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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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- chronic toxicity: oral
- Remarks:
- combined repeated dose and carcinogenicity
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP compliant OECD Guideline 453 study with minor deviation: Haematological examinations were performed on 10 instead of 20 rats/sex/group.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 993
- Report date:
- 1993
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- Deviations:
- yes
- Remarks:
- Haematological examinations were performed on 10 instead of 20 rats/sex/group.
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Chlorocresol
- EC Number:
- 200-431-6
- EC Name:
- Chlorocresol
- Cas Number:
- 59-50-7
- Molecular formula:
- C7H7ClO
- IUPAC Name:
- 4-chloro-3-methylphenol
- Details on test material:
- - Name of test material (as cited in study report): Preventol CMK
- Physical state: colourless powder
- Analytical purity: 99.90% (batch 792) and 99.70% (batch 458)
- Lot/batch No.: 792 and 458
- Stability under test conditions: Stability of the test substance in feed was confirmed for the study period.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Bor:WISW (SPF Cpb)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: F. Winkelmann, Borchen, Germany
- Age at study initiation: approx. 5-6 weeks
- Weight at study initiation: 102-139 g (males), 94-125 g (females)
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- peanut oil
- Details on oral exposure:
- VEHICLE
- Concentration in vehicle: 100% of nominal concentrations - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 24 month and 53 weeks (interim sacrifice group)
- Frequency of treatment:
- daily, free daily, free access to the diet containing the test substance.
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
400, 2000, 10000 ppm
Basis:
nominal in diet
- Remarks:
- Doses / Concentrations:
21.0, 103.1, 558.9 mg/kg bw/day (males)
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
27.7, 134.3, 743.5 mg/kg bw/day (females)
Basis:
actual ingested
- No. of animals per sex per dose:
- 50 per sex and dose level (2-year group)
10 per sex and dose level (interim sacrifice group (53 weeks) - Control animals:
- yes, concurrent no treatment
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS AND MORTALITY: Yes, at least twice daily (once daily on weekends and bank holidays)
DETAILED CLINICAL OBSERVATION: Yes, once weekly. Once weekly body surfaces and orifices, posture, general behaviour, respiration and excretory products were assessed.
BODY WEIGHT: Yes, before start of treatment, then once weekly and prior to necropsy
FOOD CONSUMPTION: Yes, week 1-13: once weekly, week 14-termination: once monthly
WATER CONSUMPTION: Yes, once monthly
OPHTHALMOSCOPIC EXAMINATION: Yes, 20 animals per sex per group: prior to start. Additional 20 animals per sex of the control and highest dose group: after 53 and 104 weeks
HAEMATOLOGY: Yes, at 10 rats/sex/group in 6 month intervals
- Parameters checked: Differential blood count using smears, haematocrit, haemoglobin concentration, erythrocyte count, leukocyte count, reticulocyte count, total platelet count, MCH, MCHC, MCV
CLINICAL CHEMISTRY:Yes, at 10 rats/sex/group in weeks 26/27, 51/52, 78/79, 103/104
- Parameters checked: Sodium, potassium, chloride, calcium, phosphate, glucose, total cholesterol, triglyceride, urea, total bilirubin, creatinine, total protein, albumin, creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase
URINALYSIS: Yes, at 10 rats/sex/group in 6 month intervals urine was collected during 16 hour intervals (overnight)
- Parameters checked: Semi-quantitative: pH, protein, glucose, ketone bodies, blood, bilirubin, sediment, urobilinogen
Quantitative: density, creatinine, protein, volume - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, all surviving animals at terminal sacrifice and on all animals dying spontaneously or sacrificed moribund during the study. At interim sacrifice 10 rats per sex and dose level.
ORGAN WEIGHTS: Yes, all surviving animals at interim and terminal sacrifice. The weight of following organs was assessed: Brain, heart, kidneys (in pairs), liver, ovaries (in pairs), testicles (in pairs), spleen.
