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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: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 16 February 1987 to 17 June 1987
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 987
- Report date:
- 1987
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 82-1 (90-Day Oral Toxicity)
- 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
Constituent 1
Test animals
- Species:
- hamster
- Strain:
- other: Bio F1 Alexander
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Acclimation period: two weeks
ENVIRONMENTAL CONDITIONS
- Temperature: 21 ± 3 °C
- Humidity: 55-75 %
- Photoperiod: 12 hours light/12 hours dark
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): Spratt's LAD 2 Standard Rodent Diet
- Storage temperature of food: -20 °C - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- GC analysis on samples taken from all dose groups from residues left in the foodhopper at the end of weeks 3, 6, 9 and 12 and in the fresh untouched diets of week 12 (used as reference).
- Duration of treatment / exposure:
- 90 days (up to 4pm on the day before terminal kill in week 14 for main group)
- Frequency of treatment:
- Feed was available ad libitum and fresh food was given once a week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 41 mg/kg diet
- Dose / conc.:
- 209 mg/kg diet
- Dose / conc.:
- 1 289 mg/kg diet
- Dose / conc.:
- 4 648 mg/kg diet
- Remarks:
- reduced after two weeks from 7500 mg/kg diet
- No. of animals per sex per dose:
- Ten (main group and recovery group for controls and 4648 mg/kg diet). Twenty for main group controls.
- Control animals:
- yes, plain diet
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
- At autopsy animals were weighed after overnight fasting to determine autopsy body weights to be used for calculating organ weights relative to body weight.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption: individual food intake calculated for periods of seven days
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before treatment started and in 11th week of treatment
- Dose groups that were examined: control and highest dose group
HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 13 weeks of treatment and from the recovery animals, after 4 weeks recovery
- Anesthetic used for blood collection: Yes (light ether anaesthesia)
- Animals fasted: Yes (18 hours)
- How many animals: all
- Parameters checked: RBC, Hb, PCV, MCV, MCH, MCHC, platelet count, WBC and differential WBC, reticulocytes, PTT and APTT. At autopsy 1.8 mL of blood was taken for clotting observations.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 13 weeks of treatment and from the recovery animals, after 4 weeks recovery
- Animals fasted: Yes (18 hours)
- How many animals: all
- Parameters checked: AST, ALT, ALP, GCT, glucose, total protein, albumin, urea, creatinine, cholesterol, phospholipids, calcium, sodium and potassium - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
- a full macroscopic examination was done on all animals and any abnormalities found were recorded.
- the following organs were weighed: brain, heart, liver, spleen, kidneys, thymus, prostate, seminal vesicles, testes, uterus and ovaries.
- for the recovery animals, the liver and kidney weights were recorded.
HISTOPATHOLOGY: Yes
- the following tissues were taken, fixed, sectioned and stained where appropriate: aorta, heart, lungs, trachea, salivary glands, liver, gall-bladder, pancreas, oesphagus, stomach, duodenum, ileum, jejunum, caecum, colon, rectum, urinary bladder, kidneys, testes, prostate, epididymides, seminal vesicle, ovaries, uterus, vagina, mesenteric lymph node, spleen, thymus, adrenals, pituitary gland, thyroid with parathyroid, skin with pelvia mammary gland, muscle (quadriceps femoris), sciatic never, brain, spinal cord, eyes and optic nerve - Statistics:
- The basic analysis consists of linear regression analysis with treatment and block effects as parameters assuming constant error variance. The regression analysis was followed by Williams's test.
With some variables, one or two animals showed outlying responses. In such cases the Williams's test was replaced by its nonparametric version and the data were summarised by medians instead of means.
The incidence of macroscopic findings was subjected to a test for trend against dose level in a 5 x 2 contingency table. The statistical significance level for the trend statistic was obtained by enumeration of all possible permutations (permutation test).
Microscopic findings obtained on an ordinal scale were subjected to Shirley's test (as modified by Williams for comparing several dose levels with a zero-dose control).
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No treatment-related clinical signs were observed.
- Mortality:
- no mortality observed
- Description (incidence):
- No treatment-related mortality was observed.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The initial diet concentration of 7,500 mg/kg diet was not tolerated, after two weeks of treatment the animals had lost weight and were only 75 % and 80 % of the weight of concurrent controls (males and females respectively). Reducing the diet concentration to 4,648 mg/ kg resulted in an immediate return to weight gain although at a slower rate than that of the controls.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- The food consumption of the males was reduced at the 1,289 and 4,648 mg/kg diet level during the entire treatment period and up to week 6 in the females of the 4,648 mg/kg diet group.
