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EC number: 201-662-5 | CAS number: 86-29-3
- 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:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Justification for type of information:
- Data is from read across substance.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 009
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Benzene-1,3-dicarbonitrile
- EC Number:
- 210-933-7
- EC Name:
- Benzene-1,3-dicarbonitrile
- Cas Number:
- 626-17-5
- Molecular formula:
- C8H4N2
- IUPAC Name:
- Benzene-1,3-dicarbonitrile
- Test material form:
- solid: particulate/powder
- Remarks:
- White powder
- Details on test material:
- The chemical was purchased from Tokyo Chemical Industry Co., Ltd. Purity was 99.9 and it was stored in a dark cool place (2-6 degree C) under a dense plug.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- The average body weights of male and female rats at the time of administration were 386 and 239 grams, respectively. The animals were placed individually in stainless steel write mesh cages (temperature 22 +/- 3 degree C; humidity of 55 +/-10%; 12/12 hour light/dark cycle). Nesting material was provided at day 0 of pregnancy. Water and food were available ad lib.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: Aqueous solution (1% methylcellulose)
- Details on mating procedure:
- No details given.
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- For male rats, the chemical was given two weeks before mating and thereafter for a total of 42 days of dosing. For female rats, the chemical was given two weeks before mating and thereafter until day 4 after delivery, for a total of 42-56 days of dosing.
- Frequency of treatment:
- Once per day
Doses / concentrations
- Remarks:
- 0 (vehicle control), 6, 25 and 100 mg/kg bw/day
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent vehicle
Examinations
- Parental animals: Observations and examinations:
- The animals were examined for mortality and clinical signs twice per day. The body weight and food intake of each male rat were measured weekly. For female rats, the body weight and food intake of each animal were measured weekly before mating; on day 1, 7, 14, 20 of gestation; and on day 0 and 4 of lactation. Female rats were examined for oestrous cycle length, number of female rats with successful copulation, paring days until copulation, number of pregnant female rats, fertility index, number of corpora lutea, number of implantation sites, implantation index, number of female rats with parturition, gestation length, gestation index and number of female rats with live pups at day 4.
- Oestrous cyclicity (parental animals):
- Yes
- Sperm parameters (parental animals):
- Morphological evaluation of the spermatogenesis was performed post-mortem.
- Litter observations:
- Specific observations for the developmental phase of the study included number of pups born, delivery index, number of pups alive at day 0 of lactation, live birth index, sex ratio, number of pups alive on day 4 of lactation, viability index, and body weight of live pups at day 0 and 4 of lactation.
- Postmortem examinations (parental animals):
- All adult male and female rats were sacrificed after treatment for gross pathology, organ weight determinations and histopathology, which included a morphological evaluation of the spermatogenesis in the male rats.
- Postmortem examinations (offspring):
- All pups were examined externally for malformations and internally for visceral variations/malformations.
- Statistics:
- Parametric data: For multiple comparisons, Bartlett's variance test, Dunnett's test.
Non-parametric data: Kruskal Wallis.
Categorical data: Fischer test.
Histopathological data: Mann-Whitney - Reproductive indices:
- Fertility index, implantation index, gestation index, and delivery index.
- Offspring viability indices:
- Live birth index and viability index.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Clinical findings included excessive salivation in male and female rats treated at 100 mg/kg.
- Mortality:
- no mortality observed
- Description (incidence):
- All animals survived to planned death.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Male rats treated at 100 mg/kg showed significantly lower body weights on day 7, 14 and 28 of dosing (mean 8.1% lower) and decreased body weight gain between day 1 and 42 of dosing (by 16.4%) when compared to the control group. Female rats treated at 100 mg/kg showed lower body weights at day 14 and 20 of gestation (mean, 9.5%), markedly decreased body weight gain between day 0 to 20 of gestation (by 22.8%), and lower body weights at day 0 and 4 of lactation (mean, 11.3%) when compared to the control group.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Deviations in food intake in male rats were minor and occurred sporadically. In female rats, marked decreases in food intake were observed in the group of animals treated at 100 mg/kg on day 0 of lactation (56% lower) and day 3 of lactation (40% lower) when compared to the control group.
