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EC number: 204-327-1 | CAS number: 119-47-1
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: acceptable, well-documented publication which meets basic scientific principles (limitations: no data to test substance homogeneity and stability given, small number of animals evaluated at study termination)
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- publication
- Title:
- Acute, subchronic and chronic toxicity studies of a synthetic antioxidant, 2,2'-methylenebis(4-methyl-6-tert-butylphenol) in rats
- Author:
- Takagi, A.; et al.
- Year:
- 1 994
- Bibliographic source:
- The Journal of Toxicological Sciences, vol. 19, 77-89
Materials and methods
- Principles of method if other than guideline:
- other: chronic toxicity feeding study
- GLP compliance:
- no
Test material
- Reference substance name:
- 6,6'-di-tert-butyl-2,2'-methylenedi-p-cresol
- EC Number:
- 204-327-1
- EC Name:
- 6,6'-di-tert-butyl-2,2'-methylenedi-p-cresol
- Cas Number:
- 119-47-1
- Molecular formula:
- C23H32O2
- IUPAC Name:
- 2-tert-butyl-6-[(3-tert-butyl-2-hydroxy-5-methylphenyl)methyl]-4-methylphenol
- Details on test material:
- 2,2'-methylenebis(6-tert-butyl-4-methylphenol), test substance from Ouchi Shinko Chemical Ind. Ltd.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- the animals was maintained at tepmerature of 24 +/- 1°C and 55 +/- 5% humidity with a 12 h light/dark cycle; rats were housed in plastic cages (5 rats/cage)
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- other: test substance contained in the diet
- Details on oral exposure:
- pellets of diet containing the substance; stored at 4°C until use
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 18 months
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 100, 300, 1000 ppm
Basis:
nominal in diet
- No. of animals per sex per dose:
- 30 per dose and sex
- Control animals:
- yes, plain diet
- Details on study design:
- Age at study initiation: 5 weeks old for both sexes; weight at study initiation: 393 +/- 21 g male, 230 +/- 15 g for female; no. of animals per sex and per dose: 30 (5 animals/group were sacrified after 6 and 12 months for hematological serum biochemical examinations)
- Positive control:
- no data
Examinations
- Observations and examinations performed and frequency:
- Clinical observations performed and frequency: general conditions was observed daily; body weight and food consumption were determined monthly; hematological and serum biochemical examination were performed for 5 animals/sex/dose group at 6, 12, 18 months
Organs examined at necropsy:
Organ weight: brain, heart, lungs, liver, kidney, spleen, adrenals, testes, ovaries, pituitary and thyroid glands
Microscopic evaluation /all groups: brain, heart, lungs, liver, kidney, spleen, adrenals, testes, ovaries, pituitary and thyroid glands, salivary glands, esophagus, stomach, small and large intestine, pancreas, urinary bladder, seminal vesicles, epididymis, ischiac nerve, uterus, prostate, mesenteric lymph nodes, thymus, spinal cord, skeletal muscle, bone marrow - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Statistics:
- Analysis of variance (ANOVA) techniques with Dunnett's or Scheffe's test for continous data and Chi square test for analysis of categorical data
Results and discussion
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 12.7 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: slight increase in relative liver weights
- Dose descriptor:
- NOAEL
- Effect level:
- 15.1 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: no adverse effects
- Dose descriptor:
- LOAEL
- Effect level:
- 42.3 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: decreased body weights, increased absolute and relative liver weights, decreased absolute and rel. testis weights, atrophy of testicular tubules and spermatogenic arrest and epididymis, hypospermia
- Dose descriptor:
- LOAEL
- Effect level:
- 54.2 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: decreased body weights, increased absolute and relative liver weights
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
NOAEL Males: 300 ppm (12.7 mg/kg bw/ day), females 300 ppm (15.1 mg/kg bw/day)
LOAEL Male: 1000 ppm (42.3 mg/kg/day), Female: 1000 ppm (54.2 mg/kg/day)
Clinical signs: no remarkalbe changes in general appearance were observed in any rat. survival rates in all treated animals were comparable to those of control (see Table below).
Body weight: Significant suppression of body weight gain was observed from the month 6 in the male group at 1000 ppm and from the month 1 in the female group at 1000 ppm.
Food/water consumption: No significant effect was observed during the study.
