2-(2-ethoxyethoxy)ethanol

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1997

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication which meets basic scientific principles.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1993

Report date:

1993

Reference 2

Reference Type:

publication

Title:

Unnamed

Year:

1997

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EU Method B.8 (Subacute Inhalation Toxicity: 28-Day Study)

Deviations:

not specified

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-(2-ethoxyethoxy)ethanol

EC Number:

203-919-7

EC Name:

2-(2-ethoxyethoxy)ethanol

Cas Number:

111-90-0

Molecular formula:

C6H14O3

IUPAC Name:

2-(2-ethoxyethoxy)ethan-1-ol

Constituent 2

Reference substance name:

2-(2'-ethoxyethoxy)ethanol

IUPAC Name:

2-(2'-ethoxyethoxy)ethanol

Details on test material:

Test material was 98.6% pure. Impurities included ethylene glycol (1%) and ethyl glycol (0.24%).
Source: Huls AG Germany
Test substance stored under nitrogen at room temperature.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd (Margate, Kent, UK)
- Age at study initiation: 8 weeks
- Housing: Stainless steel cages
- Diet (e.g. ad libitum): ad libitum except during exposure. SDS Rat and Mouse No. 1, Special Diet Services, Witham, Essex
- Water (e.g. ad libitum): ad libitum except during exposure
- Acclimation period: 12 days


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: The measured mean exposure concentrations were 0.09 +/- 0.012, 0.27 +/- 0.031, and 1.1 +/- 0.20 mg/l. Vapour only was present at the low and intermediate concentrations. The high concentration consisted of 50% vapour and 50% respirable droplets (aerosol). The mass median aerodynamic diameter of the aerosol was 3.8 microns with a geometric standard deviation of 1.68. Note that the saturated vapour pressure (theoretical max) is 0.94mg/l.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: ADG Instruments, HItchin, Hertfordshire, England. Approx 50 liters
- Method of holding animals in test chamber: The rats were placed into polycarbonate restraining tubes for exposure and were attached to the chamber such that only the snout protruded into the chamber.
- Source and rate of air: Filtered air.
- Method of conditioning air: The top section of the exposure chamber incorporated a central vapor/droplet inlet port and a tangential diluent air inlet, which served to ensure homogeneity of the test atmosphere.
- System of generating particulates/aerosols: The test atmospheres were generated by atomizing the liquid test substance with jet atomizers. A supply of filtered air was connected to the atomizer and to the chamber diluent air supply. The test aerosol passed into an elutriation column before entering the exposure chamber. Large, nonrespirable droplets were removed by sedimentation and a proportion of the droplets evaporated. The liquid test substance was metered continuously to the atomizer using a syringe pump.
- Temperature, humidity, pressure in air chamber: no data
- Air flow rate: 30 liters/min
- Air change rate: no data
- Method of particle size determination: see MMAD/GSD
- Treatment of exhaust air: no data


TEST ATMOSPHERE
- Brief description of analytical method used: During each exposure, at least three samples were taken from each chamber (by charcoal absorption tubes) to determine the concentration of test material and one sample was taken from the high dose chamber (by a cascade impactor) to determine the size distribution of the aerosol. The amount of test material collected was determined by GLC following extraction with carbon disulfide.
- Samples taken from breathing zone: yes


VEHICLE (if applicable)n/a
- Justification for use and choice of vehicle:
- Composition of vehicle:
- Type and concentration of dispersant aid (if powder):
- Concentration of test material in vehicle:
- Lot/batch no. of vehicle (if required):
- Purity of vehicle:

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

As above

Duration of treatment / exposure:

28 days

Frequency of treatment:

6 hr/day, 5 days/wk

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.085 mg/L air (analytical)

Remarks:

0.1mg/L air nominal

Doses / concentrations 2

Dose / conc.:

0.27 mg/L air (analytical)

Remarks:

0.3mg/L air nominal

Doses / concentrations 3

Dose / conc.:

1.1 mg/L air (analytical)

Remarks:

1.0 mg/L air (nominal)

No. of animals per sex per dose:

5

Control animals:

yes, sham-exposed

Details on study design:

Exposure levels selected following review of the results of a 5-day preliminary study in which no treatment-related effects were seen at exposure levels up to 2.2 mg/liter.