HISTOPATHOLOGY: Yes, all surviving animals at terminal sacrifice and from 10 animals per sex and dose level at interim sacrifice. Histopathology was performed with following organs: Adrenals, aorta, bone, bone marrow (in femur and sternum), brain, caecum, cervix, colon, duodenum, tattooed ears, epididymides, Esophagus, eyes, eyelids, extraorbital lachrymal glands, femur with knee-joint, gross lesions, Harderian glands, head, heart, ileum, jejunum, kidneys, liver, lungs, lymph nodes (mandibular and mesenteric), mammary gland, optic nerve, ovaries, oviducts, pancreas, pituitary, prostate gland, rectum, salivary glands, sciatic nerve, seminal vesicle, muscle (thigh), skin, spinal cord, spleen, sternum, stomach, testicles, thymus, thyroid gland, tongue, trachea, ureters, urethra, urinary bladder, uterus, vagina, Zymbal glands - Statistics:
- Arithmetic group means and standard deviations for body weight, food consumption, water-intake, blood and urine analysis and organ weights were determined. The values for the test collective were compared with the control collective by significance test (U-test) using the Mann-Whitney test or by Wilcoxon´s method on the significance level alpha = 5% and alpha = 1% (two-tailed).
Differences with p-values ≤ 0.01 and 0.05 were considered statistically significant.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- No treatment related death occured. Females of the mid and high dose in general poor condition.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- No treatment related death occured. Females of the mid and high dose in general poor condition.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Delayed body weight development at high dose (males and females)
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- Males of the high dose showed a higher water intake.
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Some parameters were affected.
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- mainly inceased kidney weights beginning in males at the mid dose.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- deformation of the kidneys in males of the high dose group.
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Kidney effects in males of the high dose group.
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY: The number of animals of the main groups dying during the study period was slightly lower than that of controls in the case of males, and in the case of treated females slightly higher (after 400 and 10,000 ppm) or comparable to controls. The deaths were considered to be not treatment-related.
Females showed a dose-related increase in the frequency of poor general condition, which was statistically significant in the highest dose group. In addition from week 90 (approx.) females exhibited more frequently increased abdominal circumference. Females of the mid and high dose groups showed a significant decrease in the frequency of this finding compared to control animals.
BODY WEIGHT AND WEIGHT GAIN: Body weight development was not significantly affected up to 2000 ppm. At 10,000 ppm, both sexes showed delayed body weight gain.
FOOD CONSUMPTION: No treatment-related effects were seen.
WATER CONSUMPTION: Water intake of males at 10,000 ppm was higher than that of control animals. In all other groups and in females no effects on water consumption were seen.
OPHTHALMOSCOPIC EXAMINATION: No treatment-related effects were seen.
HAEMATOLOGY: No treatment-related effects were seen.
CLINICAL CHEMISTRY: Males and females of the highest dose group showed partly statistically significant reduced cholesterol and triglyceride concentrations at all investigation time points.
In the mid dose group males and females showed a tendency to lower potassium values.
Phosphate values of males and females at the high dose were statistically significant lower.
For the other electrolytes isolated statistically significant higher and lower values were recorded at different time points. These findings were considered to be not dose-related.
URINALYSIS: No treatment-related effects were seen.
ORGAN WEIGHTS: Interim sacrifice: No effects
Terminal sacrifice: Males of the mid and high dose group showed slightly increased kidney weights.
Females of the high dose group showed slightly increased kidney weights and increased relative ovary weights.
GROSS PATHOLOGY: Interim sacrifice: No treatment-related effects were noted.
Terminal sacrifice: 6 males of the high dose group showed a deformation of kidneys. There were no other treatment-related gross pathological findings.
HISTOPATHOLOGY: NON-NEOPLASTIC: Males of the high dose group showed a increased number of papillary necroses and cortical dilatation of the collecting tubules and cortical fibroses in the kidneys.
HISTOPATHOLOGY: NEOPLASTIC: Gross pathological and histopathological investigations gave no indication of carcinogenic effects of the test compound at doses up to and including 10,000 ppm.
Effect levels
open allclose all
- Dose descriptor:
- LOAEL
- Effect level:
- 10 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: based on decreased bw gain in both sexes and kidney effects in males
- Dose descriptor:
- LOAEL
- Effect level:
- 559 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: based on decreased bw gain and kidney effects in males
- Dose descriptor:
- LOAEL
- Effect level:
- 744 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: based on decreased bw gain
- Dose descriptor:
- NOAEL
- Effect level:
- 2 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No treatment related adverse effects were seen in animals of this treatment group.
