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EC number: 470-470-3 | CAS number: 9022-75-7
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 7 August 2008 to 15 May 2009
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP study conducted according to OECD guideline 421 with minor deviation: 7 females instead of a minimum of 8 required were obtained in the control group.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 009
- Report date:
- 2009
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- yes
- Remarks:
- 7 females instead of a minimum of 8 required were obtained in the control group.
- Principles of method if other than guideline:
- Not applicable
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Details on test material:
- - Name of test material (as cited in study report): CHIMEXANE NV
- Physical state: white to beige paste
- Analytical purity: see confidential details on test material
-Impurities (identity and concentrations): see confidential details on test material
- Purity test date: 5 November 2007
- Lot/batch No.: 0135825
- Expiration date of the lot/batch: 31 October 2008
- Storage condition of test material: at room temperature and protected from humidity
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: 11 weeks
- Weight at study initiation: mean body weight for males: 430 g (range: 393 g to 461 g) and for females: 274 g (range: 257 g to 288 g)
- Housing: individually housed in wire-mesh cages; towards the end of gestation and during lactation, the females were individually housed, and with
their litter after birth
- Diet (e.g. ad libitum): SsniffR/M-H pelleted maintenance diet, SSNIFF Spezialdiäten GmbH, Soest, Germany, ad libitum
- Water (e.g. ad libitum): filtered tap water, ad libitum
- Acclimation period: 6 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 50 ± 20
- Air changes (per hr): approximately 12 cycles/hour
- Photoperiod (hrs dark / hrs light): 12 h/12 h
IN-LIFE DATES: From: 13 August 2008 To: 6 October 2008
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- purified by reverse osmosis
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test item was administered as a suspension in the vehicle. The test item was mixed with the required quantity of vehicle in order to achieve the concentrations of 10, 30 and 120 mg/mL. The dosage forms were prepared for up to 3 days or 9 days of treatment following satisfactory results in the stability test over a 3-day or 9-day storage period at +4°C and protected from light. When not in use, the dosage forms were kept at +4°C and protected from light.
VEHICLE
- Concentration in vehicle: 10, 30 and 120 mg/mL
- Amount of vehicle (if gavage): constant dosage-volume of 5 mL/kg bw/day
- Purified water, obtained by reverse osmosis using Elix 5 (Millipore SA, Saint-Quentin en Yvelines, France) - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: overnight
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: each female was placed with the same male until mating occurred or 14 days had elapsed
- After successful mating each pregnant female was caged individually - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The test item concentration in samples of each control and test item dosage form prepared for use in weeks 1, 4 and 7 was determined. The dosage form samples were assayed using a validated method. The test item concentrations in the administered dosage forms analyzed in weeks 1, 4 and 7 of treatment remained within an acceptable range of [-2.2% to +6.7%] of variation compared to the nominal values.
- Duration of treatment / exposure:
- Males: 2 weeks before mating, during the mating (maximum of 2 weeks) and post-mating periods (at least 2 weeks) until sacrifice (after the majority of the females per group had delivered; at least 6 weeks in total).
Females: 2 weeks before mating, during the mating period (maximum of 2 weeks), during gestation and lactation, until day 4 post-partum inclusive (or until sacrifice for un-mated and non-pregnant females). - Frequency of treatment:
- Once a day, 7 days a week
- Details on study schedule:
- None
Doses / concentrationsopen allclose all
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 150 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 600 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose-levels were based on the results of the 4-week toxicity study (CIT/Study No. 23232 TSR) in which the same test item was administered by gavage at the dose-levels of 50, 150 and 600 mg/kg/day:
- no mortality occurred at any dose-level,
- at 50 mg/kg/day, epithelial cell hyperplasia and/or submucosal edema were seen in the forestomach of one male and one female,
- at 150 mg/kg/day, ptyalism was noted in all animals and epithelial cell hyperplasia, hyperkeratosis, submucosal edema and erosion or ulceration were noted in the forestomach of one male and one female,
- at 600 mg/kg/day, ptyalism and loud/abdominal breathing were noted in all animals. Epithelial cell hyperplasia, hyperkeratosis, submucosal edema and erosion or ulceration were noted in the forestomach of three males and three females. - Positive control:
- None
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: each animal was checked at least twice a day for mortality and signs of morbidity during the treatment period and once a day during the acclimation period.
CLINICAL OBSERVATIONS: Yes (including evidence of resorption for the females)
- Time schedule: each animal was observed at least once a day, at approximately the same time
BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of each male was recorded once before group allocation, on the first day of treatment (day 1), then once a week until sacrifice. The body weight of each female was recorded once before group allocation, on the first day of treatment (day 1), then once a week until mated (or until sacrifice) and on days 0, 7, 14 and 20 post-coitum and days 1 and 5 post-partum.
