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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-[(2-ethylhexyl)oxy]ethanol
EC Number:
216-323-7
EC Name:
2-[(2-ethylhexyl)oxy]ethanol
Cas Number:
1559-35-9
Molecular formula:
C10H22O2
IUPAC Name:
2-[(2-ethylhexyl)oxy]ethan-1-ol
Specific details on test material used for the study:
Test item: E thylene Glycol 2-Ethylhexyl Ether.
Test item identity (including alternative names): Eastman EEH.EEH.
CAS number: 1559-35-9.
Intended use: Substance used in industry.
Appearance: Liquid.
Storage conditions: In a refrigerator (2 to 8C).
Supplier: Sponsor
Batch number: TXEG.
Expiry date: Two years from receipt.
Purity: 100%.

Test animals

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 appropriate 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 pairing.
Cage distribution The cages were distributed on the racking to equalize, as far as possible, environmental 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 prophylactic 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.

Administration / exposure

Route of administration:
oral: gavage
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 balance 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.
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 balance 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 observed), 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.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
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.
Positive control:
no

Examinations

Observations and examinations performed and frequency:
Serial Observations

Mortality A viability check was performed near the start and end of each working day. Animals were killed for reasons of animal welfare where necessary.
.
Clinical and Behavioral Observations 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, obervations of the animals and their cages were recorded at least once per day.
Signs Associated with Dosing

Detailed observations were performed to establish and confirm a pattern of signs in association with dosing according to the following schedule:
F0 males Week 1 - daily
Week 2 onwards - once each week
F0 females Week 1 - daily
Week 2 - once
Gestation phase - Days 0, 7, 14 and 20
Lactation phase - Days 1, 6 and 12
Detailed observations were recorded at the following times in relation to dose administration:
Pre-dose observation
One to two hours after completion of dosing
As late as possible in the working day

Detailed physical examination and arena observations
Before treatment commenced and during each week of treatment and on Days 0, 7, 14 and 20 after mating and Days 1, 6 and 12 of lactation, detailed physical examination and arena observations were performed on each animal. On each occasion, the examinations were performed at approximately the same time of day (before dosing during the treatment period), by an observer unaware of the experimental group identities. “Blind” recording was not possible for animals during pairing or for females after mating and during lactation, for logistical reasons, therefore observations were made on these occasions without “blinding”.
Sacrifice and pathology:
Collection table in "other" section.
Statistics:
Information is not included as the stats section is 3x larger than what this box allows. If you want us to give you information, don't stop us from entering it! There's no reason to limit the characters in the stats section!

Results and discussion

Results of examinations

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 consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
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:
no effects observed
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
Description (incidence and severity):
Group mean adjusted epididymides, testes and prostate weights were high in males treated with EEH at all dose levels (50, 150 or 500 mg/kg/day); Mean adjusted liver weights were high and spleen weights were low in males treated at 500 mg/kg/day .
Group mean spleen weights were high in females treated with EEH at all dose levels (50, 150 or 500 mg/kg/day).
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Effect levels

Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects found

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

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)byoral gavageadministration 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.