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EC number: 203-933-3 | CAS number: 112-07-2
- 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
- Study period:
- 1988
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with national standard methods
- Remarks:
- A fully peer reviewed GLP study carried out by a reputable organisation to recognised scientific principles. Glycol ether acetates are rapidly hydrolysed in vivo to the parent glycol ethers by plasma esterases and will show the same systemic toxicity as the latter. Data here reported here is from a drinking water study with 2-butoxyethanol. Full details of the justification for the use of an analogue for this end point are included in the document appended to chapter 13 of this dossier.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 993
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Remarks:
- , no significant deviations noted
- Principles of method if other than guideline:
- Toxicology study carried out following a range finder study to determine appropriate doses. Exposure by drinking water with normal end points used for such a repeat dose study, including histopathology, haematology, clinical chemistry, urinalysis and reproductive system parameters.
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 2-butoxyethanol
- EC Number:
- 203-905-0
- EC Name:
- 2-butoxyethanol
- Cas Number:
- 111-76-2
- Molecular formula:
- C6H14O2
- IUPAC Name:
- 2-butoxyethanol
- Details on test material:
- - Supplier: Aldrich Chemicals Co, Milwaukee.
- Lot number: BT00504LP
- Analytical purity: 100.1% by functional group titration, 100.5% by GC against reference compound. Purity taken as >99%
- Impurities (identity and concentrations): <0.1% water, <0.0012meq acid/g of compound
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Taconinc Farms (Germantown, NY)
- Age at study initiation: 6 weeks
- Housing: 5 per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 1-2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature: 60-77F
- Humidity: 20-70% RH respectively
- Photoperiod: fluorescent tube, 12hrs/day.
IN-LIFE DATES: From: 14-16 June 1988 for base studies. 31/8 to 1/9 1988 for clinical pathology studies. Stop exposure studies: 17/8/98
To: 13-14 Sept 1988 for base studies. 6/7 and 21/22 Sept 1988 for clinical pathology studies. Stop exposure studies: 16/8/98
Administration / exposure
- Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on oral exposure:
- No further information to add
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Preliminary studies confirmed stability of stock solutions (10,000ppm) for 3 weeks under stored in the dark at 4C and for 4 days in rodent drinking water bottles.
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- continous
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
0, 750, 1500, 3000, 4500 or 6000 ppm
Basis:
nominal in water
- Remarks:
- Doses / Concentrations:
82, 151, 304, 363, 470 mg/kg
Basis:
other: actual ingested - females
- Remarks:
- Doses / Concentrations:
69, 129, 281, 367, 452 mg/kg
Basis:
other: actual ingested - males
- No. of animals per sex per dose:
- 10 for base studies. 20 for clinical pathology studies
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: 2 week range finder study
- Rationale for selecting satellite groups: used for clinical chemistry 1 and 3 (10 animals per sex and per time point.) - Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- CAGE-SIDE OBERVATIONS: Yes
- All rats were observed twice daily throughout the study.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at the beginning of the study and then weekly until the end of the study.
BODY WEIGHT: Yes
- Time schedule for examinations: recorded at the beginning of the study and then weekly until the end of the study.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Estimates of compound consumption based on water consumption by rats as shown above in doses/concentration section. Measured by cage twice per week.
HAEMATOLOGY: Yes, Series 7000 cell counter and a Series 810 whole blood platelet analyzer (Baker Instruments). Supplemental groups of 10 rats/sex/group/time point were included for haematology and clinical chemistry observations at weeks 1 and 3. Parameters checked: HgB, HCT, RBC count, MCV, MCH, MCHC, platelets, reticulocytes, WBC total and differential count, nucleated erythrocytes, methemoglobin concentrations, bone marrow cellularity.
CLINICAL CHEMISTRY: Yes, measured with a Cobra Fara analyser (Roche Diagnostics). Parameters examined: urea nitrogen, creatinine, total protein, albumin, ALP, ALT, creatine kinase, bile acids.
URINALYSIS: Yes
- Time schedule for collection of urine: last 24 hours prior to sacrifice
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No, but no water during collection period.
- Parameters checked: volume, gravity, pH
OTHER: Evaluations of vaginal cytology and sperm morphology were done for the three highest doses tested. Results concerning these examinations are reported in more detail in the reprotoxicity section. - Sacrifice and pathology:
- GROSS PATHOLOGY: Sacrifice: 70% CO2:30% O2 asphyxiation. Yes, complete autopsies were made on all study rats. Organs examined in control and high dose groups: adrenals, bone (femur) with marrow, brain (3 transverse sections), esophagus, eyes, heart/aorta, intestines, (cecum, duodenum, jejunum, ileum, colon, rectum), kidneys, larynx, liver, lung, lymph node (mesenteric, mandibular), mammary gland, nasal cavity and turbinates, ovaries, pancreas, parathyroids, pituitary, pharynx, preputial or clitoral glands, prostate, salivary gland, seminal vesicles, skin, spinal cord, spleen, stomach (fore and glandular), testes, thigh muscle, thyroid, tongue, trachea, urinary bladder, uterus, vagina, all gross lesions. In low dose group: bone marrow, epididymis, liver, spleen, testis and uterus. Organs weighed: heart, liver, kidney, lung, thymus and testes were examined.