FOOD CONSUMPTION: Yes
The quantity of food consumed by each male was recorded once a week, over a 7-day period, from the first day of treatment until sacrifice.
The quantity of food consumed by each female was recorded once a week, over a 7-day period, from the first day of treatment through gestation (days 0-7, 7-14, 14-20 post-coitum intervals) and lactation (days 1-5 post-partum interval) until sacrifice.
During the mating period, the food consumption was noted for neither males nor females.
WATER CONSUMPTION: No - Oestrous cyclicity (parental animals):
- The estrous cycle stage was recorded daily until the female was positive for mating.
- Sperm parameters (parental animals):
- No data
- Litter observations:
- PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
- the total litter size and numbers of pups of each sex were recorded as soon as possible after birth. The litters were observed daily in order to note the number of live, dead and cannibalized pups. An external examination of each pup was carried out and any external malformation was noted.
- the pups were observed daily, including during weekends and public holidays, for clinical signs or abnormal behavior.
- the weight of each pup was recorded on days 1 and 5 post-partum.
GROSS EXAMINATION OF PUPS:
Pups were sacrificed at post-partum day 5. A macroscopic examination was performed for all pups, including those found dead. Macroscopic lesions were preserved in 10% buffered formalin (or another appropriate fixative) and were not microscopically examined in a first instance. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: after the delivery of the majority of the females per group
- Maternal animals: on day 5 post-partum; females which did not mate: 24-26 days after the last day of the mating period; females which had not delivered on day 25 post-coitum: on day 25 or day 26 post-coitum
GROSS NECROPSY
Gross necropsy consisted of examination of the external surfaces, all orifices, the cranial cavity, the external surfaces of the brain, the thoracic, abdominal and pelvic cavities with their associated organs and tissues and the neck with its associated organs and tissues.
In all females, the number of implantation sites and corpora lutea was recorded.
In the females which did not mate or were apparently non-pregnant, the presence of implantation sites on the uterine horns were checked using ammonium sulphide staining technique.
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 1 were weighed and/or prepared for microscopic examination (10% buffered formalin (except for testes and epididymides which were fixed in Davidson’s fixative) - Postmortem examinations (offspring):
- Not applicable
- Statistics:
- Data other than organ weights: mean values were compared by one-way analysis of variance and the Dunnett test (mean values being considered as normally distributed and variances being considered as homogeneous). Percentage values were compared by the Fisher exact probability test.
Organ weights: PathData software (version 6.2b5) was used for the statistical analysis of organ weight data (level of significance: 0.05 or 0.01). - Reproductive indices:
- Pre-implantation loss = 100 × (Number of corpora lutea - Number of implantation sites) / Number of corpora lutea
Post-implantation loss = 100 × (Number of implantation sites - Number of live concepti) / Number of implantations
Mating index = 100 × Number of mated animals / Number of paired animals
Fertility index = 100 × Number of pregnant female partners / Number of mated pairs
Gestation index = 100 × Number of females with live born pups / Number of pregnant females
Live birth index = 100 × Number of live born pups / Number of delivered pups - Offspring viability indices:
- Viability index on day 4 post-partum = 100 × Number of surviving pups on day 4 post-partum / Number of live born pups
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Excessive salivation, loud breathing and/or half-closed eyes transiently throughout the treatment period in the males or for a few days in the females
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At 600 mg/kg/day, during week 1, males gained less weight than controls and an initially lower mean food consumption was noted in males and females.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- At 600 mg/kg/day, during week 1, males gained less weight than controls and an initially lower mean food consumption was noted in males and females.
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- not specified
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Details on results (P0)
Males
At 600 mg/kg/day, all males presented excessive salivation (recorded as ptyalism) throughout the study (from day 4 or 5 until day 44). Half-closed eyes were observed in 9/10 males transiently throughout the study and loud breathing was noted in 7/10 males for a few days generally towards the end of the treatment period.
At 150 mg/kg/day, excessive salivation was observed transiently throughout the treatment period in 9/10 rats. In addition to excessive salivation, loud breathing and half-closed eyes were noted towards the end of the treatment period in one male, together with hypoactivity and emaciated appearance.
At 50 mg/kg/day, no test item treatment-related clinical signs were noted.
