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EC number: 214-787-5 | CAS number: 1194-65-6
- 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: inhalation
Administrative data
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 01 March 2002 to 30 October 2002
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2002
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.8 (Subacute Inhalation Toxicity: 28-Day Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Dichlobenil
- EC Number:
- 214-787-5
- EC Name:
- Dichlobenil
- Cas Number:
- 1194-65-6
- Molecular formula:
- C7H3Cl2N
- IUPAC Name:
- 2,6-dichlorobenzonitrile
- Test material form:
- solid: particulate/powder
- Details on test material:
- - Physical state: solid
- Storage condition of test material: room temperature
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD(SD)IGS BR
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: approximately 7 weeks old
- Weight at study initiation: 175-198 g (males); 165-184 g (females)
- Housing: individually in suspended, stainless steel, wire-mesh type cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 8 days
ENVIRONMENTAL CONDITIONS
- Temperature: 66-73 °F
- Humidity: 30-58 %
- Photoperiod: approximately 12 hours fluorescent light per day
Administration / exposure
- Route of administration:
- inhalation: dust
- Type of inhalation exposure:
- nose only
- Vehicle:
- air
- Remarks on MMAD:
- MMAD / GSD: Mean MMAD
2.3 mg/M3 - 1.64 ± 0.169 µ/M; 5.1 mg/M3 - 2.11 ± 0.165 µ/M; 12.0 mg/M3 - 1.62 ± 0.113 µ/M
Mean GSD
2.3 mg/M3 - 1.653 ± 0.223; 5.1 mg/M3 - 1.753 ± 0.332 µ/M; 12.0 mg/M3 - 1.620 ± 0.136 µ/M - Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 63 L stainless steel and acrylic nose-only exposure chamber with stainless steel baffle (see Figure below).
- Method of holding animals in test chamber: nose-only restraint tubes
- System of generating particulates/aerosols: test substance was packed into a cylindrical holder with high pressure to provide a compact, uniform surface. A scraping blade in a Wright Dust Feeder (WDF) rotated over the surface removing small amounts of the test substance. The dislodged test substance entered the air stream passing through the WDF and was transported out of the WDF into the jet mill. The jet mill pulverized the test substance by directing air streams containing the test substance particles into each other from opposing directions. Smaller pulverized particles exited the jet mill whereas larger particles went through the pulverization process again. The test substance then passed through a cyclone which further separated out the larger particles from the aerosol prior to entering the exposure chamber.
- Temperature, humidity, pressure in air chamber: 20-24 °C; relative humidity 40-60 %
- Air flow rate: 83, 82, 70 and 68 L/min for controls, low dose, mid dose and high dose groups respectively.
- Air change rate: at least 64 per hour
- Method of particle size determination: particles were accelerated through a nozzle in a TSI Aerodynamic Particle Sizer and measuring the time taken for each particle to pass between two closely spaced laser beams - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Chamber atmosphere samples for the gravimetric determination of the test material exposure levels were collected. The samples were withdrawn from the breathing zone of the animals in the exposure chambers through glass-fibre filters.
The gravimetric test material exposure levels were measured at least twice during the exposure. The aerosol concentration was calculated as the filter weight gain in mg divided by the volume of air sampled. The volume of air sampled was calculated as the sample flow rate multiplied by the sample duration.
The samples collected were transferred to polypropylene jars, diluted with HCl solution and analysed with HPLC. - Duration of treatment / exposure:
- Six hours
- Frequency of treatment:
- Once per day, 5 days/week for 20 exposure days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 2.3 mg/m³ air (analytical)
- Dose / conc.:
- 5.1 mg/m³ air (analytical)
- Dose / conc.:
- 12 mg/m³ air (analytical)
- No. of animals per sex per dose:
- Ten
- Control animals:
- yes
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes - evaluation of the skin, fur, eyes, ears, nose, oral cavity, thorax, abdomen, external genitalia, limbs and feet, respiratory and circulatory effects, autonomic effects such as salivation, nervous system effects including tremors, convulsions, reactivity to handling, bizarre behaviour and palpatation of tissue masses.
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION:
- Food consumption: Yes - weekly
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to the start of the test and again prior to termination
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination of the study
- Anaesthetic used for blood collection: Yes, carbon dioxide
- Animals fasted: Yes
- How many animals: all
- Parameters checked: haemoglobin, erythrocyte count, absolute and percent reticulocytes, platelets, prothrombin time, activated partial thromboplastin time, total and differential leucocyte counts, hematocrit, MCV, MCH and MCHC.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination of the study
- Animals fasted: Yes
- How many animals: all
- Parameters checked: sodium, potassium, chloride, calcium, phosphorus, glucose, urea nitrogen, cholesterol, total bilirubin, total protein, albumin, globulin, albumin/globulin ratio, creatinine, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase and sorbitol dehydrogenase.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: prior to termination of the study
- Dose groups that were examined: all
- Battery of functions tested: motor activity / functional observational battery - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
- The following organs were weighed: adrenals, brain, kidneys, liver, heart, lungs, pituitary, ovaries, prostate, spleen, testes, thymus, thyroids and uterus.
HISTOPATHOLOGY: Yes
- The following organs/tissues were sampled: adrenals, aorta, sternum with bone marrow, femur with bone marrow, bone marrow smears, brain, caecum, colon, duodenum, epididymis, eyes, harderian gland, heart, ileum, jejunum, kidneys, lacrimal gland, larynx, liver, lungs, mandibular and mesenteric lymph nodes, mammary gland (females only), nasal tissues, oesophagus, optic nerves, ovaries, pancreas, pituitary, prostate, rectum, salivary gland, sciatic nerves, seminal vesicle, skeletal muscle, skin, spinal cord, spleen, stomach, testes, thymus, thyroid/parathyroid, tongue, trachea, urinary bladder, uterus, vagina and all gross lesions. - Statistics:
- Levene's test was used to assess homogeneity of group variances. If Levene's test was not significant (p≥0.01)< Dunnett's test was used to compare each treatment group with the control group. If Levene's test was significant (p<0.01), comparisons with the control group were made using Welch's t-test with Bonferroni correction.
