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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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 24 March 1988 to 15 August 1989
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 989
- Report date:
- 1988
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 991
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- yes
- Remarks:
- 18 mated females instead of 20 were used in the study
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
- Deviations:
- yes
- Remarks:
- 18 mated females instead of 20 were used in the study
- 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:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: 3.00-4.48 kg at mating
- Housing: individually in stainless steel cages
- Diet: ad libitum
- Water: mains water ad libitum
- Acclimation period: at least 19 days before mating
ENVIRONMENTAL CONDITIONS
- Temperature: 16-22 °C
- Humidity: 40-70 %
- Air changes: minimum of 15 per hour
- Photoperiod: 14 hours light/10 hours dark
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 1 % gum tragacanth
- Details on exposure:
- Suspensions of the test material in vehicle were prepared weekly and dispensed as daily aliquots
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of each test formulation were taken from the first and second weekly preparations for analysis.
- Details on mating procedure:
- Each female was mated with one proven stud New Zealand White buck.
- Duration of treatment / exposure:
- To mated females from days 7 to 19 of gestation.
- Frequency of treatment:
- Once daily
- Duration of test:
- Animals were killed on day 29 of gestation.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 15 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 45 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 135 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 18
- Control animals:
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily during gestation
BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 7, 13, 19, 23 and 28 of gestation.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined: days 0-7, 7-13, 13-19, 19-23, and 23-29 of gestation. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number and intrauterine position of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: pregnancy status - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: Yes: [all per litter] - Statistics:
- Levene's test was used to test for equality of variances between groups for body weight gain (except days 7-13), food intake, uterus weight and mean litter weight. Where there was a significant difference between groups using one-way analysis of variance, pairwise t-tests between treated groups and the control were conducted. Where Levene's test was significant (p<0.05), non-parametric tests were performed.
Major and minor external/visceral defects and major skeletal defects were analysed by comparing the proportion of litters in the treated groups with one defect to the proportion in the control group using the Fisher exact test.
Kruskal-Wallis non-parametric analysis of variance was performed on all other parameters. Where there was a significant overall difference between groups (p<0.05), the Wilcoxon Rank Sum Test was performed for each treated group against the controls. - Indices:
- Percentage pre-implantation loss = ((no. of corpora lutea - no. of implantation sites) / no. of corpora lutea) x 100
Percentage of post-implantation loss = ((no. of implantation sites - no. of live young) / no. of implantation sites) x 100
Females as % of males = (no. of females / no. of males) x 100
Fertility index = (no. of females pregnant / no. of females mated) x 100
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- The clinical condition of surviving animals was generally comparable in all groups.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Four of the treatment animals died or were killed, two in the low dose and one in both the median and high dose groups. The distribution between the treated groups did not indicate an effect of treatment.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Group mean body weight gain of the high dose animals was significantly lower than the controls. The majority of high dose animals lost weight from day 7 to day 13 of gestation. In three animals the loss persisted until treatment ceased. There was no adverse effect of treatment on weight gain at the low or intermediate dose level.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food intake of high dose animals was significantly lower than controls over the treatment period. No significant differences were observed at the low and intermediate dose levels.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Necropsy revealed no treatment-related lesions.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- Necropsy revealed no treatment-related lesions.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Maternal developmental toxicity
- Number of abortions:
- not examined
- Pre- and post-implantation loss:
- effects observed, treatment-related
- Description (incidence and severity):
- The number of corpora lutea and implantations per dose were comparable in all groups. Pre-implantation loss was within the expected range in all groups. Post-implantation loss was higher than controls in the high dose group. The increase was mainly attributable to two atypical litters (number 66 and 72) and was not statistically significant. The number of foetuses per litter was correspondingly reduced. The incidence of intrauterine deaths in the low and intermediate dose groups was lower than controls and litter size was marginally increased.
- Total litter losses by resorption:
- not examined
- Early or late resorptions:
- not examined
- Dead fetuses:
- not examined
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- The number of pregnant animals surviving to day 29 of gestation was between 14 and 16 in every group.
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- Pregnancy incidence was 100 % in the low dose and 94.4 % in all other groups.
- Other effects:
- not examined
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 45 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Foetal weight was lower than controls in the high dose group. The reduction was not statistically significant and was attributable to three atypical litters (number 66, 71, and 72). There was no adverse effect on foetal weight in the low and intermediate dose groups.
