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EC number: 402-860-6 | CAS number: 110553-27-0 CG 25-1320; IRGANOX 1520; TK 12229/1
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1987 - 1988
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 988
- Report date:
- 1988
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- (May 12, 1981)
- Deviations:
- no
- Remarks:
- No treatment during gestation days 16-18, as this was not required in the OECD testing guideline 414 version valid at that time. Amount of vehicle higher than recommended (0.5ml instead of 0.4 ml/100g bw/day).
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 4,6-bis(octylthiomethyl)-o-cresol
- EC Number:
- 402-860-6
- EC Name:
- 4,6-bis(octylthiomethyl)-o-cresol
- Cas Number:
- 110553-27-0
- Molecular formula:
- C25 H44 O S2
- IUPAC Name:
- 2-methyl-4,6-bis[(octylsulfanyl)methyl]phenol
- Details on test material:
- - Storage: room temperature
- Physical state: liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Wiga GmbH, 8741 Sulzfeld, West Germany
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 180 to 245 g
- Housing: Prior to mating and during mating, the female rats were housed in groups of twenty to twenty-five in communal cages.Mated female rats were individually housed in solid floor macrolone cages of type II with stainless steel lids (dimensions: 260 mm x 200 mm x 140 mm; E. Becker & Co GmbH, 4620 Castrop-Rauxel, West Germany).
- Diet: ad libitium
- Water: ad libitium
- Acclimation period: one week
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 °C
- Humidity (%): 40 to 70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 19.03.1987 To: 23.04.1987 (date of last necropsy)
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- arachis oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Solubility of the test item
- Concentration in vehicle: 0, 10, 30 and 60 mg/ml
- Amount of vehicle (if gavage): 5ml/kg bw/day - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples for analysis were taken from dose formulations prepared for each dose level on 27.03.1987 (beginning of treatment), deep-frozen immediately after formulation, and sent to the study sponsor for analysis in dry ice, inadvertently not before 15.07.1987. Based on the analytical data, it was concluded that the test article was sufficiently stable during the application period.
- Details on mating procedure:
- The male and female animals were mated at a ratio of 1 : 4 in communal cages during the night.
The females were examined on the following morning for the presence of sperm and/or a vaginal plug.
The day on which sperm and/or a vaginal plug were observed was designated day 0 of gestation. - Duration of treatment / exposure:
- Day 6 to 15 post-coitum (inclusive)
- Frequency of treatment:
- daily
- Duration of test:
- Day 6- 15 with treatment, maintained without treatment until day 20 post-coitum and were sacrificed and examined on that day.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 150 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Dose selection rationale: Based on the results of a screening study (Report no. 614-380/42,dated March 1986)
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations :signs of ill-health, toxicity, behavioural change, mortality
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: see above
BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of each inseminated female rat was recorded on days 0, 6 to 15, and 20 post-coitum and evaluated for days 0, 6, 10, 15, and 20 postcoitum.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
The food consumption of each inseminated female rat was recorded for days 0 to 6, 6 to 10, 10 to 15, and 15 to 20 post-coitum.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: any abnormalities were recorded. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Individual foetal weights and sex of the foetuses
Intra-uterine deaths were classified as follows:
Early resorptions showed decidual or placental tissues only.
Late resorptions showed embryonic or foetal tissue in addition to placental tissue but excluded foetuses dying in utero within approximately two days
prior to the terminal kill. Dead foetuses included only the foetuses dying in utero within approximately the last two days. - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: see below
Half of the foetuses from each litter (taking every second foetus in accordance with the position in the uterine horn, if possible) were eviscerated
and preserved in 95 per cent ethanol for determination of skeletal abnormalities (Alizarin staining technique).
The remaining half was fixed in Bouin's fixative for determination of vis ceral abnormalities (Wilson technique).
The uteri of apparently non-pregnant females were immersed in a 10 per cent solution of ammonium sulphide to reveal evidence of implantation (Salewski technique).
