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EC number: 445-760-8 | CAS number: 122886-55-9
- 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
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- November 12, 2012 ~ April 04, 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: This study was performed according to OECD guidelines and GLP priciples.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- (1995)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 445-760-8
- EC Name:
- -
- Cas Number:
- 122886-55-9
- Molecular formula:
- C31H48N4O2 (component: N,N’’-(methylenedi-4,1-phenylene)bis(N’-octylurea)) C41H68N4O2 (component: N-(4-((4-(((octadecylamino)carbonyl)amino)phenyl)methyl)phenyl)-N’-octylurea) C51H88N4O2 (component: N,N’’-(methylenedi-4,1-phenylene)bis(N’-octadecylurea))
- IUPAC Name:
- 3-octadecyl-1-[4-({4-[(octadecylcarbamoyl)amino]phenyl}methyl)phenyl]urea; 3-octadecyl-1-[4-({4-[(octylcarbamoyl)amino]phenyl}methyl)phenyl]urea; 3-octyl-1-[4-({4-[(octylcarbamoyl)amino]phenyl}methyl)phenyl]urea
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
- Details on test material:
- - Name of test material (as cited in study report): KY-EU
- Physical state: White powder
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD(SD) rats, Specific Pathogen Free (SPF)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: ORIENT BIO Co., Ltd. (143-1, Sangdaewon-Dong, Jungwon-Gu, Seongnam-Si, Gyeonggi-Do, Korea)
- Age at study initiation: male 9 weeks , female 9 weeks
- Weight at study initiation: Males: 326.9 - 394.0 g; Females: 208.5 - 266.7 g
- Fasting period before study: no data available
- Housing: Administration : Two animals per cage were housed in stainless steel cages; Mating period : One female and one male were housed in stainless steel cages; Gestation and lactation period : Maternal rats and fetuses were housed individually in polycarbonate cage
- Diet (e.g. ad libitum): free access to pellet diet for rat (Cargill Agri Purina, Inc., 56-4, Soryong-dong, Gunsan-si, Jeonbuk, Korea)
- Water (e.g. ad libitum): free access to filtered and UV irradiated water
- Acclimation period: 19 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): min 21.5 ℃, max 22.7 ℃
- Humidity (%): min 49.0 %, max 54.8 %
- Air changes (per hr): 10 ∼ 15) changes/hr
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 11-12-2012 To: 23-01-2013
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.5%(w/v) aqueous methylcellulose solution
- Details on exposure:
- The test substance, prepared by the test substance preparation method, was orally administered once a day, 7 days a week.
- Details on mating procedure:
- Normally, 1:1 (one male to one female) mating was used in this study. Each morning the females were examined for the presence of a sperm or a vaginal plug. Day 0 of pregnancy was defined as the day which a vaginal plug or a sperm was found. Pregnancy was determined with implantation marks on the uterus at necropsy was performed.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Homogeneity was evaluated for the formulation of the first day and fifth week before administration. Sample solutions were prepared by sampling from upper, middle and bottom in bottle with KY-EU formulation. Homogeneity was assessed by coefficient of variation (C.V (%)) and content (%).
C.V (%) for the formulations of the first day were 4.1 %, 2.4 % and 1.4 % for G2, G3 and G4. And contents (%) were 91.3 %, 92.7 % and 105.8 % for G2, G3 and G4,
respectively. These results met the acceptance criteria (C.V (%) ≤ 5.0 %, Content (%): 100 ± 10 %). C.V (%) for the formulations of the fifth week were 4.0 %, 1.3 % and 3.6 % for G2, G3 and G4, respectively. And contents (%) were 96.0 %, 101.1 % and 101.0 % for G2, G3 and G4, respectively. These results met the acceptance criteria (C.V (%) ≤ 5.0 %, Content (%): 100 ± 10 %).
Homogeneity and content (%) of KY-EU in 0.5 % methylcellulose were analyzed in accordance with validated analytical method (KTR/Study No. : KG-2012-374). KY-EU formulations for the first day and fifth week were considered homogeneous and accurately prepared. - Duration of treatment / exposure:
- Male rats were exposed at each dose levels for 2 weeks prior to mating, during mating period and 2 weeks post mating period (at least 28 or more days).
Female rats were exposed at each dose levels from 2 weeks prior to mating, to day 3 of lactation including the mating and gestation period. - Frequency of treatment:
- Once dayly, 7 days a week
- Details on study schedule:
- Male rats were administered by oral gavage at each dose levels for 2 weeks prior to mating, during mating period and 2 weeks post mating period (at least 28 or more days).
Female rats were administered by oral gavage at each dose levels from 2 weeks prior to mating, to day 3 of lactation including the mating and gestation period.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
250, 500 and 1000 mg/kg b.w.