- Reduction in number of live offspring:
- not examined
- Changes in sex ratio:
- not examined
- Changes in litter size and weights:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- The incidence of litters containing foetuses showing major defects was significantly higher than controls in the high dose group. Again the increase was mainly attributed to litters 66, 71, and 72 suggesting that these were mediated by maternal toxicity. There was no adverse effect of treatment on the incidence of major defects in the low or intermediate dose groups. The incidence of minor defects or variations did not indicate an effect of treatment at any of the dose levels investigated.
- Skeletal malformations:
- not specified
- Visceral malformations:
- not specified
- Other effects:
- not examined
Effect levels (fetuses)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 45 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: embryotoxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 45 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: fetotoxicity
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Table 1: Mean weight (kg), body weight gain (kg) and food intake (g)
Dose group (mg/kg bw/day) | |||||
Day | Parameter | 0 | 15 | 45 | 135 |
0 | Body weight | 3.63 | 3.61 | 3.76 | 3.68 |
7 | Body weight | 3.78 | 3.77 | 3.91 | 3.84 |
Body weight gain | 0.15 | 0.16 | 0.15 | 0.16 | |
Food intake | 201 | 204 | 212 | 212 | |
13 | Body weight | 3.83 | 3.84 | 3.97 | 3.70*** |
Body weight gain | 0.05 | 0.07 | 0.06 | -0.14 | |
Food intake | 175 | 184 | 184 | 115*** | |
19 | Body weight | 3.94 | 3.97 | 4.08 | 3.80 |
Body weight gain | 0.11 | 0.13 | 0.11 | 0.10 | |
Food intake | 168 | 171 | 170 | 124* | |
23 | Body weight | 4.03 | 4.0 | 4.16 | 3.85 |
Body weight gain | 0.09 | 0.04 | 0.08 | 0.05 | |
Food intake | 148 | 141 | 158 | 132 | |
29 | Body weight | 4.16 | 4.03** | 4.23 | 4.00 |
Body weight gain | 0.13 | 0.02 | 0.07 | 0.15 | |
Adjusted body weight | 3.58 | 3.48 | 3.68 | 3.51 | |
Food intake | 127 | 92 | 118 | 122 | |
Total mean | Body weight gain | 0.53 | 0.42 | 0.47 | 0.32 |
Food intake | 166 | 161 | 171 | 144 |
*P<0.05; ***P<0.001
Table 2: Group incidence of foetuses with defects
Dose group (mg/kg bw/day) | |||||
Observation | 0 | 15 | 45 | 135 | |
Number of foetuses examined | 142 | 154 | 146 | 115 | |
External and visceral effects | Major | 0 | 1 | 1 | 11** |
Minor | 5 | 14 | 2 | 12 | |
Variants | 46 | 47 | 70 | 39 | |
Skeletal | Major | 1 | 0 | 0 | 24 |
Minor | 33 | 45 | 36 | 16 | |
Variants | 128 | 141 | 130 | 106 | |
Total number of foetuses showing major defects | 1 | 1 | 1 | 26 |
** P<0.01
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of the test, administration of the test material at 135 mg/kg bw/day elicited maternal toxicity, characterised by maternal weight loss at the onset of dosing and reduced food intake over the treatment period. In three animals, the reaction was so severe as to elicit corresponding foetal effects. The litters of these animals showed reduced foetal weight and an increased incidence of intrauterine deaths and major abnormalities. In the remaining litters, the incidence of foetal effects did not greatly differ from normal values. There was no adverse effect of treatment, maternal or foetal, at 15 or 45 mg/kg/day in either this or the previous study (Barker, 1989b). The NOAEL for both maternal and embryo/foetotoxicity in this study is 45 mg/kg bw/day.
- Executive summary:
In a GLP compliant study conducted in line with standardised guidelines OECD 414 and EPA OPP 83-3, the effect of the test material on developmental toxicity was determined in the rabbit.
Rabbits were administered the test material by oral (gavage) at 0, 15, 45 and 135 mg/kg bw/day. Administration of the test material at 35 mg/kg bw/day elicited maternal toxicity, characterised by maternal weight loss at the onset of dosing and reduced food intake over the treatment period. In three animals, the reaction was so severe as to elicit corresponding foetal effects. The litters of these animals showed reduced foetal weight and an increased incidence of intrauterine deaths and major abnormalities. In the remaining litters, the incidence of foetal effects did not greatly differ from normal values. There was no adverse effect of treatment, maternal or foetal, at 15 or 45 mg/kg/day in either this or the previous study (Barker, 1989b).
The NOAEL for both maternal and embryo/foetotoxicity in this study is 45 mg/kg bw/day.
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