Structural deviations were classified as:
Malformations: rare and/or probably lethal e.g. hydrocephaly.
Variations: changes which regularly occur also in control groups and which are not of functional significance. - Statistics:
- For body weight, body weight gain, food consumption, and mean foetal weight (overall, males, females) the analysis of variance was performed with one factor TREATMENT followed by the Newman-Keuls test for multiple group comparison. Number of corpora lutea, number of implantation, number of foetuses, preimplantation loss, post-implantation loss, and proportion of male foetuses were statistically analysed using the Kruskal-Wallis-test.
In case of suspected significance (probability > chi square < 0.05), the four groups were compared two by two using the Wilcoxon two-sample test (normal approximation - with continuity correction of 0.5).
All significances found (at least p < 0.05) are indicated in the respective tables.
The statistical evaluation was performed with the standard software package SAS release 6.02. - Indices:
- pregnancy indices
pre-implantation loss
post-implantation loss
sex ratio - Historical control data:
- Historical control data is included in the report.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no behavioural changes and no clinical observations in any animal of all groups.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- In group 4 (300 mg/kg) body weight gain during gestation, particularly during late gestation, was reduced (16 % less than the control group from day 10 to 15 post-coitum, and 8 % less from day 15 to 20 post-coitum). The difference in comparison with the control group was not statistically significant. This reduced body weight gain is considered to be related to treatment with the test item. Body weight gain of groups 2 (50 mg/kg) and 3 (150 mg/kg) was comparable with the concurrent control group.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Mean daily food consumption was slightly lower in group 4 (300 mg/kg) than in the control group, particularly during treatment. In groups 2 (50 mg/kg) and 3 (150 mg/kg) mean daily food consumption was
comparable with the control group. - Description (incidence and severity):
- At necropsy unilateral dilatation of the renal pelvis was found in one female of group 3 (150 mg/kg) and two females of group 4 (300 mg/kg). The nature of these findings is considered not to be treatment-related.
Maternal developmental toxicity
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- Pre-implantation loss was high in the control group and in group 4 (300 mg/kg). As pre-implantation loss of group 4 (300 mg/kg) was only slightly higher than in the control group (which remains in the upper range obtained from historical background data, this finding is considered to be incidental. In groups 2 (50 mg/kg) and 3 (150 mg/kg) there was no effect on pre-implantation loss. There was no effect of treatment on post-implantation loss, post-implantation loss was lowest in group 4 (300 mg/kg).
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- There was no effect of treatment on pregnancy incidence
Effect levels (maternal animals)
- Dose descriptor:
- NOEL
- Effect level:
- 150 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
Results (fetuses)
- Fetal body weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Mean foetal weight was slightly increased in group 4 (300 mg/kg). Differences to the control group were statistically significant. This finding must be considered in relation to the reduced mean number of foetuses per female in the highest dose group and not in relation to treatment. Mean foetal weights of groups 2 (50 mg/kg) and 3 (150 mg/kg) were comparable with the control group.
- Reduction in number of live offspring:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The mean number of foetuses per dam was slightly lower in group 4 (300 mg/kg). This finding is considered to be related with the slightly reduced mean number of implantations per female and not considered to treatment-related. The mean number of foetuses per dam in groups 2 (50 mg/kg) and 3 (150 mg/kg) was comparable with the control group.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Sex distribution of foetuses did not reveal any compound-related effect.
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- An external malformation as micrognathia was found in one foetus of group 2 (50 mg/kg). A further foetus in a second litter of the same dose group showed bilateral anophthalmia. In group 3 (150 mg/kg), one foetus with apodia was observed. In group 4 (300 mg/kg) as well as in the control group no malformations were found.
