphenol was investigated in vitro with epidermal membranes from human abdominal skin. The publication revealed a permeability coefficient of 9.16 × 10E–4/minute corresponding to 55 × 10E–3 cm/hour (4 g/L, lag time 17 minutes, 25°C). No damage of the membrane was observed (Roberts et al., 1977). Absorption of Preventol KMX via both the oral and the dermal route is evident as in the acute oral and the acute dermal study performed with Preventol KMX at least similar clinical signs of toxicity occurred. Upon oral gavage of 2000 mg/kg bw 2/3 animals died and clinical signs of toxicity comprised of decreased motility, narrowed palpebral fissure, piloerection, lateral position, abdominal position, tremor, and labored breathing (Gillissen, 2011; see chapter 7.2.1 acute oral toxicity). After dermal application of Preventol KMX at a dose of 1000 mg/kg bw to females and 2000 mg/kg bw to males under semiocclusive conditions for 24 hours also decreased motility, narrowed palpebral fissure and piloerection were seen in animals of both sexes (Gillissen, 2011; see chapter 7.2.3 dermal oral toxicity). Additional to this findings bloody urine was observed after dermal application. This may indicate the substance to be systemically available.
Based on the above mentioned effects it is likely that Preventol KMX is absorbed after oral, dermal and inhalation exposure. Subsequently transformation via glucuronidation and sulphatation into the respective conjugates will occur. Both, the parent and the conjugated substance will be eliminated quickly via the urine. Excretion via the feces may occur as parent compound and maybe as glutathione conjugate, but to a much lesser extent. No accumulation of Preventol KMX in different tissues and organs is to be expected after absorption as excretion is almost complete.
Conclusion
Taking all this together, this validates the attempt to make a safe analogue approach from 4-chloro-3-methylphenol, to 2-chloro-m-cresol and 6-chloro-m-cresol. Hence, 4-chloro-3-methylphenol is determined as a suitable read-across substance to predict toxicity endpoints and toxicokinetic parameters in the chemical risk assessment of reaction mass of 6-chloro-m-cresol, 2-chloro-m-cresol and m-cresol (Preventol KMX). To support the read across additional data of m-cresol will be used. Detailed justifications for the read-across is provided in the technical dossier (see IUCLID Section 13) as well as in the Chemical Safety Report (see Part B).
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