HISTOLOGY: Tissues to be examined fixed, embedded, sectioned and stained (H&E) for microscopic examination. Tissues were examined from all control group and treated rats. Bone marrow cells collecetd from right femur for total nucleated cell counts.
OTHER: A stop-exposure group of 30 male rats was also included. 30 males were dosed at 0, 1500, 3000 and 6000ppm for 60 days. Groups of 10 were sacrificed at this time point and then 30 and 56 days after recovery. - Other examinations:
- none
- Statistics:
- Parametric multiple comparison methods: Organ and body weight
Non-parametric multiple comparison methods: clinical chemistry/haematology data
Jonckheere's test: for trend/dose response.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Some diarrohea noted but no other clinical observations.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weights in the two top dose groups were notably less than controls, particularly in females where the top dose was only 80% of the control animal weights by the end of the study.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- In males and females there were reductions in drinking water consumption in the higher dose groups, this being clearly concentration related in females, from a mean of 18.8 ml/day in the control group to 10.7 ml/day in the 6000 ppm exposure group
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- A markedly macrocytic and mildly hypochromic anaemia was observed at each time point (clearly indicated by reduced RBC count and less clearly by reduced HCT and HgB concentrations) and reticulocyte counts were moderately increased in weeks 1 and 13. For males there was a decrease in erythrocyte counts at all time points in the 3000 ppm and greater groups, while in females the decrease occurred in the 1500 ppm and greater groups. A consistent thrombocytoapenia was observed at all time points in males and females of the 4500 and 6000 ppm groups; it also occurred in females of the 3000 ppm group at week 13.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased BUN and creatinine along with mild decreases in total protein and albumin at weeks 3 and 13. Changes in clinical chemistry were consistent with decreased food intake. ALP increased in high dose group week 1 and two highest dose groups week 13.
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Decreased volume and increased specific gravity, consistent with reduced drinking water intake.
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Absolute thymus weight reduced in two highest dose groups by week 13. All other changes observed considered secondary to body weight changes.
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Treatment related changes observed in the liver, spleen and bone marrow of both sexes. Liver lesions, present in all dose groups, included cytoplasmic alteration of minimal to mild severity (more eosinophilic, hepatocellular degeneration (centrilobular and including shrunken hepatocytes, densely stained nucleii, intensely eosinophilic staining) and pigmentation (Kupffer cell cytoplasm which stained positively for iron), present at all doses, but particularly 3 highest doses. Females were slightly more susceptible. Hyperplasia of the bone marrow also observed (3000ppm and upwards) along with increased hematopoeisis in the spleen and hemosiderin pigmentation (1500ppm upwards). All effects showed a clear dose response.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Decreased in epididymis weight were consistent with reduced body weight changes. All males showed reduced sperm concentration compared to controls. There were no significant changes seen with the females although there was evidence that the females in the two highest dose groups spent more time in diestrus and less in proestrus, metestrus and estrus than control animals.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- < 69 other: mg/kg/bw
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
- other: No other adverse effects observed.
- Dose descriptor:
- NOAEL
- Effect level:
- < 82 other: mg/kg/bw
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- histopathology: non-neoplastic
- other: No other adverse effects observed.
Target system / organ toxicity
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 69 mg/kg bw/day (actual dose received)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- no
Any other information on results incl. tables
No lesions were seen in the stop exposure group, despite the fact that the animals in the 1500ppm dose group accidentally received ethoxyethanol during week 6. As no lesions were seen, none of the organs from this group were processed for examination.
Applicant's summary and conclusion
- Conclusions:
- No NOAEL established due to cystoplasmic alterations seen in liver histopathology of both males and females rats at lowest dose tested. NOAEL for effects associated with haemolysis was 69mg/kg in males and 82mg/kg in females.
- Executive summary:
In a well conducted drinking water study, rats were exposed to 2 -butoxyethanol at concentrations ranging from 750 -6000ppm for a period of 90 days. A NOAEL was not established in the study as the lowest dose tested, equivalent to 69mg/kgbw in males and 82mg/kgbw in females, due to minimal to mild cytoplasmic alterations to hepatocytes being observed at this dose. These were primarily centrilobular hepatocytes and the changes were characterised as shrunken hepatocytes, densely stained nucleii or intense eosinophilic staining and were seen in both sexes. No other adverse changes were observed at this concentration. Benchmark analysis of the results indicated an BMDL10 of 27 and 20mg/kgbw/day for males and females respectively.
Synopsis
NOAEL (91day), rat, male <69mg/kg/day
NOAEL (91day), rat, female <82mg/kg/day
On a molar basis, these results would need to be increased by a factor of 1.36 to covert to equivalent values for butoxyethyl acetate.
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