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EC number: 248-765-1 | CAS number: 27987-25-3
- 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
Endpoint summary
Administrative data
Description of key information
2_Gen (RA 84 -61 -7): NOAEL = 1200 ppm (Tox. Science, 2005)
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Remarks:
- compared to standard rep. dose studies, no blood examinations and limited number of organs
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 416
- Version / remarks:
- 1983
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Details on species / strain selection:
- IGS (international genetic standard)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan, Inc. (Astugi breeding center)
- Age at study initiation: (P) 5 wks; (F1) 3 wks (time of weaning)
- Housing: polycarbonate cages with bedding for lab. animals
- Diet (e.g. ad libitum): ad lib (NIH-07M, CLEA, Japan Inc.)
- Water (e.g. ad libitum): ad lib.
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 -25°C
- Humidity (%): 35-75%
- Air changes (per hr): 12/h
- Photoperiod (hrs dark / hrs light): 12/12h - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Mixing appropriate amounts with (Type of food): NIH-07M, CLEA, Japan Inc. - Duration of treatment / exposure:
- > 90 days
- Frequency of treatment:
- continuous
- Dose / conc.:
- 240 ppm
- Remarks:
- app. 16mg/kg (males), 21mg/kg (females)
- Dose / conc.:
- 1 200 ppm
- Remarks:
- app. 80mg/kg (males), 104mg/kg (females)
- Dose / conc.:
- 6 000 ppm
- Remarks:
- app. 402mg/kg (males), 511mg/kg (females)
- No. of animals per sex per dose:
- 24
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: A preliminary dose range finding study was conducted with DCHP administered to rats at doses of 0, 600, 2000, 6000 or 20000 ppm during the period from three weeks or more pre-mating through the mating period, until necropsy for the males, and through gestation and lactation periods until postnatal day 21 (PDN 21) for the females. With regard to effects on the parental animals, in the 20000 ppm group, inhibition of body weight gain and increase in hepatic weights were observed in males and females, along with increase in adrenal weights and decrease in the weights of the thymus, spleen and ovary in the females. In the 6000 and 2000 ppm groups, increase or a tendency for increases in hepatic weights were found in both females and males, and a similar tendency was also shown in the females of the 600 ppm group. No effects on reproductive functions, delivery or lactation were found in any dose group. Regarding effects on the offspring, inhibition of body weight gain was observed in both males and females of the 20000 ppm group, and a similar trend was found in the 6000 ppm group. Based on these findings, the highest dose for the main study set at 6000 ppm, with middle and lowest doses of 1200 and 240 ppm, respectively, by dividing with the common ratio of 5.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: during b.w. measurements
BODY WEIGHT: Yes
- Time schedule for examinations: weekls
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
HORMONE MEASUREMENT
- Time schedule: at necropsy
- Animals: 6 females proestrous (after lactation) and 6 males per P and F1 treatment group - randomly selected
- Hormones analyzed: testosterone, FSH, LH (males), estradiol, FSH, LH (females)
ESTROUS CYCLE DETERMINATION
SPERM ANALYSIS
count, motility, morphology - Sacrifice and pathology:
- All animals sacrificed or found dead
ORGAN WEIGHTS
- all animals
- brain, pituitary gland, thyroid including parathyroid, liver, kidneys, adrenal glands, spleen, testes, epididymes (whole and caudal parts), prostate (ventral lobe), seminal vesicles (including the coagulating glands), ovaries, and uterus (including the cervical region)
HISTOPATHOLOGY
- high dose and control: brain, pituitary gland, thyroid including parathyroid, liver, kidneys, adrenal glands, spleen, testes, epididymes, seminal vesicles (including coagulating glands), prostate (ventral lobe), ovaries, uterus (including the cervical region), vagina, and mammary glands
- low and mid dose: liver, thyroid, kidney (males), testes (F1 only), adrenals (F1 only)
- all macroscopically abnormal sights were additionally examined - Statistics:
- Using weights of bilateral organs, the sums of the left and right organs were employed for statistical analysis.
Metric data were analyzed for homogeneity of variance by Bartlett’s method (Bartlett, 1937). When the variance was homogeneous, one-way ANOVA was carried out. When not homogeneous a Kruskal-Wallis’s test (Kruskal and Wallis, 1952) was performed. When a significant inter-group difference was found, Dunnett’s method (Dunnett, 1955) or a Dunnett type multiple-comparison method (Dunnett, 1964) were applied. For some examination items, the Kruskal-Wallis test was applied first, and when a significant inter-group difference was found, Dunnett type multiple-comparison method was conducted. Numerical data were analyzed by the Fisher’s exact probability method (Fisher, 1955). The level of statistical significance was basically set at 5%.
