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EC number: 216-323-7 | CAS number: 1559-35-9
- 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
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Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Specific details on test material used for the study:
- Test material information
Ethylene Glycol 2-Ethylhexyl Ether
Specific details on test material used for the study
Test item: Ethylene Glycol 2-Ethylhexyl Ether.
Test item identity (including alternative names): Eastman EEH
CAS number: 1559-35-9.
Intended use: Substance used in industry.
Appearance: Liquid.
Storage conditions: In a refrigerator (2 to 8C).
Supplier: Sponsor
Batch number: TXEG.
Expiry date: Two years from receipt.
Purity: 100%. - Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- The rat was chosen as the test species because it is accepted as a predictor of toxic change in man and the requirement for a rodent species by regulatory agencies. The Crl:CD(SD) rat (virgin) strain was used because of the historical control data available at this laboratory.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Environmental Control
Rodent facility Limited access - to minimize entry of external biological and chemical agents and to
minimize the transference of such agents between rooms.
Air supply Filtered fresh air which was passed to atmosphere and not recirculated.
Temperature and relative humidity Monitored and maintained within the range of 20-24ºC and 40-70
%. There were no deviations from these ranges.
Lighting Artificial lighting, 12 hours light : 12 hours dark.
Electricity supply Public supply with automatic stand-by generators.
Animal Accommodation
Cages Cages comprised of a polycarbonate body with a stainless steel mesh lid; changed at appropr
iate intervals. Solid (polycarbonate) bottom cages were used during the acclimatization, pre-pairing,
treatment, gestation, littering and lactation periods. Grid bottomed polypropylene cages were used
during pairing. These were suspended above absorbent paper which was changed daily during p
airing.
Cage distribution The cages were distributed on the racking to equalize, as far as possible, enviro
nmental influences amongst the groups.
Bedding Solid bottom cages contained softwood based bark-free fiber bedding, which was changed
at appropriate intervals each week.
Number of animals per cage Pre-pairing: up to five animals of one sex, Pairing: one male and one
female, Males after mating: up to five animals, Gestation: one female, Lactation: one female + litter
Environmental Enrichment
Aspen chew block A soft white untreated wood block; provided to each cage throughout the study
[(except during pairing and lactation (returned on Day 13 of lactation)] and replaced when necessary.
Plastic shelter Provided to each cage throughout the study (except during pairing and lactation) and
replaced at the same time as the cages.
Diet Supply
Diet SDS VRF1 Certified pelleted diet. A sample (100g) of each batch of diet used was retained
within Pharmacy (frozen -10 to -30ºC) until finalization of the report. Samples were discarded after
finalization of the report. The diet contained no added antibiotic or other chemotherapeutic or prop
hylactic agent.
Availability Non-restricted (removed overnight before blood sampling for hematology and blood
chemistry investigations).
Water Supply
Supply Potable water from the public supply via polycarbonate bottles with sipper tubes. Bottles
were changed at appropriate intervals.
Availability Non-restricted. - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- Details on route of administration
Dosing was restricted to the F0 generation. Animals of the F1 generation were not dosed directly.
Route Oral gavage using a suitably graduated syringe and a rubber catheter inserted via the mouth.
Treated at constant doses in mg/kg/day.
Volume dose 5 mL/kg body weight.
Individual dose volume Calculated from the most recently recorded scheduled body weight.
Control (Group 1) Vehicle at the same volume dose as treated groups.
Frequency Once daily at approximately the same time each day.
Formulation A daily record of the usage of formulation was maintained based on weights. This bal
ance was compared with the expected usage
stirred using a magnetic stirrer before and throughout the dosing procedure.
Vehicle
corn oil
Details on oral exposure
Dosing was restricted to the F0 generation. Animals of the F1 generation were not dosed directly.
Route Oral gavage using a suitably graduated syringe and a rubber catheter inserted via the mouth.
Treated at constant doses in mg/kg/day.
Volume dose 5 mL/kg body weight.
Individual dose volume Calculated from the most recently recorded scheduled body weight.
Control (Group 1) Vehicle at the same volume dose as treated groups.
Frequency Once daily at approximately the same time each day.