Chi-square test for homogeneity was used to analyse Functional Observational Battery results except for continuous data.
Log transformation was performed on leucocyte counts prior to analysis.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no test material related clinical observations seen in the study.
- Mortality:
- no mortality observed
- Description (incidence):
- No unscheduled deaths occurred during the course of the study.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was no clear test material effect on the body weight. The mean weight for the females in the highest dose group was statistically lower than the control mean weights. However, this decrease appeared to be due to one animal, therefore this is not clearly test material related.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was no test material related effect on food consumption. The statistically significant differences that occurred in some weeks were sporadic and showed no relationship to dose.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- No test material related Ophthalmoscopic effects were seen.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- When compared to controls, no toxic effects on haematology were observed after 28 days for male or female rats exposed up to the highest dose level.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related toxic effects on clinical chemistry parameters were observed for males or females exposed up to the highest dose level. Any observed alterations were not dose dependent and were considered related to inter-day collection variety.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Motor activity evaluations revealed no test material related effects. There was no test material related effect seen on any of the functional observational categories of activity/arousal, neuromuscular, sensorimotor, autonomic, or physiological measurements. The only statistically significant differences seen in the highest dose group was in hind limb grip strength and body temperature in the males. No difference was seen in fore limb strength and neither of these differences was seen in the females. These differences were therefore considered to be spurious and not related to the test material.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No test material related organ weight changes occurred in either sex.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No test material related macroscopic observations were noted in either sex.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- There were no test material related microscopic effects noted in either sex.
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
Effect levels
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 12 mg/m³ air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No test material related effects were seen.
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Mean body weights (g)
Dose group (mg/mm3) | |||||
Time (weeks) | Sex | 0.0 | 2.3 | 5.1 | 12.0 |
-1 | M | 183.0 | 192.2* | 194.3* | 180.1 |
1 | M | 233.8 | 237.1 | 240.0 | 229.7 |
2 | M | 282.9 | 278.8 | 280.5 | 277.6 |
3 | M | 318.9 | 309.6 | 309.3 | 312.6 |
4 | M | 337.2 | 324.5 | 326.0 | 333.0 |
-1 | F | 169.4 | 173.7 | 172.3 | 169.3 |
1 | F | 192.4 | 188.3 | 192.8 | 185.3 |
2 | F | 209.5 | 201.9 | 207.0 | 198.5 |
3 | F | 226.1 | 214.2 | 222.1 | 209.9* |
4 | F | 232.1 | 222.7 | 228.3 | 216.8 |
*significantly different from control (P<0.05)
Table 2: Selected haemotology values
Dose group (mg/m3) | |||||
Parameter | Sex | 0.0 | 2.3 | 5.1 | 12.0 |
Platelets (K/mm3) | M | 1205.0 | 1013.2 | 921.1** | 1045.7 |
F | 1033.3 | 1089.5 | 879.9 | 1139.1 | |
APTT (sec) | M | 30.18 | 19.38** | 19.58** | 31.00 |
F | 23.44 | 16.93** | 17.47** | 21.50 | |
Prothrombin time (sec) | M | 17.67 | 14.80** | 14.65** | 17.27 |
F | 13.98 | 14.64 | 14.14 | 13.66 |
**significantly different from control (P<0.01)
Table 3: Selected clinical chemistry values
Dose group (mg/m3) | |||||
Parameter | Sex | 0.0 | 2.3 | 5.1 | 12.0 |
Sodium (mEq/L) | M | 148.2 | 151.2** | 150.8** | 149.0 |
F | 146.3 | 148.6 | 149.2* | 147.5 | |
Potassium (mEq/L) | M | 7.18 | 6.11 | 5.99* | 6.98 |
F | 7.44 | 6.52 | 5.97** | 7.50 | |
Sorbital dehydrogenase (U/L) | M | 16.11 | 23.58** | 23.99** | 15.77 |
F | 16.51 | 23.25* | 21.87 | 16.88 | |
Cholestoerol (mg/dL) | M | 47.1 | 57.9 | 59.2* | 48.3 |
F | 53.8 | 66.2 | 7.1** | 60.6 | |
Glucose (mg/dL) | M | 10.64 | 90.8* | 100.3 | 110.6 |
*significantly different from control (P<0.05)
**significantly different from control (P<0.01)
Table 4: Selected organ weight change values
Dose group (mg/m3) | |||||
Parameter | Sex | 0.0 | 2.3 | 5.1 | 12.0 |
Thymus (g) | M | 0.51 | 0.41* | 0.52* | 0.48 |
Thymus/body weight %x10 | M | 1.70 | 1.39* | 1.75 | 1.63 |
Thymus/brain weight %x10 | M | 2.87 | 2.22* | 2.83 | 2.67 |
Ovary/bodyweight %x10 | F | 7.18 | 6.28 | 5.96* | 6.80 |
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of the test, the test material had no toxic effect at 2.3, 5.1 and 12 mg/m³. The NOEL was determined to be 12 mg/m³.
- Executive summary:
In a GLP compliant repeat dose (inhalation) study conducted in line with standardised guideline EU Method B.8, the effects of the repeat dose of the test material in rats was determined.
Under the conditions of the test, no toxic effect was seen at 2.3, 5.1 and 12 mg/m3 and the NOEL was determined to be 12 mg/m3.
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