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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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP and OECD Guideline study (TG 421), acceptable documented (abstract and result tables in English, publication in Japanese)
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 999
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- 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:
- purity: 98.2%, produced by Sumitomo Chemical, Lot No: 710140
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Weight at study initiation: (P) Males: 332-383 g; Females: 206-238 g
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: in 5% gum arabic
- Details on exposure:
- oral (gavage)
- Details on mating procedure:
- Male/female percage: 171, length of cohabitation: at the most 14 d, until proof of pregnancy (formation of vaginal closing or sperm detection in vagina)
- Duration of treatment / exposure:
- male: 50-52 d, female: 40-48 d (from 14 days before mating to the day 3 of lactation)
- Frequency of treatment:
- daily
- Details on study schedule:
- age at study initiation was 10 wk old (332-383 g for male, 206-238 g for female)
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 12.5, 50, 200, 800 mg/kg bw and day
Basis:
other: nominal
- No. of animals per sex per dose:
- 12/per dose group/sex
- Control animals:
- yes, concurrent vehicle
- Positive control:
- none
Examinations
- Parental animals: Observations and examinations:
- clinical observations: general appearance twice a day, organ weights: testis, epididymis, cauda epididymis, ovary, microscopic evalauations:( control and all teatment groups): testis, caput epididymis, (control and 800 mg/kg group): seminal vesicle, ovary
- Sperm parameters (parental animals):
- Parameters examined in male parental generations:
testis weight, epididymis weight, sperm count in testes, sperm count in epididymides, sperm motility, viability, sperm morphology - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals
- Maternal animals: All surviving animals - Statistics:
- Dunnett's or Scheffe's test for continuous data and Chi square test for quantal data
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Other effects:
- effects observed, treatment-related
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- effects observed, treatment-related
- Reproductive performance:
- no effects observed
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 12.5 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: no adverse effects
- Dose descriptor:
- LOAEL
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: Giant cell formation in the testes, decreases in sperm motility ratio and number of sperms in the epididymis cauda, increase in abnormal sperm ratio
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: no adverse effects
- Dose descriptor:
- LOAEL
- Effect level:
- 200 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: decreased body weight gain, lower food consumption, dreased number of corpora lutea, decreased number of implantation scars and number of pup born
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not specified
- Mortality / viability:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not specified
Details on results (F1)
NOAEL: male reproductive toxicity: 12.5 mg/kg bw/day
NOAEL developmental toxicity: 50 mg/kg bw/day
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 50 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Pups (200 mg/kg bw): Pup numbers on day 0 and 4 of lactation were decreased
- Remarks on result:
- other: Pups (800 mg/kg bw): the number of pups on day 0 and 4 of lactation, live birth index, and body weights of both sexes on day 4 of lactation were decreased, and the number of stillbirths was increased
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Parental animals:
Males and females: no mortality and clinical signs recorded.
Males (50 mg/kg bw): Giant cell formation in the testes, decreases in sperm motility ratio and number of sperms in the epididymis cauda, and an increase in abnormal sperm ratio