- 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 treatment-related ophthalmoscopic abnormalities were observed.
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Haematology effects indicated a very slight, reversible, macrocytic tendency in the highest dose group. Withdrawal of treatment for 4 weeks resulted in an increased number of platelets, reticulocytes and neutrophils, in the males at this dose level, indicating an active bone marrow.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- The prostate showed a dose-related weight reduction. Uterus and spleen weights, absolute and relative, were reduced at the 4,648 mg/kg diet level of the females; however, histopathology examination did not show any abnormality.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- There were indications of reversible morphological and functional effects on the liver. Following the withdrawal of treatment it was evident that the liver had recovered normal function and morphology
An increase in the incidence of mineralisation in the prostate at 209 - 4,648 mg/kg diet levels was noted. Tubular degeneration in the testes and decreased numbers of spermatocytes in the epididymis were seen in the 4,648 mg/kg diet group. Gall-bladder calculi occurred in both sexes at the highest diet level, this effect remained after the recovery period. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No histopathological abnormalities were seen in uterus and spleen in the female group at the 4,648 mg/kg diet level .
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
Effect levels
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 41 mg/kg diet
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical biochemistry
- gross pathology
- haematology
- organ weights and organ / body weight ratios
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Body weight gain (g)
Dose rate (mg/kg diet, actual) | ||||||||
Time period (weeks) | Sex | 0 | 41 | 209 | 1289 | 7500/4648 | 7500 /4648 (R) | |
-2 - 0 | M | 19.4 | 19.2 | 20.9 | 21.6 | 19.3 | ||
F | 20.2 | 21.7 | 21.1 | 20.0 | 17.8 | |||
1 - 3 | M | 16.4 | 18.0 | 17.7 | 15.4 | -12.5** | ||
F | 15.2 | 14.2 | 16.9 | 15.2 | -10.3** | |||
4 - 6 | M | 15.8 | 17.6 | 14.5 | 13.8 | 7.4** | ||
F | 14.5 | 14.6 | 15.6 | 15.6 | 18.0* | |||
7 - 9 | M | 5.8 | 6.7 | 4.7 | 5.0 | 2.9** | ||
F | 8.5 | 8.7 | 10.6 | 9.3 | 12.6** | |||
10 - 13 | M | 1.0 | 0.4 | 0.0 | -1.1 | 5.2** | ||
F | -1.6 | 0.3 | 2.7 | -1.3 | 8.8** | |||
14 - 17 | M | 2.0 (R) | 15.6** | |||||
F | -0.7 (R) | 6.5* |
*statistical significant P≤0.05; **statistical significant P≤0.01
Table 2: Food consumption (g)
Dose rate (mg/kg diet, actual) | |||||||
Time period (weeks) | Sex | 0 | 41 | 209 | 1289 | 7500/4648 | 7500/4648 (R) |
-2 - 0 | M | 116 | 114 | 118 | 113 | 117 | |
F | 130 | 128 | 130 | 123 | 125 | ||
1 - 3 | M | 175 | 171 | 176 | 163* | 130** | |
F | 189 | 184 | 190 | 183 | 155** | ||
4 - 6 | M | 183 | 177 | 177 | 171** | 150** | |
F | 193 | 189 | 198 | 197 | 173** | ||
7 - 9 | M | 161 | 159 | 152 | 151* | 133** | |
F | 187 | 177 | 182 | 176 | 169 | ||
