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EC number: 701-339-3 | CAS number: -
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1998-11-11 to 1998-12-10
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Not a guideline study. However, study carried out to GLP, and data appears well documented and scientifically reasonable.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 999
- Report date:
- 1999
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- In male rats, the systemic toxicity (including to the liver and reproductive organs) was assessed following three weeks dietary exposure to the US or EU versions of the phthalate ester, Santicizer(R) 261.
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 1,2-Benzenedicarboxylic acid, benzyl isononyl alkyl esters
- EC Number:
- 701-339-3
- Cas Number:
- 68515-40-2
- Molecular formula:
- C24H30O4
- IUPAC Name:
- 1,2-Benzenedicarboxylic acid, benzyl isononyl alkyl esters
- Details on test material:
- - Name of test material (as cited in study report): Two products tested: US Santicizer(R) 261 Plasticizer and European Santicizer(R) 261 Plasticizer
- Substance type: no data
- Physical state: no data
- Analytical purity: US Santicizer(R) 261 Plasticizer >98% pure; European Santicizer(R) 261 Plasticizer 98.75% pure
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: no data
- Lot/batch No.: US Santicizer(R) 261 Plasticizer Lot No. 83198; and European Santicizer(R) 261 Plasticizer Lot No. 7K3033
- Stability under test conditions: no data
- Storage condition of test material: The high and low diets for both the US and EU Santicizers were stable frozen for at least 36 days
- Other: The two Santicizers may contain different relative concentrations of the same components and/or different components.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl: CD(SD)BR
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Raleigh, NC,
- Age at study initiation: Probably about 80 days
- Weight at study initiation: 334-360 g
- Housing: Rats individually housed in solid-bottom polycarbonate cages with stainless steel wire lids with Sani-Chip(R) cage bedding
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: A "one-week quarantine"
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-23
- Humidity (%): 51.2-62.3
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): Purina certified rodent chow(R)
- Storage temperature of food: "frozen" - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The stored frozen feed was analysed on 5 January 1999 [no further details given in study report]
- Duration of treatment / exposure:
- 21 days
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
75, 750 and 1500 mg/kg bw/day
Basis:
other: target dose levels
- Remarks:
- Doses / Concentrations:
about 60, 600 and 1200 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 6 males/dose
- Control animals:
- yes, plain diet
- other: positive control
- Details on study design:
- - Rationale for animal assignment (if not random): by a randomization procedure, stratified by body weight
- Positive control:
- Di(2-ethylhexyl) phthalate (DEHP), a known testicular and liver toxin, was examined at 1500 mg/kg bw/day only
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: a.m. and p.m.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once daily
The cage-side observations included changes in skin and fur, eyes, mucous membranes, respiratory system, circulatory system, autonomic and central nervous sytem, somatomotor activity, and behaviour pattern.
BODY WEIGHT: Yes
- Time schedule for examinations: 0, 7, 14 and 21 days
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- 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
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
OTHER: Peroxisomal Acyl-CoA oxidase activity, an indication of hepatic peroxisome proliferation, was measured in the livers of the controls and treated rats at sacrifice. - Sacrifice and pathology:
- GROSS PATHOLOGY: Performed, but no details on extent of examination. Organ weights (liver, brain, testis and epididymis) also assessed
HISTOPATHOLOGY: Limited to one testis from each rat in the high-dose group and in the untreated and positive controls - Other examinations:
- Acyl-CoA oxidase activity in the liver assessed
- Statistics:
- Krusal-Wallis one-way analysis of variance by ranks was used to test for differences among dose groups for each test material. Whenever the results of this test were significant (p<0.05), the Mann-Whitney U test was used to make individual comparisons between untreated controls and test material-exposed groups for each test material for that measure (a one-tailed test was used for all parameters except for body weight, organ weight and feed consumption which were examined in a two-tailed test). Jonckheere's test for k independent samples was used to identify significant dose-response trends for each test material. For these data a Chi-square test for independence was used to analyse for differences among treatment groups, and the Cochran-Armitage test for linear trend of proportions was used to determine dose-related linear trends for each test material. When Chi-square revealed significant (p<0.05) differences between groups, then a one- or two-tailed Fisher's exact probability test was used for pair-wise comparisons between each test material-exposed group and the controls.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
All rats survived to scheduled sacrifice. Piloerection was observed in one untreated control animal (on day 7), in 2 males given the EU Santicizer(R) 261 at the top dose on day 1 and in one rat on days 2, 5 and 7, in none of the animals exposed to the US Santicizer(R) 261, and in 2 males exposed to DEHP on day 5 and one rat on day 7. In addition, one rat given the high dose EU Santicizer(R) 261 exhibited a sore shoulder on days 14-21 (relevance to treatment unknown).