Males (200 mg/kg bw): Atrophy of the testes and epididymides, decreases in the absolute and relative testis and epidymis weights, atrophy of seminiferous tubules, degeneration of seminiferous tubules, a decrease in sperm in the epididymis cauda and giant cell formation were noted in the testes, a decrease in the sperm motility ratio and an increase in the abnormal sperm ratio
Males (800 mg/kg bw): A transient decrease in food consumption, atrophy of the testes, epididymides and seminal vesicles, decreases in the absolute and relative testis and epididymis weights, atrophy of seminiferous tubules in the testes, on sperm examination: no motile sperm werenoted, the number of abnormal sperm tended to increase, and the number of sperm in the epididymis cauda were decreased
Females (200 mg/kg bw): Supression of body weight gain during the lactation period, lower food consumption was evident during the pre-mating, pregnancy and lactation periods, decrease in the number of corpora lutea, decrease in number of implantation scars and number of pups born, 1 dam was unable to deliver pups, and 1 dam lost all their pups during the lactation period
Females (800 mg/kg bw): Supression of body weight gain was noted during the pregnancy and lactation periods, lower food consumption was noted during the pre-mating, pregnancy and lactation periods; decrease in the number of corpora lutea, decrease in number of implantation scars and number of pups born, 1 dam was unable to deliver pups, and 1 dam lost all their pups during the lactation period
Offspring:
Pups (200 mg/kg bw): Pup numbers on day 0 and 4 of lactation were decreased
Pups (800 mg/kg bw): the number of pups on day 0 and 4 of lactation, live birth index, and body weights of both sexes on day 4 of lactation were decreased, and the number of stillbirths was increased
Table body weights parental animals
Male (number) | 12 | 12 | 12 | 12 | 12 |
Dose level (mg/kg/day) | 0 | 12.5 | 50 | 200 | 800 |
Body weight (g) | 535.8 ± 41.7 | 536.5 ± 33.5 | 544.3 ± 31.4 | 539.7 ± 35.7 | 514 ± 34.4 |
Female (number) | 12 | 12 | 12 | 12 | 12 |
Body weight (g) | 310.4 ± 12.3 | 312.2 ± 18.9 | 310.7 ± 17.2 | 287.4 ± 13.3** | 281.9 ± 22.9** |
Significantly different from control (**:p<0.01)
Testis and epididymis weights in male
Male (number) | 12 | 12 | 12 | 12 | 12 |
Dose level (mg/kg/day) | 0 | 12.5 | 50 | 200 | 800 |
Testis absolute wt. (g, Mean ± SD) | 3.550 ± 0.333 | 3.598 ± 0.320 | 3.558 ± 0.302 | 2.983 ± 0.767* | 1.736 ± 0.263** |
Testis relative wt. (g%, Mean ± SD) | 0.666 ± 0.082 | 0.674± 0.072 | 0.655 ± 0.046 | 0.557 ± 0.157* | 0.338 ± 0.050** |
Epididymis absolute wt. (g, Mean ± SD) | 1.255 ± 0.143 | 1.343 ± 0.118 | 1.196 ± 0.113 | 1.108 ± 0.125* | 0.924 ± 0.100** |
Epididymis relative wt. (g%, Mean ± SD) | 0.235 ± 0.034 | 0.250± 0.024 | 0.220 ± 0.018 | 0.205 ± 0.027* | 0.180 ± 0.020** |
(* p<0.05, **p<0.01)
Histopathological changes in testis and epididymis male
Dose level (mg/kg/day) | 0 | 12.5 | 50 | 200 | 800 |
Testis | |||||
Atrophy, seminiferous tuble | 0/12 | 0/12 | 0/12 | 6/12** | 12/12** |
Degeneration, seminiferous tuble | 0/12 | 0/12 | 0/12 | 1/12 | 0/12 |
Decrease, sperm | 0/12 | 0/12 | 0/12 | 1/12 | 0/12 |
Giant cell formation | 0/12 | 0/12 | 2/12 | 2/12 | 0/12 |
Epididymis | |||||
Decrease, sperm | 0/12 | 0/12 | 0/12 | 9/12** | 12/12** |
( * p<0.05, ** p<0.01)
Sperm abnormality in male
Dose level (mg/kg/day) | 0 | 12.5 | 50 | 200 | 800 |
Sperm motion parameters | |||||
After 30 min. incubation | |||||
Motility ratio (%) | 71.96 ±9.69 | 74.92 ± 7.81 | 60.42± 10.26** | 14.50 ± 21.75** | 0.00 ± 0.00** |
Curvilinear velocity (um/s) | 348.95 ±20.87 | 369.08 ± 16.17* | 364.94± 18.14 | 301.08 ± 104.59 | - |
Bear cross frequency (Hz) | 30.64 ±1.77 | 30.16 ± 1.59 | 32.91± 1.70** | 29.98 ± 10.51* | - |
Morphology of sperm | |||||
Abnormal ratio (%) | 1.55 ±3.63 | 0.55 ± 0.55 | 8.11± 6.33** | 56.33 ± 29.03** | - |
Viabity (%) | 98.57 ±2.04 | 99.56 ± 0.47 | 89.19± 11.47** | 71.68 ± 9.31** | - |
Survivability (%) | 83.29 ±6.87 | 86.44 ± 3.27 | 66.03± 17.79** | 39.03 ± 15.16** | - |
Number of sperms (left epididymis cauda x106) | 207.41 ±60.16 | 222.42 ± 49.26 | 128.00± 39.88** | 60.73 ± 29.17* | - |
Number of sperms/g (left epididymis cauda x106) | 707.41±153.02 | 704.85 ± 154.64 | 503.29± 159.44** | 238.88 ± 102.42** | - |
(*p <0.05, **p<0.01)
Table: Organ weights of female rats
Dose level (mg/kg/day) | 0 | 12.5 | 50 | 200 | 800 |