Females
At 600 mg/kg/day, during nearly the whole treatment period (including premating, gestation and lactation periods), almost all females presented excessive salivation and had half-closed eyes. Loud breathing was observed in one female at the end of the premating period, beginning and end of gestation and during lactation until terminal sacrifice, in another female during gestation and in four other females during the lactation period only.
One female, which was sacrificed on day 25 post-coitum due to absence of delivery, showed loud breathing on day 24 post-coitum.
At 150 mg/kg/day, one female showed excessive salivation transiently during the premating period, during gestation (on day 0 post-coitum only) and during lactation (from days 3 to 4 post-partum). Excessive salivation was also noted in one female from days 7 to 9 post-coitum.
At 50 mg/kg/day, only one female showed pallor of extremities and eyes, piloerection, round back and reddish vaginal discharge during lactation.
BODYWEIGHT:
Males
At 600 mg/kg/day, during week 1, males gained less weight than controls (23 g versus 44 g, p<0.001). However, throughout the study, mean body weights remained relatively unchanged compared to controls (-6% on day 43). The overall mean body weight gain was slightly lower than controls: 117 g versus 151 g, not statistically significant.
At 50 and 150 mg/kg/day, body weights were unaffected by the test item treatment.
Females
No test item treatment-related effects were noted at any dose-level during the premating period. From day 0 to day 7 of pregnancy, the mean body weight gain at 600 mg/kg/day was slightly lower than that of controls (22 g vs. 30 g) and mean body weights were slightly lower on day 7
and day 14 of pregnancy (315 g vs. 342 g, p<0.01, on day 7 of pregnancy and 355 g vs. 382 g, p<0.01, on day 14 of pregnancy). Thereafter, during pregnancy and lactation mean body weight gains were similar to those of the controls.
At 50 and 150 mg/kg/day, the mean body weight gains were similar to those of the controls during pregnancy and lactation.
FOOD CONSUMPTION:
Males
At 600 mg/kg/day, an initially lower mean food consumption was noted in the males when compared to controls (days 1 to 8: 30 g/day/male versus 34 g/day/male, -12%, p<0.001). Thereafter, similar mean food consumption was noted between all groups.
At 50 and 150 mg/kg/day, treatment with the test item had no effects on the mean food consumption.
Females
At 600 mg/kg/day, at the start of the premating period, females consumed less food than controls (days 1 to 8: 19 g/day/female versus 23 g/day/female, -17%, p<0.001). A similar effect was noted at the start of the gestation period (interval days 0 to 7 post-coitum: 24 g/day/female versus 30 g/day/female, -20%, p<0.01).
At 50 and 150 mg/kg/day, mean food consumption was generally unaffected by treatment with the test item whatever the study period; some slight differences were recorded but were transient and not dose-related.
REPRODUCTIVE DATA:
Mating data: Except for one female given 150 mg/kg/day, all pairs mated and the mean number of days of pairing before mating was 6.2, 3.0, 2.3 or 3.3 days.
Estrous cycles: No anomaly was detected in estrous stages that could be considered to be test item treatment-related. At 150 mg/kg/day, one female which did not mate was in diestrus for 6 consecutive days.
Fertility data: Three control, two low-dose and two high-dose females were not pregnant.
Delivery data: All groups had a similar mean duration of gestation and groups treated with the test item had similar mean numbers of corpora lutea and implantation sites per litter as the controls. The mean number of pups were delivered per litter and the mean number of live pups per litter on day 1 p.p. were unaffected by the test item treatment.
ORGAN WEIGHTS:
Statistically significant decrease in absolute and relative ovary weights was noted in females treated from 150 mg/kg/day (see table 2). However, given the absence of microscopic findings and the absence of significant decrease of pregnancy successes in rats from these groups, these findings were considered to be due to chance (i.e. bear no relationship to treatment) and be of no toxicological importance.
MACROSCOPIC EXAMINATION:
No treatment related macroscopic changes were noted in treated F0 parent animals. The gross changes noted in treated rats were those that may be occasionally encountered in rats of this age, strain and source breeder.
MICROSCOPIC EXAMINATION:
No treatment-related microscopic findings were noted in the testes, epididymides and ovaries of treated rats at any dose-levels.
Microscopic changes noted in the treated animals either were observed at similar incidence and severity as the control group or were those that are occasionally observed in control untreated rats.
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- systemic toxicity
- Effect level:
- 150 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Excessive salivation transiently throughout the treatment period in the males or for a few days in the females
- Dose descriptor:
- NOEL
- Remarks:
- mating and fertility
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
Details on results (F1)
The number of pups dying between days 1 and 4 or 5 post-partum was not impacted by the test
item treatment. In addition, no test item treatment-related clinical signs were noted for any pup.