BODY WEIGHT AND WEIGHT GAIN
No statistically significant differences in body weight or body weight gain were seen in the rats receiving about 60 mg/kg bw/day (of either the EU or US versions) compared to the untreated controls, whereas both test materials produced a statistically significant and dose-related reduction in body weight gain from 600 mg/kg bw/day, particularly during the first week.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
For those rats exposed to the EU version, food consumption was significantly reduced (compared to the untreated controls) at the top dose during the first 2 weeks (and returned to normal thereafter) and also during the second week at 600 mg/kg bw/day. With the US version the reduction in food consumption was evident only at the top dose during the first week. Food consumption was unaffected at the lowest dose of about 60 mg/kg bw/day (for either version). Due to the initial decrease in food intake (which was likely due to palatability problems) in the two test groups (and also in those animals receiving DEHP), phthalate intake was less during the first exposure week. Overall, the mean intakes for the US Santicizer(R) 261 were 62.5, 601.5 and 1206 mg/kg bw/day and for the EU Santicizer(R) 261 were 63.3, 593.1 and 1259 mg/kg bw/day, at 0.1, 1, and 2% in the diet, respectively. The overall mean intake of DEHP at 2% in the diet was 1093.9 mg/kg bw/day.
ORGAN WEIGHTS
Compared with untreated controls, both test materials produced statistically significant increases in relative liver weight, this being evident from 600 mg/kg bw/day with the EU version and at 1200 mg/kg bw/day with the US version. Neither compound affected absolute weights of the epididymis, testis or brain. The positive control, DEHP, produced an increase in relative liver weight and a decrease in absolute testis weight.
GROSS PATHOLOGY
There were apparently no gross necropsy findings at sacrifice (extent of examination unclear from study report).
HISTOPATHOLOGY: NON-NEOPLASTIC
At 1200 mg/kg bw/day, minimal testicular degeneration was seen in 1/6 and 4/6 rats given the US and EU versions, respectively. All six of the rats given DEHP exhibited testicular lesions, while there were none in the six untreated controls.
OTHER FINDINGS:
There was a statistically significant increase in acyl-CoA oxidase activity (an indication of peroxisome proliferation) in the livers of rats given the US or EU versions of Santicizer(R) 261 at 600 and 1200 mg/kg bw/day, when compared with untreated controls. The same effect was also observed in the positive controls given DEHP.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 60 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- other: see 'Remark'
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- In a 3-week feeding study in which male rats were given two different formulations of Santicizer(R) 261 (one EU and one US) at around 60, 600 and 1200 mg/kg bw/day, effects observed from 600 mg/kg bw/day included reduced body weight gain and increases in liver weight and acyl-CoA oxidase activity (an indication of peroxisome proliferation). The EU version of the test material had a slightly greater effect, but the difference between the two versions was minimal.
- Executive summary:
Groups of six male rats were fed either the US or EU versions of Santicizer(R) 261 at 0 (untreated controls), 1 or 2% in the diet, or DEHP at 2% in the diet (positive control), for 3 weeks. Overall, these dietary concentrations corresponded to actual mean intakes for the US test material of 62.5, 601.5 and 1206 mg/kg bw/day and for the EU version of 63.3, 593.1 and 1259 mg/kg bw/day. The overall mean intake of DEHP at 2% in the diet was 1093.9 mg/kg bw/day.
There were no deaths during the 3-week exposure period. Piloerection (a non-specific indicator of stress) was observed in one untreated control rat, and in "one to two" males in the high-dose EU Santicizer(R) 261 group and the DEHP group. One rat given the high-dose of the EU version exhibited a sore shoulder in the third week of exposure, but the relevance to treatment is not discussed in the study report.
No statistically significant differences in body weight or body weight gain were seen in the rats receiving about 60 mg/kg bw/day (of either the EU or US versions) compared to the untreated controls, whereas both test materials produced a statistically significant and dose-related reduction in body weight gain from 600 mg/kg bw/day (probably related to the significant reduction in food consumption seen at these higher doses).
Compared with untreated controls, both test materials produced statistically significant increases in relative liver weight, this being evident from 600 mg/kg bw/day with the EU version and at 1200 mg/kg bw/day with the US version. Neither compound affected absolute weights of the epididymis, testis or brain. The positive control, DEHP, produced an increase in relative liver weight and a decrease in absolute testis weight.
There were apparently no gross necropsy findings at sacrifice, although the extent of examination is unclear from the study report. At 1200 mg/kg bw/day, minimal testicular degeneration was seen in 1/6 and 4/6 rats given the US and EU versions, respectively. All six of the rats given DEHP exhibited testicular lesions, while there were none in the six untreated controls.
There was a statistically significant increase in acyl-CoA oxidase activity (an indication of peroxisome proliferation) in the livers of rats given the US or EU versions of Santicizer(R) 261 at 600 and 1200 mg/kg bw/day, when compared with untreated controls. The same effect was also observed in the positive controls given DEHP.
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