Formulation A daily record of the usage of formulation was maintained based on weights. This bal
ance was compared with the expected usage
as a check of correct administration. No significant discrepancy was found. Formulations were
stirred using a magnetic stirrer before and throughout the dosing procedure.
Analytical verification of doses or concentrations
yes
Duration of treatment / exposure
Rats were exposed for 2 weeks of pre-mating, two weeks for mating (until signs of mating are observe
d), gestation and through lactation day 14. Females and their litters are sacrified on lactation day 14.
Males are killed on gestation day 35.
Frequency of treatment
Daily. - Details on mating procedure:
- Pairing commenced After a minimum of two weeks of treatment.
Male/female ratio 1:1 from within the same treatment groups.
Duration of pairing Up to two weeks.
Daily checks for evidence of mating Ejected copulation plugs in cage tray and sperm in the vaginal smear.
Day 0 of gestation When positive evidence of mating was detected.
Male/female separation Day when mating evidence was detected.
Pre-coital interval Calculated for each female as the time between first pairing and evidence of mating. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Females treated from 2 weeks pre-mating, 2 weeks of mating, gestation and through lactation day 14.
Males treated from 2 weeks pre-mating, 2 weeks of mating and through week 5 of gestation. - Duration of treatment / exposure:
- n/a
- Frequency of treatment:
- Daily
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Rats were treated for 2 weeks prior to mating, 2 weeks for mating. Females were treated through lactation day 15 while males were sacrificed in week 5 of gestation. An FOB was conducted at the start and end of treatment. At necropsy, tissues were weighed and fixed for histopathology, gross observations were taken, blood was collected for hematology and clinical chemistry.
For the repro screen, rats were mated and the females delivered, and litters were kept to lactation day 14. At necropsy, males and females had reproductive organs kept for histopathology. The pups were given a gross necropsy and litter values were recorded.
Clinical observations Examined at approximately 24 hours after birth (Day 1 of age) and then daily thereafter for evidence of ill health or reaction to treatment; these were on an individual offspring basis or for the litter as a whole, as appropriate.
Litter size Daily records were maintained of mortality and consequent changes in litter size from Days 1-13 of age.
Sex ratio of each litter Recorded on Days 1, 4, 7 and 13 of age.
Individual offspring body weights Days 1, 4, 7 and 13 of age.
Ano-genital distance Day 1 - all F1 offspring.
Nipple/areolae count Day 13 of age - male offspring. - Positive control:
- no
- Parental animals: Observations and examinations:
- Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages were inspected daily for evidence of animal ill-health amongst the occupant(s). Any deviation from normal was recorded at the time in respect of nature and severity, date and time of onset, duration and progress of the observed condition, as appropriate.
During the acclimatization period, observations of the animals and their cages were recorded at least once per day. - Oestrous cyclicity (parental animals):
- Dry and wet smears were taken as follows:
Dry smears For 15 days before pairing using cotton swabs.
Wet smears Using pipette lavage during the following phases:
For 14 days before treatment (all females including spares); animals that failed to exhibit 4-5 day cycles were not allocated to study.
After pairing until mating.
For four days before scheduled termination (nominally Days 11 to 14 of lactation). - Litter observations:
- Clinical observations Examined at approximately 24 hours after birth (Day 1 of age) and then daily thereafter for evidence of ill health or reaction to treatment; these were on an individual offspring basis or for the litter as a whole, as appropriate.
Litter size Daily records were maintained of mortality and consequent changes in litter size from Days 1-13 of age.
Sex ratio of each litter Recorded on Days 1, 4, 7 and 13 of age.
Individual offspring body weights Days 1, 4, 7 and 13 of age.
Ano-genital distance Day 1 - all F1 offspring.
Nipple/areolae count Day 13 of age - male offspring. - Postmortem examinations (parental animals):
- All adult animals were subject to a detailed necropsy. After a review of the history of each animal, a full macroscopic examination of the tissues was performed. All external features and orifices were examined visually. Any abnormality in the appearance or size of any organ and tissue (external and cut surface) was recorded and the required tissue samples preserved in appropriate fixative.