Number of dams | 12 | 12 | 12 | 12 | 12 |
Ovaries (mg) | 94.50 ± 12.06 | 91.43 ± 10.00 | 89.88 ± 8.77 | 89.69 ± 16.74 | 88.78 ± 14.65 |
Ovaries (mg%) | 30.51 ± 4.20 | 29.36 ± 3.40 | 28.90 ± 1.90 | 31.23 ± 5.75 | 31.44 ± 3.93 |
Number of estrous cases and reproductive performance
Dose (mg/kg) | 0 | 12.5 | 50 | 200 | 800 |
Number of females | 12 | 12 | 12 | 12 | 12 |
Number of estrous cases before mating (14 days) | 3.3 ± 0.5 | 3.5 ± 0.5 | 3.5 ± 0.5 | 3.7 ± 0.5 | 3.2 ± 0.6 |
Fertility index (%) | 100.0 | 100.0 | 100.0 | 91.7 | 100.0 |
number of pregnant females with live pups | 12 | 12 | 12 | 11 | 10 |
Fertility/Developmental toxicity
Dose level (mg/kg day) | 0 | 12.5 | 50 | 200 | 800 |
No. of pairs mated |
12 | 12 | 12 | 12 | 12 |
No. of pregnant females | 12 | 12 | 12 | 12 | 12 |
Corpora lutea | 16.4 ± 3.0 | 16.4 ± 2.6 | 16.3 ± 1.5 | 15.1 ± 1.4 | 14.1 ± 1.6* |
Implantation scars | 14.3 ± 3.0 | 14.7 ± 1.1 | 15.2 ± 1.3 | 13.5 ± 1.4 | 13.1 ± 1.5* |
Pups born | 13.5 ± 3.3 | 13.5 ± 1.0 | 14.8 ± 1.3 | 11.7 ± 1.4** | 12.2 ± 1.8* |
Delivery Index (%) | 93.5 ± 8.9 | 92.2 ± 5.2 | 97.3 ± 3.3 | 87.2 ± 10.5* | 92.8 ± 5.7 |
Live pups | 13.1 ± 3.2 | 13.3 ± 0.8 | 14.3 ±1.4 | 11.4± 1.0** | 12.4 ± 1.8 |
Dead pups on day 0 of lactation | 0.4 ± 0.7 | 0.2 ± 0.4 | 0.4 ± 0.5 | 0.2 ± 0.6 | 0.9 ± 2.7 |
Live birth index (%) | 97.1 ± 4.6 | 98.9 ± 2.5 | 97.2 ± 3.5 | 98.8 ± 3.9 | 89.9 ± 3.0 |
Live pups on day 4 of lactation | 13.1 ± 3.2 | 13.3 ± 0.8 | 14.3 ±1.4 | 11.4 ± 1.0** | 12.4 ± 1.8 |
Body weight of live pups (g) on day 0 Males | 6.78 ± 0.40 | 6.81 ± 0.23 | 6.90 ± 0.50 | 7.60 ± 0.52** | 6.97 ± 0.71 |
Body weight of live pups (g) on day 0 Females | 6.43 ± 0.37 | 6.40 ± 0.17 | 6.53 ± 0.44 | 7.25 ± 0.49** | 6.61 ± 0.66 |
Body weight of live pups (g) on day 4 Males | 11.02± 0.83 | 11.05 ± 0.77 | 10.58 ± 1.11 | 11.29 ± 1.14 | 9.68 ± 1.72* |
Body weight of live pups (g) on day 4 Females | 10.33 ± 0.81 | 10.36 ± 0.67 | 10.20 ± 1.15 | 10.77 ± 1.04 | 9.30 ± 1.64 |
* p<0.05, ** p<0.01)
Applicant's summary and conclusion
- Executive summary:
In a reproduction/developmental toxicity screening test (OECD Guideline 421) with rats toxic effects of the test substance Vulcanox BKF were seen. Male and females Crj:CD rates were treated with 0, 12.5, 50, 200 and 800 mg/kg bw/day test substance. In males food consumption was decreased transiently in the 800 mg/kg bw/day group. An atrophy of the testes and epididymides was noted at 200 mg/kg bw/ day and higher. In addition, atrophy of the seminal vesicles was found at 800 mg/kg bw/day. Moreover a decrease in the absolute and relative testis and epididymis weights were noted at 200 and 800 mg/kg bw/ day. A decrease in the sperm motility ratio, sperm viability ratio, sperm survivability ratio, and number of sperm in the epididymis cauda was indicated at concentration of 50 and 200 mg/kg bw/day; in addition, an increase in the abnormal sperm ratio was seen at these concentrations. At the highest dose group (800 mg/kg bw/day), no motile sperm were evident and the number of abnormal sperm tended to increase. Moreover, the total number of sperm was decreased. Histological examinations revelated giant cell formation in the testes at 50 mg/kg bw/day and higher. Atrophy and degeneration of the seminiferous tubules were noted at 200 mg/kg bw/day and at 800 mg/kg bw/day an atrophy of seminiferous tubules was found. In female rats a suppression of the body weight gain was noted in the 200 mg/kg bw/day treatment group during the lactation period. In the highest dose group (800 mg/kg bw/day) a suppression of body weight gain was seen during the pregnancy and lactation periods. Lower food consumption was noted in the 200 and 800 mg/kg bw/day groups during pre-mating, pregnancy, and lactating periods. Decreases in the number of corpora lutea, number of implantation scars, and number of pups born were noted at 200 and 800 mg/kg bw/day. In addition, 1 dam was unable to deliver pups, and 1 dam lost all their pups during the lactation period at 800 mg/kg bw/day. Based on the findings of this study, the NOAEL for reproductive toxicity is assessed to be 50 mg/kg bw/day for females and 12.5 mg/kg bw/day for males. The NOAEL for pup development is considered to be 50 mg/kg bw/day (MHWJ 1999).
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