- Dose descriptor:
- NOAEL
- Effect level:
- 103 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: No treatment related adverse effects were seen in animals of this treatment group.
- Dose descriptor:
- NOAEL
- Effect level:
- 134 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: No treatment related adverse effects were seen in animals of this treatment group.
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Summary of affected parameters upon clinical chemistry, haematology and urinalysis
|
Dose group (ppm) |
|
|||||||||
0 |
400 |
2000 |
10,000 |
Dose-related |
|||||||
sex |
male |
female |
male |
female |
male |
female |
male |
female |
male |
female |
|
parameter |
|
||||||||||
Cholesterol |
− |
− |
− |
↓** |
− |
− |
↓** |
↓** |
− |
− |
|
Triglycerides |
− |
− |
− |
↓* |
↑** |
↑* |
↓* |
↓** |
− |
− |
|
Potassium |
− |
− |
− |
− |
↓* |
↓** |
↓** |
↓** |
+ |
+ |
|
Phosphate |
− |
− |
− |
− |
− |
− |
↓** |
↓** |
+ |
+ |
|
* p < 0.05; ** p < 0.01 |
Table 2: Summary of results
|
Control |
400 ppm |
2000 ppm |
10,000 ppm |
Dose-response |
|||||
Sex |
male# |
female# |
male# |
female# |
male# |
female# |
male# |
female# |
male |
female |
Parameter |
|
|||||||||
Mortality |
8/50 |
13/50 |
5/50 |
17/50 |
5/50 |
11/50 |
6/50 |
16/50 |
– |
– |
Body weight gain |
− |
↓ |
− |
↓* |
− |
↓* |
↓** |
↓** |
− |
− |
Organ weights (rel.) |
|
|
|
|
|
|
|
|
|
|
brain |
− |
− |
− |
− |
− |
− |
− |
↑** |
− |
- |
kidneys |
− |
− |
− |
− |
↑* |
− |
↑** |
↑* |
+ |
+ |
ovaries |
− |
− |
− |
− |
− |
− |
− |
↑* |
- |
+ |
spleen |
− |
− |
− |
↑** |
− |
− |
− |
↑* |
− |
- |
liver |
− |
− |
− |
↓* |
− |
− |
− |
− |
− |
- |
Gross pathology Kidney deformation |
0/42 |
0/37 |
0/45 |
0/33 |
0/45 |
0/39 |
6/44 |
0/34 |
+ |
− |
Histopathology |
|
|
|
|
|
|
|
|
|
|
Kidneys, papillary necrosis |
|
|
|
|
|
|
|
|
|
|
unilateral |
2/50 A |
0/49 |
0/49 |
1/50 |
0/50 |
0/50 |
8/50 |
1/48 |
+ |
|
bilateral |
0/50 |
0/49 |
0/49 |
0/50 |
0/50 |
0/50 |
1/50 |
1/48 |
+ |
|
truncated papilla |
0/50 B |
0/49 |
0/49 |
0/50 |
0/50 |
0/50 |
6/50* |
0/48 |
|
|
collecting duct dilatation |
|
|
|
|
|
|
|
|
|
|
unilateral |
0/50 A |
0/49 |
0/49 |
0/50 |
0/50 |
0/50 |
3/50 |
1/48 |
+ |
+ |
bilateral |
0/50 |
0/49 |
0/49 |
0/50 |
0/50 |
0/50 |
0/50 |
1/48 |
- |
+ |
Cortical fibrosis |
0/50 C |
0/49 |
0/49 |
0/50 |
0/50 |
0/50 |
7/50* |
1/48 |
+ |
- |
Epididymides, reduced spermatozoa |
3/50 |
– |
3/49 |
– |
9/50 |
– |
11*/50 |
– |
– |
– |
Testicles, degeneration of seminiferous tubules |
2/50 |
– |
4/49 |
– |
7/50 |
– |
9/50 |
– |
– |
– |
No. of animals with neoplastic changes |
21/42 |
21/37 |
23/45 |
22/33 |
20/45 |
24/39 |
19/44 |
19/34 |
– |
– |
#number of animals affected / total number of animals |
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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