- Postmortem examinations (offspring):
- Premature deaths Where possible, a fresh macroscopic examination (external and internal) with an assessment of stomach for milk content was performed.
F1 offspring on Day 4 of age Blood sampling was undertaken (See Section 3.6.11).
Externally normal offspring were discarded without examination.
Externally abnormal offspring were examined, and retained pending possible future examination.
F1 offspring on Day 13 of age Blood sampling was undertaken (See Section 3.6.11).
All animals were subject to an external macroscopic examination; particular attention was paid to the external genitalia.
Thyroid glands were preserved from one male and one female in each litter. - Statistics:
- Information is not provided as the space needed is 3x more than what is allowed here. There is no reason why there should be a character limit in this section. If you want information, let us provide it.
- Reproductive indices:
- The incidence and percentage females showing the following classifications of estrous cycles before pairing and during treatment are presented:
Regular: All observed cycles of 4 or 5 days
Irregular: At least one cycle of 2, 3 or 6 to 10 days
Acyclic: At least 10 days without estrus
Vaginal smearing prior to termination is presented in terms of numbers of females that show estrus during this period and the cycle stage at termination.
Pre-Coital Interval
Individual intervals were tabulated for females only, for the time elapsing between initial pairing and mating. Percentage of females with pre-coital intervals calculated for durations of 1-4, 5-8, 9-12 and 13-14 days of pairing.
Mating Performance and Fertility
Individual data was tabulated. Group values were calculated for males and females separately for the following:
Percentage mating
Conception rate
Fertility index
Gestation length was calculated as the number of gestation days up to and including the day on which offspring were first observed, with Day 1 = day of mating for calculation purposes. Where parturition had started overnight, this value was adjusted by subtracting half of one day - Offspring viability indices:
- The viability of the offspring was recorded.
- Clinical signs:
- no effects observed
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- There were four decedent animals on study; all of these deaths were considered incidental and were not attributable to treatment. Details were as follows:
Group 1 Male No. 25 (Control) was killed for reasons of animal welfare due to physical injury; this male had two open wound areas on the dorsal body surface and on the scrotum. Scabs/encrustations were also seen on the dorsal body surface. These lesions were considered to be ‘fight wounds’ following observed aggression in the home cage.
Group 2 Male No. 16 (50 mg/kg/day) was killed for reasons of animal welfare reasons due to physical injury; this male had a deep open wound and encrustations on the dorsal body surface. These lesions were considered to be ‘fight wounds’ following observed aggression in the home cage.
Group 4 Female No. 72 and No. 78 (500 mg/kg/day) were killed for reasons of animal welfare due to dosing trauma. Female No. 72 was found on Day 5 of treatment to be underactive with irregular breathing, partially closed eyelids and was seen to be uncoordinated. Macroscopic examination revealed perforation of the esophagus and clear aerated fluid in the thorax; result of a dosing trauma. Female No. 78 was found on Day 23 of gestation to be hunched with piloerection, irregular breathing, pale eyes and skin. Macroscopic examination similarly revealed perforation of the esophagus with pale, viscous fluid in the thorax. In addition thoracic adhesions and thickened pericardium were observed; result of a dosing trauma. - Body weight and weight changes:
- no effects observed
- Food efficiency:
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Hematological evaluation in males treated at 50, 150 or 500 mg/kg/day, revealed mean cell hemoglobin concentration was high when compared with controls attaining statistical significance at all levels; however the increases observed were slight and there was no relationship to treatment. A slight increase was observed in the number of large unstained cells seen in males treated at 150 or 500 mg/kg/day.
In females treated at 500 mg/kg/day mean haematocrit and haemoglobin values were low when compared with controls. - Clinical biochemistry findings:
- effects observed, non-treatment-related
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The microscopic examination performed after 5 weeks of treatment or on Day 14 of lactation revealed no test item-related lesions . The incidence and distribution of all other findings were considered to be unrelated to treatment.
Lesions in the kidneys (cortical tubular degeneration/necrosis, mineralisation) were seen in several females, including in control animals, with no relationship to test item. Microscopic findings seen in the kidneys correlated with pale areas seen at necropsy.
Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and the integrity of the various cell types present within the different stages. No cell or stage abnormalities were noted. - Histopathological findings: neoplastic:
- no effects observed
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEC
- Effect level:
- 500 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food efficiency:
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 500 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed
- Reproductive effects observed:
- no
- Executive summary:
Executive summary
This study was designed toassess the general systemic toxic potential in rats, including a screen for reproductive/developmental effects and assessment of endocrine disruptor relevant endpoints, with administration of Ethylene Glycol 2-Ethylhexyl Ether (hereafter referred to as EEH) by oral gavage administration for at least five weeks.
Three groups of ten male and ten female rats received EEH at doses of 50, 150 or 500 mg/kg/day by oral gavage administration. Males were treated daily for two weeks before pairing, up to necropsy
after a minimum of five consecutive weeks. Females were treated daily for two weeks before pairing, throughout pairing, gestation and until Day 13 of lactation. Females were allowed to litter, rear their
offspring and were killed on Day 14 of lactation. The F1 generation received no direct administration of the test item; any exposure was in utero or via the milk. A similarly constituted Control group received
the vehicle, corn oil, at the same volume dose as the treated groups.
During the study, clinical condition, detailed physical examination and arena observations, sensory reactivity, grip strength, motor activity, body weight, food consumption, hematology (peripheral blood),
blood chemistry, thyroid hormone analysis, estrous cycles, pre-coital interval, mating performance, fertility, gestation length, organ weight and macroscopic pathology and histopathology investigations
were undertaken.
The clinical condition, litter size and survival, sex ratio, body weight, ano-genital distance and macropathology for all offspring were also recorded. Nipple counts were performed on male offspring
on Day 13 of age.
Results
There were no treatment related deaths and noadverse effects of treatment on clinical condition, sensory reactivity, grip strength, motor activity, body weight gain, food intake, haematology, blood chemistry or
organ weight measurements in males and females. In addition, the reproductive endpoints assessed which were unaffected by treatment included estrus cycles, pre-coital interval, gestation length, mating
performance, fertility, litter size, offspring survival or offspring sex ratio. Offspring clinical condition, body weight, body weight gain, ano-genital distance and external
development were also unaffected by treatment. Body weight gain was unaffected by treatment in males and in females before pairing. During gestation, overall weight gain in females treated at 500 mg/kg/day was low, as was food intake during Days 14-19 when compared with controls. During lactation body weight gain and food consumption were unaffected by treatment.
Hematological evaluation in males treated at 50, 150 or 500 mg/kg/day, revealed mean cell hemoglobin concentration was slightly high when compared with controls attaining statistical significance at all levels;
however the increases observed were minor and there was norelationship to treatment. A slight increase was observed in the number of large unstained cells seen in males treated at 150 or 500 mg/kg/day. In females treated at 500 mg/kg/day mean haematocrit and haemoglobin values were low when compared with controls.
Biochemical evaluation revealed no clear effect of treatment in males or females treated with EEH. Group mean adjusted epididymides, testes and prostate weights were slightly high in males treated with
EEH at all dose levels (50, 150 or 500 mg/kg/day) although there was no clear relationship to treatment with EEH; Mean adjusted liver weights were high and spleen weights were low in males treated at 500
mg/kg/day. Group mean spleen weights were slightly high in females treated with EEH at all dose levels (50, 150 or 500 mg/kg/day) although there was no clear relationship to treatment with EEH.
At macroscopic examination pale areaswere seen in the kidneys of several females, including in control animals; this correlated to lesions in the kidneys (cortical tubular degeneration/necrosis, mineralisation)
however there was no relationship to test item. No macroscopic or microscopic changes were detected in the full list of tissues examined. Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and the integrity of the various cell types present within the different stages. No cell or stage abnormalities were noted.
Conclusion
Based on the results of this study it is concluded that the No-observed-adverse-effect-level (NOAEL) of Ethylene Glycol 2-Ethylhexyl Ether (EEH) for systemic toxicity and for reproductive/developmental
effects is 500 mg/kg/day.
Reference
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 500 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
Justification for classification or non-classification
There was no reproductive/developmental toxicity observed in an OECD 422 reproductive/developmental screen. No classification is required.
Additional information
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