- 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:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Males: Slight hepatocellular hypertrophy at 100 mg/kg, a dose-dependent increase of hyaline droplets in the proximal tubular epithelium at ≥25 mg/kg and an increased tendency of tubule basophilia (indicative of renal toxicity) at 100 mg/kg. Microscopic examination of the male reproductive organs showed no treatment-related effects.
Females: Slight hepatocellular hypertrophy at 100 mg/kg. Microscopic examination of the female reproductive organs showed no treatment-related effects. - Histopathological findings: neoplastic:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects observed.
- Reproductive function: sperm measures:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The results from the spermatogenesis cycle test showed no significant effects attributed to the test chemical.
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- There were no significant effects on oestrous cycle length, number of female rats with successful copulation, paring days until copulation, number of pregnant female rats, fertility index, number of corpora lutea, number of implantation sites, implantation index, number of female rats with parturition, gestation length, gestation index, or the number of female rats with live pups at day 4.
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- >= 25 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- food consumption and compound intake
- organ weights and organ / body weight ratios
- histopathology: non-neoplastic
- reproductive function (oestrous cycle)
- reproductive function (sperm measures)
- reproductive performance
- Dose descriptor:
- LOAEL
- Effect level:
- <= 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- body weight and weight gain
- food consumption and compound intake
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not examined
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- The results from the developmental phase of the study showed a marked decrease in the number of live pups at day 0 and 4 of lactation at 100 mg/kg compared to the control group. This effect was accompanied by a marked decrease in the viability index at 100 mg/kg (mean viability, 28.0%) compared to the control group (mean viability, 97.5%).
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The mean body weights of live pups were significantly lower on day 0 and 4 of lactation at 100 mg/kg compared to the control group.
- Food consumption and compound intake (if feeding study):
- not examined
- 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
- Sexual maturation:
- not examined
- Anogenital distance (AGD):
- not examined
- Nipple retention in male pups:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Gross examination revealed a low incidence of malformations at 0 mg/kg (0.6%) and 6 mg/kg (0.6%). No gross malformations were observed at 25 or 100 mg/kg. No visceral malformations were observed at any dose level. The incidences of visceral variants, which included persistent left umbilical artery and dilatation of renal pelvis, did not differ significantly between the groups.
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Effect levels (F1)
open allclose all
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 25 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- mortality
- body weight and weight gain
- other: Gorss and visceral malformations/variations
- Dose descriptor:
- LOAEL
- Generation:
- F1
- Effect level:
- <= 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- mortality
- body weight and weight gain
Overall reproductive toxicity
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- NOAEL for systemic toxicity in male and female rats was found at ≥25 mg/kg bw/day. NOAEL for toxicity to reproduction in both male and female rats was found at ≥100 mg/kg bw/day. The observed effects on development at 100 mg/kg bw/day were not considered to be solely non-specific, secondary to maternal toxicity.
