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EC number: - | 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:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2002
- Reference Type:
- secondary source
- Title:
- Unnamed
- Year:
- 2 004
- Report date:
- 2004
- Reference Type:
- secondary source
- Title:
- Memorandum: Science Assessment for ATBC and TEC
- Author:
- Boyle K
- Year:
- 2 004
- Bibliographic source:
- Letter, August 24, 2004 from Kathryn Boyle, Inerts Team to Dan Rosenblatt, Chief, Minor Use, Inerts and Emergency Response Branch. U.S. EPA, OPPTS.
- Report date:
- 2004
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Qualifier:
- according to guideline
- Guideline:
- other: EPA OPP 86-5
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Tributyl O-acetylcitrate
- EC Number:
- 201-067-0
- EC Name:
- Tributyl O-acetylcitrate
- Cas Number:
- 77-90-7
- Molecular formula:
- C20H34O8
- IUPAC Name:
- tributyl 2-acetoxypropane-1,2,3-tricarboxylate
- Test material form:
- liquid
- Remarks:
- clear, oily
- Details on test material:
- Acetyltributyl citrate, batch # 0000016315, Expiry date: January 2002
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- Han Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Age of animals at initation of the toxicity phase of the study: 4 weeks
Administration / exposure
- Route of administration:
- oral: feed
- Details on route of administration:
- Dietary
- Details on oral exposure:
- Groups of 20 male and 20 female Han Wistar rats received Citroflex A-4 via the diet at target
dosages of 100, 300 or 1000 mg/kg/day for 13 weeks. A similarly constituted Control group received
untreated diet. A further 10 male and 10 female rats were assigned to the Control and high dosage
groups for a four-week recovery period following the 13-week treatment period. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Group mean achieved dosages over the 13 week treatment period at 100, 300 or 1000 mg/kg/day were
103, 306 and 1013 mg/kg/day for males and 102, 306 and 1024 mg/kg/day for females. - Duration of treatment / exposure:
- 13 wks for repeated dose toxicity. A 4-week recovery period was a design feature, during which high dose animals received no exposure of test material.
- Frequency of treatment:
- daily in feed
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Remarks:
- Actual: 103 mg/kg bw/d in males, 102 mg/kg bw/d in females.
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Remarks:
- Actual: 306 mg/kg bw/d in males, 306 mg/kg bw/d in females,
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- Actual: 1013 mg/kg bw/d in males, 1034 mg/kg bw/d in females
- No. of animals per sex per dose:
- 20. 10 additional male and female rats were assigned to the Control and high dose groups for a 4-week recovery period following the 13 week treatment period.
- Control animals:
- yes, plain diet
Examinations
- Observations and examinations performed and frequency:
- During the Toxicity phase of the study the animals were observed daily for general clinical signs and
a detailed physical examination was performed weekly. Bodyweights and food consumption were
recorded weekly. Sexual maturation was assessed in Weeks 4 and 5 and oestrous cycles were
assessed in Week 9. Functional observational battery tests were performed weekly throughout the
treatment period. Ophthalmoscopy examinations were performed during Week 1 and Week 13.
treatment and during Week 4 of recovery.
On completion of the treatment or recovery period, as appropriate, animals were killed and examined
macroscopically; selected organs were weighed and tissues were processed for microscopic
evaluation. Sperm samples were analysed for motility and morphology. Liver samples were removed
from five males and five females in each group and evaluated for peroxisome proliferation. - Statistics:
- For organ weights and body weight changes, homogeneity of variance was tested using Bartlett’s test followed by Behrens-fisher test or Dunnett’s test as appropriate. Macroscopic pathology and histopathology data were assessed using Fisher’s Exact test. Estrus cycles were analyzed using the Cochran-Armitage trend test. Other statistical tests used as appropriate were: Williams’ test for a dose-related response; Student’s t-test; Shirley’s non-parametric test for a dose-related response; Steel’s test; and Wilcoxon rank sum test. Significance level was p<0.05..
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Yellow staining of the perigenital and perianal areas of high dose females
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Slighlty low body weight gain for males and females of high dose group.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Slightly high haematocrit, haemoglobin concentrations and erythrocyte counts in males receiving 100, 300 or 1000 mg/kg/day, and slightly
high erythrocyte counts in females receiving 300 or 1000 mg/kg/day. Not toxicologically significant. - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Elevations in urea, glucose, sodium potassium, chloride; slightly high albumin and albumin:gobulin ratios; low calcium and phosphorus and total protein concentrations, at various doses in males and females. These biochemical values were within historical control, data ranges, except for the sodium values for males receiving 300 or 1000 mg/kg/day.
