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EC number: 309-916-8 | CAS number: 101357-19-1
- 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:
- key study
- Study period:
- 29 Aug 2017 - 22 Feb 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2018
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Benzenamine, N,N-dimethyl-, oxidized, molybdatetungstatephosphates
- EC Number:
- 309-916-8
- EC Name:
- Benzenamine, N,N-dimethyl-, oxidized, molybdatetungstatephosphates
- Cas Number:
- 101357-19-1
- Molecular formula:
- Reaction mass of C25 H30 N3. P Moy Wz O40 (y +z = 12) , C24 H28 N3. P Moy Wz O40 (y +z = 12) and C23 H26 N3. P Moy Wz O40 (y +z = 12)
- IUPAC Name:
- Reaction mass of [4-[bis[4-(dimethylamino)phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]-dimethyl-ammonium. molybdatetungstatephosphates, [4-[[4-(dimethylamino)phenyl]-[4-(methylamino)phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]-dimethyl-ammonium. molybdatetungstatephosphates and [4-[bis[4-(methylamino)phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]-dimethyl-ammonium. molybdatetungstatephosphates
- Test material form:
- solid: nanoform, no surface treatment
- Details on test material:
- SOURCE OF TEST MATERIAL
-Product number: 0345N (skin sensitisation, OECD 422, eye irritation, acute oral toxicity)
0345F (Ames test)
- Purity Preparation containing ≥80% (treat as 100%)
- Physical form/colour: Violet powder
- Expiry date: Stable for at least 5 years from delivery date
-Shape Category: spheroidal
-Shape: spherycal
-pure shape: yes
-Typical composition: ca. 100%
-range >50 and < 100%
-D10, typical value: 30 nm, range: >1.5 and < 50nm
-D50, typical value: 45 nm, range: >15 and <100nm
-D90, typical value: 60nm, range: >25 and < 150nm
-Fraction in size range 1-100nm: > 50 and <100%
-Crystallinity:
Structure:
amorphous, pure structure
-SSA: BET surface area typically ca. 32-40 m2/g for product number 345F and 0345N)
Range > 10 and < 200 m2/g
-.no surface treatment
Storage conditions: Stored at ambient conditions in the dark (away from direct light)
- Safety precautions: Routine hygienic procedures (nitrile gloves, goggles, face mask)
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 982432
- Expiration date of the lot/batch:
- Purity Preparation containing ≥80% UVCB (treat as 100%)
- Physical form/colour: Violet powder
- Manufacture/synthesis date: 21-Apr-1998
- Expiry date: Stable for at least 5 years from delivery date
- Storage conditions: Stored at ambient conditions in the dark (away from direct light)
- Safety precautions: Routine hygienic procedures (nitrile gloves, goggles, face mask)
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 10 weeks
- Weight at study initiation: Males: 331-431 g Females: 179-245 g
- Housing: Cages with standard, granulated, S8-15 sawdust bedding
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30 - 70
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/ 12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- arachis oil
- Details on exposure:
- VEHICLE
- Batch number KMO9422, KM09047
- Expiry date: August 2018
- Storage conditions: Stored at ambient conditions
- Safety precautions: Routine hygienic procedures (nitrile gloves, goggles, face mask)
- Concentration in vehicle: 20 mg/mL to 200 mg/mL
- Administration volume: 5 mL/kg - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: 1-4 days
- Proof of pregnancy: Ejected copulation plugs. Sperm within vaginal smear.
- After successful mating each pregnant female was caged (how): individually - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Validated analytical method in place before commencement of treatment.
Formulations at two concentration levels (target concentrations: 200 and 20 mg/mL) were prepared and the following parameters were determined:
• System suitability (SST)
• Linearity
• Accuracy/repeatability
• Homogeneity
• Specificity
• Limit of Quantification (LOQ) and Limit of Detection (LOD)
• Stability [autosampler, formulations (20 ± 5 ºC, in the absence of light, for 7-12 days)]
The formulations prepared at three different concentrations were analyzed twice over the course of the study to verify their correct preparation.
Control (vehicle) formulations were analyzed to confirm the absence of test item or other substances at the retention time of the test item.
Results are expected to be within ±20% of nominal value and the coefficient of variation (CV) should be ≤10%.
Other parameters were also tested, to check whether they met the following acceptance criteria:
• System Suitability Test (SST) --- CV ≤ 2%.