- Executive summary:
The chemical was given by oral gavage to 12 rats per sex per dose level at 0, 6, 25 and 100 mg/kg bw/day. For male rats, the chemical was given two weeks before mating and thereafter for a total of 42 days of dosing. For female rats, the chemical was given two weeks before mating and thereafter until day 4 after delivery, for a total of 42-56 days of dosing. Dose levels were selected based on the results from a dose range-finding study in which male and female rats were treated by oral gavage at 0, 50, 100, 200 and 400 mg/kg bw/day for a total of 14 days. The animals were examined for mortality and clinical signs twice per day. The body weight and food intake of each male rat were measured weekly. For female rats, the body weight and food intake of each animal were measured weekly before mating; on day 1, 7, 14, 20 of gestation; and on day 0 and 4 of lactation. Female rats were examined for oestrous cycle length, number of female rats with successful copulation, paring days until copulation, number of pregnant female rats, fertility index, number of corpora lutea, number of implantation sites, implantation index, number of female rats with parturition, gestation length, gestation index and number of female rats with live pups at day 4. Specific observations for the developmental phase of the study included number of pups born, delivery index, number of pups alive at day 0 of lactation, live birth index, sex ratio, number of pups alive on day 4 of lactation, viability index, and body weight of live pups at day 0 and 4 of lactation. All adult male and female rats were sacrificed after treatment for gross pathology, organ weight determinations and histopathology, which included a morphological evaluation of the spermatogenesis in the male rats. All pups were examined externally for malformations and internally for visceral variations/malformations. No mortality was observed during the dosing period. Clinical findings included excessive salivation in male and female rats treated at 100 mg/kg. Male rats treated at 100 mg/kg showed significantly lower body weights on day 7, 14 and 28 of dosing (mean 8.1% lower) and decreased body weight gain between day 1 and 42 of dosing (by 16.4%) when compared to the control group. Female rats treated at 100 mg/kg showed lower body weights at day 14 and 20 of gestation (mean, 9.5%), markedly decreased body weight gain between day 0 to 20 of gestation (by 22.8%), and lower body weights at day 0 and 4 of lactation (mean, 11.3%) when compared to the control group. Deviations in food intake in male rats were minor and occurred sporadically. In female rats, marked decreases in food intake were observed in the group of animals treated at 100 mg/kg on day 0 of lactation (56% lower) and day 3 of lactation (40% lower) when compared to the control group. There were no significant effects on oestrous cycle length, number of female rats with successful copulation, paring days until copulation, number of pregnant female rats, fertility index, number of corpora lutea, number of implantation sites, implantation index, number of female rats with parturition, gestation length, gestation index, or the number of female rats with live pups at day 4. At necropsy, male rats showed increased liver weights at ≥25 mg/kg, increased spleen weights at 100 mg/kg, decreased epididymides weights at 100 mg/kg and increased kidney weights at 100 mg/kg relative to the control data. These effects were accompanied by slight hepatocellular hypertrophy at 100 mg/kg, a dose-dependent increase of hyaline droplets in the proximal tubular epithelium at ≥25 mg/kg and an increased tendency of tubule basophilia (indicative of renal toxicity) at 100 mg/kg. Microscopic examination of the male reproductive organs showed no treatment-related effects. Furthermore, the results from the spermatogenesis cycle test showed no significant effects attributed to the test chemical. Female rats showed decreased thymus weights at ≥25 mg/kg, increased relative liver weights at ≥25 mg/kg and increased relative kidney weight at 100 mg/kg relative to the control data. These effects were accompanied by slight hepatocellular hypertrophy at 100 mg/kg. Microscopic examination of the female reproductive organs showed no treatment-related effects. The results from the developmental phase of the study showed a marked decrease in the number of live pups at day 0 and 4 of lactation at 100 mg/kg compared to the control group. This effect was accompanied by a marked decrease in the viability index at 100 mg/kg (mean viability, 28.0%) compared to the control group (mean viability, 97.5%). The mean body weights of live pups were also significantly lower on day 0 and 4 of lactation at 100 mg/kg compared to the control group. Gross examination revealed a low incidence of malformations at 0 mg/kg (0.6%) and 6 mg/kg (0.6%). No gross malformations were observed at 25 or 100 mg/kg. No visceral malformations were observed at any dose level. The incidences of visceral variants, which included persistent left umbilical artery and dilatation of renal pelvis, did not differ significantly between the groups. NOAEL for systemic toxicity in male and female rats was found at ≥25 mg/kg bw/day. NOAEL for toxicity to reproduction in both male and female rats was found at ≥100 mg/kg bw/day. The observed effects on development at 100 mg/kg bw/day were not considered to be solely non-specific, secondary to maternal toxicity.
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