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- Skeletal malformations were not detected. The incidence of skeletal variations did not reveal any treatment-related effects.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no efffects
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Table 1: Uterine and Implantation data
Control | 50 mg/kg | 150 mg/kg | 300 mg/kg | ||
n=24 | n=21 | n=20 | n=20 | ||
Corpora Lutea | total | 396 | 354 | 323 | 278 |
mean | 16.5 | 16.9 | 16.1 | 13.9 | |
Implantations | total | 296 | 289 | 267 | 202 |
mean | 12.3 | 13.8 | 13.4 | 10.1 | |
% Pre-Implantation loss | 24.0 | 16.5 | 14.6 | 28.8 | |
Live Foetuses | total | 277 | 273 | 250 | 193 |
mean | 11.5 | 13.0 | 12.5 | 9.7 | |
% of implantations | 93.3 | 94.8 | 93.5 | 96.5 | |
Early resorptions | total | 18 | 16 | 16 | 9 |
mean | 0.8 | 0.8 | 0.8 | 0.5 | |
late resorptions | total | 1 | 0 | 0 | 0 |
mean | 0.0 | 0.0 | 0.0 | 0.0 | |
Dead foetuses | total | 0 | 0 | 1 | 0 |
mean | 0.0 | 0.0 | 0.1 | 0.0 | |
Total intrauterine deaths | total | 19 | 16 | 17 | 9 |
mean | 0.8 | 0.8 | 0.9 | 0.5 | |
% Post-Implantation loss | 6.1 | 5.2 | 6.5 | 3.5 |
Table 2: Group Mean Body weight (g)
calculated from animals with live fetuses
Day of gestation | control | 50 mg/kg | 150 mg/kg | 300 mg/kg |
0 | 206.5 | 204.3 | 207.3 | 200.8 |
6 | 241.9 | 239.5 | 243.5 | 234.5 |
10 | 260.6 | 257.9 | 260 | 252.5 |
15 | 290.4 | 288.6 | 289.3 | 277.5 |
20 | 345.2 | 350.2 | 350.5 | 327.8 |
Table 3: Body weight gain (g) for different gestation stages (data for dams with live offspring) | ||||||
days 0-6 | days 6-10 | days 10-15 | days 15-20* | |||
control | 35 | 18.8 | 29.8 | 54.8 | ||
SD | 5.7 | 8.8 | 6.2 | 13.9 | ||
50mg/kg bw | 35.2 | 18.3 | 30.7 | 61.7 | ||
SD | 7.3 | 8.4 | 5.8 | 9.9 | ||
150 mg/kg bw | 36.3 | 16.5 | 29.3 | 61.3 | ||
SD | 8.1 | 7.3 | 5.9 | 9.4 | ||
300 mg/kg bw | 33.8 | 18 | 25 | 50.3 | ||
SD | 7 | 7.3 | 9.3 | 21 | ||
*Last day of treatment was day 15 | ||||||
SD = Standard Deviation |
Table 4: fetal data
control (n=24) |
50 mg/kg (n= 21) |
150 mg/kg (n= 20) |
300 mg/kg (n= 20) |
|
Number of fetuses | 277 | 273 | 250 | 193 |
mean number of fetuses per female | 11.5 | 13 | 12.5 | 9.7 |
mean litter weight (g) | 38.7 | 43.2 | 42.6 | 33.5 |
mean fetal weight (g) overall | 3.33 | 3.33 | 3.39 | 3.51 |
mean fetal weight (g) males | 3.42 | 3.42 | 3.51 | 3.53 |
mean fetal weight (g) females | 3.23 | 3.25 | 3.27 | 3.46 |
number of males | 147 | 126 | 124 | 94 |
number of females | 130 | 147 | 126 | 99 |
sex ratio in % (males : females) | 53.1 : 46.9 | 46.2 : 53.8 | 49.6 : 50.4 | 48.7 : 51.3 |
Table 5: Malformation, variation data
control | 50 mg/kg | 150 mg/kg | 300 mg/kg | |
Number of fetuses examined externally | 277 | 273 | 250 | 193 |
Number of fetuses with external malformations | 0 | 1 | 1 | 0 |
% of fetuses with external malformations | 0 | 0.4 | 0.4 | 0 |
Number of litters with external malformations | 0 | 1 | 1 | 0 |
Number of fetuses examined viscerally | 144 | 141 | 126 | 102 |
Number of fetuses with visceral malformations | 0 | 1 | 0 | 0 |
% of fetuses with visceral malformations | 0 | 0.7 | 0 | 0 |
Number of litters with visceral malformations | 0 | 1 | 0 | 0 |
Number of fetuses examined viscerally | 144 | 141 | 126 | 102 |
Number of fetuses with visceral variations | 1 | 1 | 0 | 0 |
% of fetuses with visceral variations | 0.7 | 0.7 | 0 | 0 |