Table: survival rate, body weight and food consumption: effects seen after 18 months
Males |
Females |
|||||||
Diet level (ppm) | 0 | 100 | 300 | 1000 | 0 | 100 | 300 | 1000 |
Final mean body weight (g) |
545 | 528 | 520 | 498* | 375 | 368 | 353 | 278* |
Mean food intake (g/rat/day) | 16.6 | 16.7 | 16.6 | 16.2 | 12.2 | 12.7 | 12.2 | 11.5 |
Survival rate (%) | 95 | 95 | 91 | 95 | 90 | 100 | 95 | 95 |
(* significant: not specified the degree)
Haematology: In the hematological and serum biochemical analysis, several parameters demonstrated significant alternation. However, none appeared to be of biological significance, since they did not show the same tendency throughout the experimental period and/or the degrees of change were very small.
Mortality and time to death: Survival rates in all treated groups were comparable to those of control.
Gross pathology incidence and severity: Organ weight changes:
Male: Increase in liver weight at 300 ppm (absolute (p<0.05) and relative (p<0.01)); decrease in testis weight at 1000 ppm (absolute and relative) (p<0.01)
Female: Increase in liver weight at 1000 ppm (relative) (p<0.01). no changes in ovary weights were observed in any of the treated females. no changes in other organs were observed in any treated groups for males and females.
Table: Organ weightseffects seen after 18 months
Males |
Females |
||||
Diet level (ppm) | 0 | 300 | 1000 | 0 | 1000 |
Absolute weight | |||||
Liver (g, Mean ± SD) | 12.28 ± 0.93 | 12.59 | 14.19 ± 1.35* | 7.60 ± 0.88 | 7.39 ± 0.83 |
Testis (g, Mean ± SD) | 3.28 ± 0.48 | 3.98 ± 0.54 | 0.82 ± 10.18** | ||
Relative weight | |||||
Liver (g%, Mean ± SD) | 2.37 ± 0.16 | 2.58 ± 0.16**# | 3.00 ± 0.13** | 2.08 ± 0.15 | 2.79 ± 0.35** |
Testis (g%, Mean ± SD) | 0.63 ± 0.10 | 0.82 ± 0.11 | 0.17 ± 0.05* |
( * p <0.05, ** p <0.01)
# relative liver weight 8.9 % increased compared to control
Histopathology (incidence and severity):
Histopathological lesions were only observed in the testis and epididymis of males. However, no interstitial cell tumors were apparent. In the other organs of males, no changes induced by the test substance were observed and no changes in any organs were apparent in females. No neoplastic lesions which could be attributed to the test substance were observed in any organs of males and females.
Male: Atrophy of testicular tubules and spermatogenic arrest and epididymis
hypospermia were observed in the 1000 ppm group.
Female: No significant effect was observed.
Table: Histopathological effects seen after 18 months
Diet level (ppm) | degree* | 0 | 100 | 300 | 1000 |
No. of animals | 19 | 19 | 18 | 19 | |
Testis, tubules Atrophy |
± | 0 | 1 | 0 | 0 |
+ | 0 | 0 | 0 | 0 | |
++ | 2 | 0 | 0 | 0 | |
+++ | 0 | 3 | 1 | 19 | |
Spermatogenic arrest | ++ | 2 | 0 | 0 | 0 |
+++ | 0 | 1 | 1 | 19 | |
Epididymis Hypospermia | ++ | 2 | 0 | 0 | 0 |
+++ | 0 | 1 | 1 | 19 |
CONCLUSIONS: Toxic effects in this study are suppression of body weight gain, increase in liver weight, decrease in testis weight, and histopathological lesions in the testis and the epididymis.
The NOAELs are 12.7 mg/kg/day (300 ppm) for male and 15.1 mg/kg/day (300 ppm) for female.
Applicant's summary and conclusion
- Executive summary:
In a chronic feeding study male and female Wistar rats were administered with 0, 100, 300 and 1000 ppm test substance in the diet. A suppression of the body weight gain was noted at 1000 ppm (corresponding to 42.3 mg/kg bw/d for males and 54.2 mg/kg bw/d for females). An increase in the relative liver weight was found at 300 ppm and 1000 ppm for males and 1000 ppm for females. In males a decrease of the absolute and relative testes weights and atrophy of testicular tubules were observed at 1000 ppm. In addition a spermatogenic arrest and epididymis hypospermia were noted at this concentration. The NOAELs are considered to be 12.7 mg/kg/day (300 ppm) for male and 15.1 mg/kg/day (300 ppm) for female (Takagi 1994).
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