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EC number: 265-633-9 | CAS number: 65212-76-2
- 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:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 2011-01-05 until 2011-06-03
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Remarks:
- read across substance
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 011
- Report date:
- 2011
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD 421 Reproduction/Developmental Toxicity Screening Test
- Version / remarks:
- 27 July 1995
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Reference substance 001
- EC Number:
- 603-331-4
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and batch No.of test material: Synthesia, a.s. and E0986
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: in a supplied container in dry room at the temperature < 30°C
- Stability under test conditions: 15 years
- Solubility and stability of the test substance in the solvent/vehicle: based on the sponsor information, main component is insoluble in the used vehicle, suspension; stability can not be verified analytically
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: suspended in the vehicle daily
FORM AS APPLIED IN THE TEST: suspension, yellow non-transparent, undissolved particles easily visible in the application form and homogeneity could be checked by eye
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: SPF breeding, VELAZ s.r.o., Kolec u Kladna, Czech Republic, RCH CZ 21760152
- Age at study initiation: 10 weeks
- Weight at study initiation: males 307.89 - 309.22 g, females: 224.33 - 226.55 g
- Housing: exept from mating period, two rats of the same sex per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7d
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: males from: 19.01.2011 To: 22.02.2011 females: 19.01.2011 - 13.03.2011
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- suspension
- Details on exposure:
- PREPARATION OF DOSING SUSPENSIONS:
DIET PREPARATION (non-feeding study)
- Rate of preparation of diet (frequency): daily just before administration
- Storage temperature of food: test item was administered by gavage
SUSPENSION
- Amount of suspension: 10 ml/kg bw
VEHICLE
- Lot/batch no.: Ardeapharma a.s., Sevetin, Batch No.: 0102110510, 0102121110, 0206160910, 0203071210 - Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- - homogeneity could be checked by eye
- stability of the test substance in the application form cannot be verified analytically - Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1 to 1
- Length of cohabitation: one week
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- males and females - 2 weeks prior to the mating period and during the mating period,
pregnant females - during pregnancy and till the 3rd day oflactation,
males - after mating period - totally for 28 days,
nonpregnant females (mated females without parturition) - for 25 days after the confirmed mating - Frequency of treatment:
- daily, 7d/week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 160 mg/kg bw/day (nominal)
- Dose / conc.:
- 400 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 vehicle
- Details on study design:
- - Dose selection rationale: based on data of 14d range finding study
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly in premating and mating period, during pregnancy: day 0, 7th , 14th, 20th day, during lactation: 0. or 1st and 4th day
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on lactation day 4
- Examination: macroscopic, all organs - 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 of implantations: Yes
- weight of ovaries and pituitary gland - Fetal examinations:
- - External examinations: Yes
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: No
- Head examinations: No data
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, presence of gross anomalies, physical or behavioural abnormalities
Dead pups were sexed and externally examined; the stomach was examined for the presence of milk. Pups killed on the 4th day of lactation were sexed and subjected to external examination of the cranium, and to macroscopic examination of the thoracic and abdominal tissues and organs.
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities - Statistics:
- The ANOVA test - Analysis of Variance (QC.Expert 2.5) at significance level 0.05 was used for the statistical analysis. This statistical analysis was used for the results of body weight, biometry of organs and number of pups. Control group with vehicle was compared with three treated groups. The results statistically significant on probability level 0.05 are indicated by figures with asterisk in the summary tables.
- Indices:
- Male mating index
number of males with confirmed mating x 100 / number ofmales cohabited
Female mating index
number of sperm-positive females x l00 / number of females cohabited
Male fertility index
number of males impregnating a females x 100 / number ofmales cohabited
Female fertility index
number ofpregnant females x 100 / number of sperm-positive females
Gestation index
number of females with live born pups x l00 / number of pregnant females
Survival index
number of live pups on day 4 post partum* x l00 / number of pups born alive+
Note: * WIthout shll born pups (dead pups WIth anaenallungs)
+ with dead pups with aerial lungs
Pre-implantation loss: Number of corpora lutea - number of implantations
Post-implantation loss: Number of implantations - number of live births
Post-natal loss: Number of live births - number of alive at postuatal day 4 - Historical control data:
- yes, 13 control groups from Reproduction / Developmental Toxicity Screening tests
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- - yellowish colored excrements at dose levels of 400 (since the 3rd week of application) and 1000 (since the 1st week of application) mg/kg bw/day
- in females the colouring was not discovered in all females in the last week of substance application - Mortality:
- no mortality observed
- Description (incidence):
- - no unscheduled deaths observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- - no statistically significant differences compared to the control groups
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- - absolute and relative weights of testes, epididymis and pituitary gland similar in treated and control males
- in females at 1000 mg/kg bw/day: absolute weights of evaluated organs were slightly lower whilst relative weights of ovaries and pituitary gland were balanced
- relative weight of uterus of the high dose group was decreased against the control
No statistically significant differences were detected. - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - colouring of chymus in caecum and stomach recorded in all males of the dose level 1000 mg/kg/day
- no effects observed in male animals of the mid- and low-dose groups
- macroscopic changes of genital organs recorded in control and treated females dilatation of uterine horns, atrophy of one uterine horn and absence of one oviduct in one high-dose female
- stomach and content of intestine substance coloured in all females of the middle and the highest dose level and one female of the lowest dose level
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- The number of corpora lutea and implantations was insignificantly decreased at the dose level 1000 mg/kg/day compared to control.
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- Pre-implantation losses were slightly increased at the dose level 1000 mg/kg/day. Slightly increased post-implantation losses were described at the dose level 160 mg/kg/day. No significant differences were detected in post-natal losses.