BODY WEIGHT:
On day 5 p.p., at 600 mg/kg/day, male and female mean pup body weight was minimally lower than in controls. This correlated to slightly lower mean body weight gain noted in the pups during the lactation period, when compared to controls (3.8 g vs. 4.4 g, statistically non-significant). Changes were of similar amplitude in males and females. These changes were considered to be negligible.
At 50 and 150 mg/kg/day, no test item treatment-related differences were noted compared to controls.
SEX RATIO:
The mean percentage of male pups was between 43.4% and 55.7% at birth and between 41.5% and 56.6% on day 5 post-partum. There were thus no effects of the test item on the sex ratio of the pups at any dose-level.
NECROPSY FINDINGS:
There were no test item treatment-related macroscopic post-mortem observations in pups found dead or sacrificed on day 5 post-partum.
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Remarks:
- developmental toxicity
- Generation:
- F1
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Table 2: mean final body weights and mean ovaries weights
Dose (mg/kg bw/day) |
0 |
50 |
150 |
600 |
Number of females |
n = 10 |
n = 10 |
n = 10 |
n = 10 |
Final mean body weight (g) |
352.9 ± 27.34 |
351.8 ± 22.42 |
370.3 ± 26.07 |
345.0 ± 26.35 |
Number of pregnant females |
n = 7 |
n = 8 |
n = 9 |
n = 8 |
Ovaries mean weight (g) |
0.21686 ± 0.027 |
0.20538 ± 0.036 |
0.16889 ± 0.027 ** |
0.17650 ± 0.024 * |
Mean % body |
0.05926 ± 0.009 |
0.05766 ± 0.013 |
0.04553 ± 0.010 * |
0.04989 ± 0.005 |
Mean ± SD; */**): Dunnett's test based on pooled variances at 5% (*) or 1% (**) level
Applicant's summary and conclusion
- Conclusions:
- Under the experimental conditions of this study, it was considered that the No Observed Adverse Effect Level (NOAEL) for systemic toxicity is 150 mg/kg bw/day, the No Observed Effect Level (NOEL) for mating and fertility is 600 mg/kg bw/day and the NOAEL for developmental toxicity is 600 mg/kg bw/day.
- Executive summary:
In a GLP study conducted according to OECD guideline 421, Chimexane NV was administered daily by oral gavage to male and female Sprague-Dawley rats (10/sex/dose) at dose-levels of 50, 150 or 600 mg/kg bw/day for 2 weeks before mating, during mating, gestation and until day 4 post-partum for the females, and after the majority of the females per group had delivered, for the males. A control group received the vehicle (purified water) under the same experimental conditions.
During the dosing period, each F0 animal was observed twice daily for mortality and once daily for clinical signs. Body weight was recorded once before group allocation, on the first day of treatment and then about once a week until sacrifice. Food consumption was recorded about once a week, over a 7-day period, from the first day of treatment until sacrifice (except during the mating period). Animals were paired for a maximum of 14 days and the estrous cycle stage was recorded each morning until mating occurred. All F0 females of all groups were allowed to deliver normally and to rear their progeny until day 5 p.p.. Gestation and litter parameters were recorded and during the lactation period each pup was observed daily for survival and clinical signs. Pup body weight was recorded on days 1 and 5 p.p.. A macroscopic post-mortem examination was performed on all F0 parent animals and on all pups. All macroscopic lesions were sampled and preserved. Testes, epididymides, prostate and seminal vesicles from all F0 males and ovaries from all F0 females which delivered and were sacrificed on day 5 p.p. were weighed. Testes, epididymides, ovaries and any macroscopic lesions from F0 high-dose and control parent animals were microscopically examined.
The test item elicited effects at 600 mg/kg bw/day including transient reduced body weight gain and food consumption, particularly in the males, and excessive salivation, loud breathing and half-closed eyes in both sexes. There were no effects on mating, fertility, gestation or delivery and survival of the pups was not affected during the first days of lactation. There were no treatment-related macroscopic or microscopic findings. Similar clinical signs (excessive salivation) were observed in animals treated at 150 mg/kg bw/day but at a much lower incidence. These signs were considered not to be adverse. No other effects were observed. No treatment-related effects were observed at 50 mg/kg bw/day.
Under the experimental conditions of this study, it was considered that the No Observed Adverse Effect Level (NOAEL) for systemic toxicity is 150 mg/kg bw/day, the No Observed Effect Level (NOEL) for mating and fertility is 600 mg/kg bw/day and the NOAEL for developmental toxicity is 600 mg/kg bw/day.
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