10 - 13 | M | 193 | 185 | 178* | 179* | 171** | |
F | 214 | 212 | 222 | 207 | 212 | ||
14 - 17 | M | 194 (R) | 199 | ||||
F | 226 (R) | 216 |
Table 3: Selected clinical chemistry values
Dose rate (mg/kg diet, actual) | ||||||||
After treatment period (13 weeks) | After recovery period (4 weeks) | |||||||
Parameter | Sex | 0 | 41 | 209 | 1289 | 4648 | 0 | 4648 |
AST (U/L) | M | 34 | 39 | 34 | 33 | 37 | 40 | 31** |
F | 43 | 47 | 41 | 36 | 33* | 42 | 35 | |
ALT (U/L) | M | 53 | 56 | 54 | 65** | 64** | 62 | 56 |
F | 73 | 84* | 101* | 85* | 100** | 94 | 84 | |
ALP (U/L) | M | 161 | 149 | 161 | 163 | 168 | 138 | 180** |
F | 213 | 202 | 200 | 194 | 200 | 228 | 223 | |
Glucose (mmol/L) | M | 4.64 | 4.05 | 4.62 | 4.08 | 4.66 | 4.07 | 4.73 |
F | 5.16 | 5.21 | 5.05 | 5.74 | 4.25* | 4.71 | 4.98 | |
T. prot (g/L) | M | 70.1 | 69.6 | 69.1 | 69.3 | 71.3 | 70.9 | 72.6* |
F | 72.4 | 72.2 | 73.1 | 72.4 | 75.3* | 75.7 | 73.2 | |
Albumin (g/L) | M | 55.4 | 55.6 | 55.7 | 57.2 | 59.8** | 45.3 | 46.8* |
F | 53.4 | 53.3 | 54.2 | 55.2 | 60.1* | 43.2 | 41.7* | |
Urea (mmol/L) | M | 7.00 | 6.76 | 7.30 | 7.31 | 8.33** | 7.98 | 7.73 |
F | 8.10 | 7.88 | 8.26 | 8.71 | 9.39* | 9.02 | 8.46 | |
Creat (µmol/L) | M | 28.5 | 27.0 | 27.0 | 26.0* | 25.0** | 27.2 | 26.8 |
F | 31.0 | 29.0 | 29.4 | 28.6 | 26.0** | 29.5 | 27.3** | |
Chol. (mmol/L) | M | 3.45 | 2.99+ | 2.78 ++ | 2.94+ | 4.27 ++ | 3.64 | 3.59 |
F | 4.08 | 4.18 | 4.56 | 4.88** | 6.31** | 4.76 | 4.75 | |
Ph. Lip. (mmol/L) | M | 2.91 | 2.70 | 2.61 | 2.74 | 3.65** | 2.95 | 3.06 |
F | 3.10 | 3.24 | 3.62** | 3.67** | 4.82** | 3.19 | 3.40 | |
Sodium (mmol/L) | M | 147.2 | 147.7 | 145.4 | 146.9 | 147.1 | 147.0 | 145.0 |
F | 145.8 | 146.3 | 145.5 | 146.4 | 145.3 | 146.3 | 143.8* |
*statistical significant, P≤0.05; **statistical significant, P≤0.01; results of Student's test since the mean response is not a monotonic function of dose: + P≤0.05, ++ P≤0.01
Table 4: Selected absolute and relative organ weights
Dose rate (mg/kg diet, actual) | |||||||||
After treatment period (13 weeks) | After recovery period (4 weeks) | ||||||||
Organ | Sex | 0 | 41 | 209 | 1289 | 4648 | 0 | 4648 | |
Body weight (g) | M | 138 | 140 | 137 | 133 | 101** | 139 | 119** | |
F | 136 | 139 | 147 ++ | 138 | 128+ | 136 | 131 | ||
Brain (g) | abs1 | M | 0.980 | 0.985 | 0.990 | 0.995 | 0.990 | - | - |
rel1 | M | 0.709 | 0.690 | 0.730 | 0.752* | 0.955* | - | - | |
Heart (g) | abs | M | 0.536 | 0.529 | 0.528 | 0.525 | 0.437** | - | - |
rel1 | M | 0.390 | 0.381 | 0.385 | 0.397 | 0.435** | - | - | |
abs | F | 0.591 | 0.569 | 0.574 | 0.578 | 0.547* | - | - | |
rel | F | 0.436 | 0.411 | 0.391 | 0.419 | 0.428 | - | - | |
Liver (g) | abs | M | 4.39 | 4.34 | 4.29 | 4.97** | 6.66** | 4.42 | 4.44 |
rel | M | 3.18 | 3.09 | 3.12 | 3.73** | 6.59** | 3.17 | 3.72** | |
abs | F | 4.74 | 4.93 | 5.52** | 6.36** | 8.78** | 4.93 | 5.11 | |
rel | F | 3.47 | 3.54 | 3.75* | 4.59** | 6.84** | 3.60 | 3.88 | |
Spleen (g) | abs | M | 0.112 | 0.118 | 0.107 | 0.107 | 0.074** | - | - |
rel | M | 0.081 | 0.085 | 0.077 | 0.081 | 0.074 | - | - | |