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Low urinary pH and high urinary protein concentrations at 13 weeks in males receiving 1000 mg/kg/day. These changes were within historical control data ranges and were not apparent at the end of the Recovery period.
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- After 13 weeks of treatment, high bodyweight-relative liver weights were recorded for males and females that received 1000 mg/kg/day. This resolved on completion of the Recovery period.
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Liver peroxisome proliferation after 13 weeks with a statistically significant increases in mean palmitoyl CoA oxidase activity in mid dose males and in high dose males and females, with a statistically significant increase in the mean supernatant protein concentration. Hepatocyte hypertrophy was recorded in the livers of high dose male and female rats.
- Other effects:
- no effects observed
- Description (incidence and severity):
- No statistically significant effects on sperm motility, sperm counts or morphology.
- Details on results:
- Haematological investigations in Week 13 indicated slightly high haematocrit, haemoglobin
concentrations and erythrocyte counts in males receiving 100, 300 or 1000 mg/kg/day, and slightly
high erythrocyte counts in females receiving 300 or 1000 mg/kg/day. These inter-group differences
are not considered to be toxicologically significant, were within historical control data ranges for
these parameters at this laboratory and were not apparent at the end of the Recovery period.
Biochemical examination of the blood plasma in Week 13 indicated high urea concentrations in males
receiving 300 mg/kg/day and in males and females receiving 1000 mg/kg/day, high glucose
concentrations in females receiving 1000 mg/kg/day, high sodium concentrations in males receiving
100, 300 or 1000 mg/kg/day, high potassium concentrations in males receiving 1000 mg/kg/day, high
chloride concentrations in males and females receiving 300 or 1000 mg/kg/day and low calcium and
phosphorus concentrations in females receiving 1000 mg/kg/day. In addition, slightly high albumin
concentrations, with corresponding increases in the albumin to globulin ratio, were recorded in males
receiving 300 or 1000 mg/kg/day, and slightly low total protein concentrations, also resulting in a
corresponding increase in the albumin to globulin ratio, were recorded for females receiving
1000 mg/kg/day. High urea concentrations were still apparent at the end of the recovery period in
females that had previously received 1000 mg/kg/day whilst all other inter-group differences showed
full recovery. The biochemical values of the blood plasma noted above were within historical control
data ranges, except for the sodium values for males receiving 300 or 1000 mg/kg/day.
Urinalysis investigations revealed low urinary pH and high urinary protein concentrations in Week 13
in males receiving 1000 mg/kg/day. These changes were within historical control data ranges and
were not apparent at the end of the Recovery period.
Liver peroxisome evaluation after 13 weeks of treatment indicated statistically significant increases in
mean palmitoyl CoA oxidase activity in males given 300 mg/kg/day and in males and females given
1000 mg/kg/day. Statistically significant increases in the mean supernatant protein concentrations
were also reported in these same dose groups.
Hepatocyte hypertrophy was recorded in the liver of rats receiving 1000 mg/kg/day. In males this
finding tended to occur in the centrilobular region whilst in females it tended to be more generalised.
Hepatocytic hypertrophy was not evident at the end of the Recovery period.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- A 13-week dietary toxicity study was undertaken in weanling F1-generation Han Wistar male and female rats which had been exposed to the test material during gestation and weaning (for approximately 6 weeks). The parental generation of these rats (F0) had been exposed to this substance for 4 weeks prior to mating and 1 week during cohabitation. A 4 week recovery period was included after the 13 weeks of exposure of adult animals (F1). Doses were 100, 300 and 1000 mg/kg bw/d. No significant clinical signs or gross pathology was observed in males or females. Non-specific toxicity was obsrved in high dose animals characteristic of adaptive changes of liver and kidney. These included weak peroxisome proliferation (not relevant to humans), hepatocyte hypertrophy, and alterations in kidney function as seen in clinical chemistry and urinalysis parameters. The NOEL for these potentially non-adverse findings was 100 mg/kg bw/d for males and 300 mg/kg bw/d for females. The overall NOAEL was 1000 mg/kg bw/d for both sexes.
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