For clinical signs, necropsy, and histopathological findings, no statistical analyses were performed. - Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Significantly reduced body weight in high dose females. The body weight of mid dose females was reduced at several intervals throughout the study, but final body weight was comparable to controls.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Reduced food consumption in high dose females (11 - 12% in the first 2 weeks of gestation)
Compound intake (mean +/- SD):
males low dose mid dose high dose
10 week period 15.88 ± 1.07 79.57 ± 3.32 401.8 ± 15.6
females
Total study period 20.80 104.19 510.7
Pre-mating 17.70 ± 0.95 88.83 ± 6.39 434.6 ± 29.6
Gestation 14.30 ± 0.88 69.77 ± 4.04 349.0 ± 15.8
Lactation (days 0-21) 37.92 ± 2.50 191.6 ± 12.3 932.8 ± 58.2 - Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- - 6000 ppm: increased relative and absolute liver weight in high dose animals and increased absolute and relative thyroid weight in high dose males was noted.
- Organ weight differences were either adaptive or secondary to reduced body weight. - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- enlarged liver in high dose animals
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- - diffuse hypertrophy of hepatocytes in the mid and high dose
- hypertrophy of thyroid follicular cells in mid and high dose males and high dose females
- increase in hyaline droplets in the renal proximal tubular epithelium in high dose males accompanied with the appearance of eosinophilic microbodies.
- These finding were considered not relevant, as liver hypertrophy is considered a rat-specific effect and the renal changes were concluded to be related to increased depostion of a2U globulin, which is also a rat specific effect. The thydroidal changes were considered to be linked to hypertrophy of hepatocytes. - Other effects:
- no effects observed
- Description (incidence and severity):
- No treatmentrelated effects were observed for the sperm motility rate, number of homogenization-resistant spermatids in the testis, number of sperm in the caudal epididymis, and incidence of morphologically abnormal sperm.
Hormone levels (testosterone, estradiol, FSH, LH) were not affected by treatement. - Details on results:
- Results are provided for the F0 parental generation only. For details on offspring / F1 parental generation please refer to the section on reproductive toxicology.
- Dose descriptor:
- NOAEL
- Effect level:
- 1 200 ppm
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- Remarks on result:
- other: app. 80mg/kg (males), 104mg/kg (females)
- Critical effects observed:
- no
Reference
Organ weight differences were either adaptive or secondary to reduced body weight. Histopathology revealed adaptive hypertrophy of hepatocytes and male rat specifichyaline droplets in the renal proximal tubular epithelium derived from a2µ globulin.
Table 1. Daily chemical intake (mg/kg)
|
|
0 (control) |
240 ppm |
1200 ppm |
6000 ppm |
P0 males |
|
|
|
|
|
|
Total study periodb |
- |
15.88 ± 1.07a |
79.57 ± 3.32 |
401.8 ± 15.6 |
P0 females |
|
|
|
|
|
|
Total study periodc |
- |
20.8 |
104.19 |
510.7 |
|
Pre-matingd |
- |
17.70 ± 0.95 |
88.83 ± 6.39 |
434.6 ± 29.6 |
|
Gestatione |
- |
14.30 ± 0.88 |
69.77 ± 4.04 |
349.0 ± 15.8 |
|
Lactationf |
- |
37.92 ± 2.50 |
191.6 ± 12.3 |
932.8 ± 58.2 |
amean ± sd
bDuring the period of 10 weeks
cThe mean daily intake fort he study (pre-mating + gestation + lactation periods).
dPre-mating period (10 weeks)
eGestation length (Days 21-23)
fLactation period (Days 0-21)
Endpoint conclusion
- Dose descriptor:
- NOAEL
- 80 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
Additional information
Bis(methylcyclohexyl)phthalate was not tested in a repeated dose study. Instead, data are adapted from the structurally similar dicyclohexyl phthalate (DCHP). A detailled read across justification has been attached to section 13.
The toxicity of DCHP was evaluated in a two generation test according to OECD 416, in which male and female Sprague-Dawley (SD) rats of parental (F0) and F1 generation were exposed to DCHP in the diet at concentrations of 0 (control), 240, 1200 or 6000 ppm for more than 90 days, including a premating period of at least 10 weeks. Examinations included histopathology of several organs, detailled sperm analysis, estrous cycle length, hormone analysis, sexual maturation, and reproductive indices, but lacked further analysis of blood or urine parameters. No significant differences were observed in any dose groups for the following indices: number of days required for completion of copulation, number of estrous stages missed until completion of copulation, mating index, fertility index, gestation length, gestation index, birth index and number of implantations. Adverse effects in the high dose F0 animals were limited to reduced body weight (gain) and reduced food consumption (app - 8%). Organ weight differences were either adaptive or secondary to reduced body weight. Histopathology revealed adaptive hypertrophy of hepatocytes and male rat specifichyaline droplets in the renal proximal tubular epithelium derived from a2µ globulin.
Consequently, the NOAEL was 1200 ppm, which equals app. 80mg/kg in males and 104mg/kg in females, based on effects on body weight and food consumption.
Data were only provided for the F0 parental generation. For details on offspring and F1 parental animals, please refer to the section on reproductive toxicity.
Justification for classification or non-classification
Repeated exposure for more than 90 -days with the read across substance DCHP did not cause adverse effects up to 80 - 100mg/kg. Even at app. 500mg/kg, effects were limited to general signs of toxicity, i.e., reduced body weight and food consumption. Similar effects are also expected for the registered substance bis(methylcyclohexyl)phthalate. No classification is required according to EU GHS for STOT RE.
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