Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: guideline study under GLP
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- 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
- 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
- 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
- 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
- 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
- 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..
- 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. - 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
- Key result
- Critical effects observed:
- no
- 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.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2002
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD 408 modified
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: US EPA OPPTS 870.3100 modified
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- yes
- Remarks:
- no analysis of uterine contents GD 20
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD 433 EOGRTS
- Version / remarks:
- without extentions
- Principles of method if other than guideline:
- Four week repeated dose exposure to adult rats prior to mating, with gravid females exposed during gestation and weaning (6 weeks).
- 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
- Details on test animals or test system and environmental conditions:
- Wistar Han rats
Administration / exposure
- Route of administration:
- oral: feed
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical verification occurred; doses were not lower than target doses.
- Details on mating procedure:
- Males and females cohabitated and mated (1 week).
- Duration of treatment / exposure:
- P males and females were treated for four weeks prior to mating until scheduled sacrifice. They cohabitated and mated (1 week). After mating, males were sacrificed and toxicity was assessed . Females (P) were placed in separate cages and allowed to deliver, nurse and wean offspring, and then sacrificed. The F1 offspring were placed on test diets for 13 weeks. after which aa recovery groups was test material free for 4 weeks.
- Frequency of treatment:
- daily in feed
- Duration of test:
- 24 weeks (EOG) plus 4 weeks recovery
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, plain diet
- Details on study design:
- At the completion of the in utero phase, F1 rats that had been exposed to test material from conception through gestation and continuously from the time of birth were selected (20 unrelated males and 20 unrelated females per dose group for the main study; and 10 unrelated males and 10 unrelated females for the control and high dose recovery groups) and transferred to the 13-week study.
Examinations
- Maternal examinations:
- Parental animals were evaluated for reproductive endpoints (mating performance, fertility, gestation length and parturition, litter size, numbers of implantations, survival and growth), and F1 animals were evaluated for sexual maturation (balano-preputial separation, vaginal opening, anogenital distance, retained areolae in males, sperm assessments), estrous cyclicity, physical appearance, ophthalmologic effects, neurobehavioral effects, growth, food consumption, survival, hematology, blood chemistry, urinalysis, peroxisome proliferation, organ weights, gross pathology and histopathology. A full range of tissues were retained for theP males and females and reproductive organ tissues were retained for F1 males and females. Microscopic examinations were performed on a standard set of tissues for P males and females, as well as tissues found to be abnormal at necropsy.
- Ovaries and uterine content:
- Animals allowed to deliver litters naturally.
- Fetal examinations:
- F1 animals were evaluated for sexual maturation (balano-preputial separation, vaginal opening, anogenital distance, retained areolae in males, sperm assessments), estrous cyclicity, physical appearance, ophthalmologic effects, neurobehavioral effects, growth, food consumption, survival, hematology, blood chemistry, urinalysis, peroxisome proliferation, organ weights, gross pathology and histopathology. A full range of tissues were retained for the Pyes males and females and reproductive organ tissues were retained for F1 males and females.
- 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.
- Historical control data:
- yes
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- 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
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
- Details on results:
- Maternal toxic effects:no effects. There was no effect of treatment upon the F1 generation before they were assigned to the Toxicity phase of this study at approximately four weeks of age.
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
- Description (incidence and severity):
- Oestrous cycles, mating performance and fertility were unaffected by four weeks of exposure to tet material at dietary concentrations targeted to generate an intake of 1000 mg/kg/day.
- Details on maternal toxic effects:
- Maternal toxic effects:no effects. There was no effect of treatment upon the
F1 generation before they were assigned to the Toxicity phase of this study at approximately four
weeks of age.
Details on maternal toxic effects:
Estrous cycles, mating performance, fertility, gestation length and parturition, were all unaffected by treatment. Litter size, survival and growth were similar in all groups and within expected historical control ranges. Although numbers of implantations and litter size at 1000 mg/kg/day were marginally lower than concurrent control group levels, they were within the laboratory’s historical control ranges.
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.
Anogenital distance in both sexes and retention of areolar regions in male offspring were unaffected
by treatment.
There were no macroscopic findings at necropsy of the F0 adults or surplus F1 offspring that were
attributable to treatment.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: no effects
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- not examined
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- not examined
- Visceral malformations:
- not examined
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
Anogenital distance and sexual maturation in both sexes and retention of areolae in male offspring were unaffected by treatment. There were no adverse effects on sperm motility, counts or morphology. There were no findings at necropsy of surplus offspring that were considered to be treatment-related.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- A 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. The parental generation of these rats (P) had been exposed to this substance for 4 weeks prior to mating and 1 week during cohabitation. Doses were 100, 300 and 1000 mg/kg bw/d. There were no adverse effects observed in reproductive indices or in gross and histopathology in the P generation. There were no significant effects on sperm development or oestrus cycles. There were no adverse effects observed in gestation length, parturition, litter size, survival or growth of offspring. Necropsies of surplus offspring showed no adverse effects. The NOAEL for reproduction and for developmental toxicity was 1000 mg/kg bw/d. Data can be read-across between the structural analogues based on common breakdown products. This is adequate to fulfill the information requirements, to be the basis for classification and labelling decisions, and for risk assessment.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.