• Calibration curve --- R2 ≥ 0.99; deviation of the calibration standards ≤ 10% (75% should comply). - Duration of treatment / exposure:
- 5 - 8 weeks
- Frequency of treatment:
- once daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: Doses selected based on preliminary results obtained from 14-Day non GLP Dose range finder study
- Rationale for animal assignment (if not random): Random
- Other:
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily
BODY WEIGHT: Yes
- Time schedule for examinations: On day 1 and weekly thereafter
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once a week - Oestrous cyclicity (parental animals):
- Dry smears Using inoculation loops during the following phases:
• For 14 days before treatment (all females including spares); animals that failed to exhibit 4-5 day cycles were not allocated to study.
• Daily from the beginning of treatment period until evidence of mating.
• On the day of necropsy
A cotton swab impregnated in physiological saline was used in order to check the evidence of mating during the mating period. - Sperm parameters (parental animals):
- At necropsy miicroscopic examination of the epididymus, prostate and seminal vesicles with coagulating glnads and testes were examined , seminiferous tubules were also evaluated with respect to their stage in the spermatogenic cycle and the integrity of the various cell types present within the different stages.
- Litter observations:
- Clinical observations Observed 24 hours after the considered birth and then daily for evidence of ill-health or reaction to maternal treatment
Litter size Daily from Day 1-13 of age
Sex ratio Days 1, 4, 7 and 13 of age
Individual offspring body weights
Days 1, 4, 7 and 13 of age
Ano-genital distance Day 1 - all F1 offspring
Nipple/areolae count Day 13 of age - male offspring. - Postmortem examinations (parental animals):
- SACRIFICE
F0 Males After final investigations completed (after 5 weeks of treatment)
F0 Females failing to produce viable litter (not pregnant)
Day 25-26 after mating
F0 Females whose litters die before Day 13
On or after day last offspring dies
Females killed at termination
Day 14-16 of lactation
F1 Offspring Selected offspring for thyroid hormone analysis – Day 4 of age (two females per litter where possible)
Scheduled sacrifice - Day 13-15 of age
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. Complete necropsy performed for F0 animals (five males and five lactating females with a surviving litter per group). Number of uterine implantation sites counted and checked.
HISTOPATHOLOGY / ORGAN WEIGHTS
All tissues from the animals above were prepared for microscopic examination and weighed, respectively.
Routine staining 4-5 um sections stained with hematoxylin and eosin, except testes which are also stained with periodic acid-Schiff
Extension of initial examination Liver from five males in Group 2 and five males in Group 3 selected at scheduled euthanasia. - Postmortem examinations (offspring):
- F1 offspring on Day 4 of age Blood sampling taken from two females per litter where possible.
External macroscopic examination.
F1 offspring
on Day 13 of age Blood sampling taken from two males and two females per litter, where possible.
Thyroid gland was retained from one male and one female in each litter where possible.
All animals were subjected to an external macroscopic examination; particular attention was paid to the external genitalia. - Statistics:
- Statistical analysis was performed on the following data types at each time point separately:
- Body weight, using absolute weights
- Food consumption, over appropriate study periods
- Blood chemistry and hematology (including coagulation)
- Hormone analyses
- Organ weights, both absolute and adjusted for terminal body weight
- Grip strength and motor activity
- Estrous cycles pre-coital interval
- Mating performance and fertility
- Gestation length
- Litter data (litter size, offspring survival, offspring body weight) ano-genital distance, average for each litter adjusted for litter average pup body weight
- Number of nipples/areolae in male pups counted on post natal Day 13 - Reproductive indices:
- - Grip strength and motor activity
- Estrous cycles pre-coital interval
- Mating performance and fertility
- Gestation length
- Litter data (litter size, offspring survival, offspring body weight) ano-genital distance, average for each litter adjusted for litter average pup body weight
- Number of nipples/areolae in male pups counted on post natal Day 13
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not specified
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Effect levels (P0)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- ca. 1 000 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
- food efficiency
- water consumption and compound intake
- clinical biochemistry
- organ weights and organ / body weight ratios
- gross pathology
- reproductive function (oestrous cycle)
- reproductive function (sperm measures)
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- no
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
- Other effects:
- not specified
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Effect levels (F1)
- Key result
- Dose descriptor:
- NOEL
- Generation:
- F1
- Effect level:
- > 1 000 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
- food efficiency
- water consumption and compound intake
- clinical biochemistry
- organ weights and organ / body weight ratios
- gross pathology
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- The No Observed Effect Level (NOEL) for reproductive / developmental toxicity was considered to be 1000 mg/kg/day, taking into account that there was no effect on estrous cycle, pre-coital interval, mating performance, fertility and gestation length or in the offspring on litter size, survival, sex ratio, clinical signs, body weights, anogenital distances or macropathology.
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