abs | F | 0.166 | 0.151 | 0.164 | 0.157 | 0.126** | - | - | |
rel | F | 0.122 | 0.110 | 0.112 | 0.114 | 0.100** | - | - | |
Kidneys (g) | abs1 | M | 1.005 | 0.975 | 0.990 | 0.990 | 0.900** | 0.949 | 0.903 |
rel1 | M | 0.735 | 0.690 | 0.725 | 0.755 | 0.880** | 0.683 | 0.760** | |
abs1 | F | 1.160 | 1.190 | 1.255 | 1.230 | 1.205 | 1.151 | 1.019* | |
rel1 | F | 0.840 | 0.835 | 0.830 | 0.925 | 0.905** | 0.848 | 0.779** | |
Thymus (g) | abs | M | 0.040 | 0.048 | 0.043 | 0.042 | 0.034* | - | - |
rel | M | 0.029 | 0.034 | 0.030 | 0.030 | 0.031 | - | - | |
Prostate (mg) | abs | M | 388 | 342 | 313* | 297** | 182** | - | - |
rel | M | 283 | 247 | 228* | 224** | 182** | - | - | |
Sem. ves. (g) | abs | M | 1.41 | 1.35 | 1.19 | 1.19 | 0.72* | - | - |
rel | M | 1.01 | 0.97 | 0.84 | 0.90 | 0.70** | - | - | |
Testes (g) | abs | M | 3.27 | 3.26 | 3.07 | 3.15 | 2.20** | - | - |
rel | M | 2.38 | 2.35 | 2.25 | 2.39 | 2.19 | - | - | |
Uterus (g) | abs | F | 0.40 | 0.41 | 0.37 | 0.35 | 0.30** | - | - |
rel | F | 0.29 | 0.29 | 0.25 | 0.26 | 0.23* | - | - |
*statistical significant, P≤0.05; **statistical significant, P≤0.01; 1 medians are presented and nonparameteric test was applied because of an outlying observation; results of Student's t-test since the mean response is not a monotonic function of dose: + P≤0.05, ++P≤0.01
Table 5: Selected microscopic observations
Dose rate (mg/kg diet, actual) | |||||||||
Sex | After treatment period (13 weeks) | After recovery period (4 weeks) | |||||||
0 | 41 | 209 | 1289 | 4648 | 0 | 4648 | |||
Numbers examined | M | 20 | 10 | 10 | 10 | 9 | 10 | 10 | |
F | 20 | 10 | 10 | 10 | 10 | 10 | 10 | ||
Organ | Observation | ||||||||
Epididymis | No abnormalities | M | 19 | 10 | 4 | ||||
Spermatocytes decreased | M | 1 | 0 | 5* | |||||
Gallbladder | No abnormalities | M | 20 | 10 | 9 | 9 | 2** | 8 | 2 |
No abnormalities | F | 20 | 10 | 10 | 9 | 0** | 9 | 0** | |
Prostate | No abnormalities | M | 16 | 9 | 6 | 5 | 5 | ||
Mineralisation (marginal/slight/moderate) | M | 0/0/1 | 0/0/1 | 0/1/2 | 1/3/0 | 0/2/1 | |||
Prostatis (marginal/slight/moderate) | M | 0/2/2 | 0/0/1 | 0/0/2 | 1/2/0 | 0/1/1 | |||
Testes | No abnormalities | M | 18 | 2 | |||||
Tubules degenerated (marginal/slight/moderate/marked) | M | 0/1/0/1 | ** 2/0/4/1 |
* incidences yielding statistical significance (P≤0.1) in a two-sided test against trend with dose level; **Shirley's test P≤0.1
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of the test, the NOEL of the test material in a 90 day repeat dose study in the hamster was determined to be 41 mg/kg diet.
- Executive summary:
In a GLP compliant repeat dose (oral) study conducted in line with EPA OPP 82-1, the effects of the repeat dose of the test material over 90 days was determined. Hamsters were fed a diet containing 0, 41, 209, 1289 and 4648 mg/kg diet (7500 mg/kg diet for first two weeks) test material.
Under the conditions of the test, the NOEL of the test material in a 90 day repeat dose study in the hamster was determined to be 41 mg/kg diet.
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