Basis:
nominal conc.
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- The dose-levels were selected on the basis of the results of the pilot study by 5-week oral route (gavage) in Sprague-Dawley rats (KTR/Study No. : KG-2012-465). KY-EU was given orally by gavage to rats at 500 and 1000 mg/kg B.W.. There was a significant body weight loss in the 1000 mg/kg B.W. group in female rats. Therefore, 1000 mg/kg B.W. was used as the high dose and doses of 250 and 500 mg/kg B.W. were selected as the medium and low dose, respectively, using a scaling factor of 2.
- Positive control:
- no
Examinations
- Parental animals: Observations and examinations:
- - Clinical signs including mortality, moribundity, general appearances, deaths and behavior changes were checked once a day during the non-treatment period and twice a day during the treatment period and recorded with date, time of finding and duration.
- Body weight and body weight gain:
All animals were weighed on animal arrival and allocation. Males and females were measured on the first day of dosing, weekly after and at termination. During the gestation and lactation periods, females were measured as follow:
1) During the gestation periods : Days 0, 3, 6, 9, 12, 15, 18 and 20 of gestation
2) During the lactation periods : Days 0 and 4 of lactation
- Food consumption: Rats were supplied with a certain amount of diet on days of body weight measurement and food consumption was recorded for the animals on the following days. During the mating periods, food consumption was not measured. In addition, on day 4 of lactation a diet was supplied on day 3 of lactation and food consumption was recorded on the following day.
- Absolute organ weight were measured and their relative organ weight (organ-to-body weight ratios) were calculated from the terminal body weight for the following organs of all live animals when they were sacrificed. 10 % neutral buffered formalin was used for fixation and preservation, except testes, epididymides and eyeball. Bouin's fixative was used for testes and epididymides and Davidson's solution was used for eyeball.
- Histopathology examination: Gross finding organ, testes, epididymides, ovaries and uterus were embedded in paraffin, sectioned, stained with hematoxylin and eosin (H&E) and examined microscopically in the vehicle control and 1000 mg/kg B.W. groups. - Oestrous cyclicity (parental animals):
- A vaginal smear was taken daily for each female during the pre-mating period (14 days) and regularity and length of the cycle was examined.
- Litter observations:
- litter size, body weight on PND 0 and 4, sex ratio, mortality
- Postmortem examinations (parental animals):
- Necropsy finding, organ weight, histopathological findings
- Postmortem examinations (offspring):
- Necropsy finding
- Statistics:
- Program : SPSS ver.19 (SPSS Korea Data Solution Co., Ltd.)
One-way analysis of variance (ANOVA) with Dunnett or Scheffe nonparametric ANOVA with Mann-Whitney U-test
P < 0.05 or 0.01 - Reproductive indices:
- pregnancy period, No. of corpora lutea, No. of implantation, pre- and post- implantation loss, fertility, pregnancy and delivery indices, mating index, sex ratio, viability
- Offspring viability indices:
- live pups on PND 0 and 4, dead pups on PND 0, viability index
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Details on results (P0)
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
Details on results (F1)
No treatment-related effect was seen in all treatment groups in the following parameters examined: gestation length, the number of corpora lutea, implantation sites, delivery index, live and dead pups, live and death rate to implantation, sex ratio, viability index, body weight of pups in both sexes on day 0 of lactation and pre- and post-implantation losses. By observation of live pups at birth, there were no externally malformed pups in any groups. At necropsy of pups, no gross finding was observed in any groups.
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Based on the results, it was determined that the repeated oral dose of KY-EU to parental animals resulted in no adverse effects on all parameters examined at 1000 mg/kg B.W .. Therefore, No Observed Adverse Effect Level (NOAEL) of the test substance is considered to be above 1000 mg/kg B.W . in both sexes for general toxicity, reproductive capability and F1 neonates.
- Executive summary:
A Reproduction and Developmental Toxicity Screening Test with KY-EU in male and female Rats was performed according to OECD 421 guideline and GLP principles.
No treatment-related changes were observed in body weight, absolute and relative organ weight of parental rats.
There were no treatment-related changes in estrus cycle, fertility and pregnant indices among the groups.
There were no treatment-related changes in the number of corpora lutea and implantations, pre-implantation loss, post-implantation loss, litter size at birth, neonatal death, sex ratio of neonates, viability index, body weight of neonates on day 0 and 4 of lactation or gross finding at any of the doses tested.
Based on the results, it was determined that the repeated oral dose of KY-EU to parental animals resulted in no adverse effects on all parameters examined at 1000 mg/kg B.W .. Therefore, No Observed Adverse Effect Level (NOAEL) of the test substance is considered to be above 1000 mg/kg B.W . in both sexes for general toxicity, reproductive capability and F1 neonates.
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