Number of litters with visceral variations | 1 | 1 | 0 | 0 |
Number of fetuses examined skeletally | 133 | 132 | 124 | 91 |
Number of fetuses with skeletal malformations | 0 | 0 | 0 | 0 |
% of fetuses with skeletal malformations | 0 | 0 | 0 | 0 |
Number of litters with skeletal malformations | 0 | 0 | 0 | 0 |
Number of fetuses examined skeletally | 133 | 132 | 124 | 91 |
Number of fetuses with skeletal variations | 133 | 132 | 123 | 91 |
% of fetuses with skeletal variations | 100 | 100 | 99.2 | 100 |
Number of litters with skeletal variations | 24 | 21 | 20 | 18 |
Total Number of malformed fetuses | 0 | 2 | 1 | 0 |
Total number of litters with malformed fetuses | 0 | 2 | 1 | 0 |
Average % malformed fetuses | 0 | 0.7 | 0.4 | 0 |
Applicant's summary and conclusion
- Conclusions:
- In conclusion, administration of the test substance during organogenesis by oral gavage at a dose level of 300 mg/kg elicited slight maternal toxicity (16% reduction in body weight gain and - possibly - slightly reduced food consumption), but no embryotoxicity, and no teratogenicity. Administration of 50 and 150 mg/kg did not elicit any maternal toxicity, embryotoxicity, or teratogenicity.
- Executive summary:
Groups of 25 sexually mature and mated female rats received the test item by oral gavage at dosages of 50, 150, or 300 mg/kg daily for ten consecutive days from day 6 to 15 post-coitum, inclusive. A further group of 25 rats of the same strain which received the vehicle (arachis oil) over the same period served as the control group. The animals were sacrificed on day 20 post-coitum. After conclusion of the present study with including the evaluation of the data, the results of the study can be summarized as follows:
There were no clinical observations and no necropsy findings which might be considered to be related to treatment. At a dose level of 300 mg/kg, maternal body weight gain during gestation was slightly reduced. This is considered to be a slight maternally toxic effect of the compound. Mean daily food consumption was slightly lower in group 4 (300 mg/kg) than in the control group. This finding might be a slightly toxic effect of treatment. There was no effect of treatment on pregnancy incidence. There was no effect of treatment on implantations. Post-implantation loss was not affected by the test item. The mean number of foetuses per dam was slightly reduced in group 4 (300 mg/kg). This finding is considered to be related with the slightly reduced mean number of implantations per female and not to be a compound-related effect. Sex distribution was not affected by treatment. Mean foetal weight of group 4 (300 mg/kg) was slightly increased. This finding is considered to be related with the slightly reduced mean number of foetuses per female in this group and not to indicate any effect of treatment. Nature and incidence of malformations and variations did not reveal any compound-related effect.
In conclusion, administration of the test article during organogenesis by oral gavage at a dose level of 300 mg/kg elicited slight maternal toxicity (slightly reduced body weight gain and - possibly - slightly reduced food consumption), but no embryotoxicity, and no teratogenicity. Administration of 50 and 150 mg/kg did not elicit any maternal toxicity, embryotoxicity, or teratogenicity.
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