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- The number of duration of pregnancy was comparable between the control and treated groups.
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- The number of females achieving pregnancy was comparable between the control and treated groups.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: no effects observed
- Remarks on result:
- other: no effects observed
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- - mean weights of the litters and pups were balanced in the control and treated groups period
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- - total number of live pups (on the day of parturition / 1st day after parturition and the 4th day after parturition) at the dose level 1000 mg/kg/day was lower than at the control
- mean number of pups per litter at the dose level 400 mg/kg/day was increased compared to control
The statistical evaluation of the number of live pups did not find any significant changes. - Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Sex ratio of pups was balanced in treated and control groups.
- External malformations:
- no effects observed
- Description (incidence and severity):
- - no statistically significant pathological findings were recorded in pups of contral group and treated groups
- Details on embryotoxic / teratogenic effects:
- Pups with macroscopical findings were recorded only sporadically at the dose levels 400 and 1000 mg/kg/day.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No statistically significant effects observed.
- Remarks on result:
- other: no effects observed
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Table 1: Histopathological (microscopical) findings in females
Microscopical findings (number of affected animals) | ||||
Pathological findings | Dose level | |||
0 | 160 | 400 | 1000 | |
Number of examined animals | 12 | 12 | 12 | 12 |
Without microscopical changes | 4 | 4 | 8 | 3 |
Pituitary gland: cysts | 0 | 0 | 0 | 1 |
Ovaries: follicular or luteal cysts | 0 | 1 | 0 | 1 |
Uterus: signs of previous gravidity | 5 | 6 | 4 | 4 |
Uterus: hydrometra | 3 | 0 | 0 | 4 |
Vagina: blood and/or cell detritus in lumen | 2 | 2 | 0 | 0 |
Table 2: Total number of live pups and sex distribution/ratio
Number of pups and sex (mean per litter) | ||||||||
Dose level | 0 | 160 | 400 | 1000 | ||||
Day of study | Total number (mean) | Number of males and females | Total number (mean) | Number of males and females | Total number (mean) | Number of males and females | Total number (mean) | Number of males and females |
0/1 day first check of litter after parturition | 81 (11.57) | 45 M, 36 F | 99 (11.00) | 51 M, 48 F | 87 (12.43) | 44 M, 43 F | 68 (11.33) | 37 M, 31 F |
4th day of lactation | 78 (11.14) | 43 M, 35 F | 99 (11.00) | 51 M, 48 F | 86 (12.29) | 43 M, 43 F | 67 (11.17) | 37 M, 30 F |
M: male pups, F: female pups
Table 3: Overview of the reproduction parameters of the study
Reproduction data | ||||
Observed parameters | Dose level | |||
0 | 160 | 400 | 1000 | |
Paris started (N) | 12 | 12 | 12 | 12 |
Females showing evidence of copulation (N) | 12 | 12 | 12 | 12 |
Females achieving pregnancy (N) | 8 | 10 | 9 | 8 |
Females with abortion (N) | 1 | 1 | 2 | 2 |
Conceiving days (duration of mating) 1-5 (N) | 12 | 11 | 12 | 12 |
Conceiving days (duration of mating) 6-10 (N) | 0 | 1 | 0 | 0 |
Mean duration of mating (days) | 2.42 | 2.25 | 1.83 | 1.92 |
Pregnancy ≤ 21 days (N) | 1 | 2 | 2 | 1 |
Pregnancy = 22 days (N) | 4 | 5 | 4 | 4 |
Pregnancy ≥ 23 days (N) | 2 | 2 | 1 | 1 |
Mean duration of pregnancy (days) | 22.14 | 22.00 | 21.86 | 22.00 |
Females with live pups born (N) | 7 | 9 | 7 | 6 |
Females with live pups at day 4 after parturition (N) | 6 | 9 | 7 | 6 |
Corpora lutea/pregnant females (mean) | 11.63 | 12.40 | 11.11 | 10.88 |
Implantations/pregnant females (mean) | 10.88 | 11.80 | 10.56 | 9.63 |
Live pups/mother at birth (mean) | 11.57 | 11.00 | 12.43 | 11.17 |
Live pups/mother at day 4 after parturition (mean) | 11.14 | 11.00 | 12.29 | 11.17 |
Sex ratio (M/F) at birth (mean) | 6.43/5.14 | 5.67/5.33 | 6.29/6.14 | 6.17/5.17 |
Sex ratio (M/F) at day 4 after parturition (mean) | 6.14/5.00 | 5.67/5.33 | 6.14/6.14 | 6.17/5.00 |
Litter weight at birth (mean) | 76.31 | 71.91 | 80.29 | 69.55 |
Litter weight at day 4 after parturition (mean) | 128.53 | 112.28 | 121.97 | 118.15 |
Pup weight at birth (mean) | 6.67 | 6.58 | 6.51 | 6.24 |
ABNORMAL PUPS | 10.02 | 10.32 | 9.96 | 10.72 |
Mothers with 0 (N) | 0 | 0 | 0 | 0 |
Mothers with 1 (N) | 0 | 0 | 1 | 1 |
Mothers with ≥ 2 (N) | 0 | 0 | 0 | 0 |
Applicant's summary and conclusion
- Conclusions:
- The influence of the test substance treatment expressed mainly at the highest dose level (limit dose) - decrease of absolute and relative weight of prostate gland and occurrence of atrophie changes in prostate gland of parental males.
The NOAEL (No Observed Adverse Effect Level) for DEVELOPMENT of pups was established as 1000 mg/kg body weight/day.
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