Examinations

Observations and examinations performed and frequency:

Rats were weighed prior to the start of exposure and weekly during exposure.
Clinical signs were recorded daily and during exposure.
Food and water consumption were measured weekly and daily, respectively.
Samples of blood were taken from the orbital sinus under light anaesthesia during the final week of exposure. Blood samples were examined for packed cell volume, hemoglobin, red cell count, white cell count (total and differential), platelet count, thrombotest, creatinine phosphokinase, total protein, albumin, globulin, glucose, urea nitrogen, bilirubin, creatinine, cholesterol, sodium, potassium, calcium, phosphate, chloride, glutamic-pyruvic transaminase, glutamic oxaloacetic transaminase, and gamma glutamyl transferase.

Sacrifice and pathology:

All animals were killed at the end of the 4-week exposure.
The adrenals, kidneys, liver, lungs and testes were weighed and fixed.
All gross abnormalities, heart, larynx, head, pharynx, spleen and trachea were also fixed. Nasal passages were decalcified with formic acid.
All fixed tissues were examined microscopically for the control and high dose group, and the larynx (males only) and turbinates from rats in the other groups were also examined.

Statistics:

If data consisted predominantly of one particular value, Fisher's exact and Mantel's test were used to assess difference from mode. Barlett's test for heterogeneity of variance between treaments, with or without logarithmic transformation. If not significant, one way ANOVA. If significant heterogeneity of variance was present and could not be removed, Kruskal-Wallis analysis of rank used followed by Shirley's test. Student's t test and Williams test used for dose related response analysis although only latter reported. Where appropriate analysis of covariance was used in place of ANOVA.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

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:

not specified

Water consumption and compound intake (if drinking water study):

effects observed, non-treatment-related

Description (incidence and severity):

A slight increase in water consumption in females exposed to 1.1 mg/l was not considered to be biologically significant.

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

- High dose group: Slight increase in eosinophilic inclusions in the olfactory epithelium. Focal necrosis of the ventral cartilage in 3/5 male rats
- Mid dose group: Focal necrosis in the ventral cartilage in 2/5 male rats. No effects in female rats
-Low dose group: no effects

Mild local irritation of the larynx and nasal turbinates was found in rats exposed to 0.27 or 1.1 mg/l (numbers affected were not listed). Foci of necrosis in the small ventral cartilage of the larynx were noted in males exposed to these concentrations (2/5 and 3/5, respectively). There was no evidence of damage to the overlying spuamous epithelium. There was a slight increase in eosinophilic inclusions in the olfactory epithelium of the nasal mucosa of rats exposed to 1.1 mg/l (9/10 treated vs. 5/10 control, all graded "trace" or "minimal"). These inclusions were predominantly located on the dorsal and ventral scrolls of ethmoturbinate 3, but were also found on numbers 2 and 5.

Histopathological findings: neoplastic:

not specified

Details on results:

The only changes attributable to treatment were observed in the respiratory tract.

Effect levels

1

Dose descriptor:

NOAEC

Remarks:

systemic effects

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

2

Dose descriptor:

NOAEC

Remarks:

local effects

Effect level:

0.09 mg/L air

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Local irritation of the respiratory tract

3

Dose descriptor:

NOAEC

Remarks:

local effects

Effect level:

0.27 mg/L air

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Local irritation of the respiratory tract by aerosol

Target system / organ toxicity

Critical effects observed:

yes

Lowest effective dose / conc.:

0.27 mg/L air

System:

respiratory system: upper respiratory tract

Organ:

nasal cavity

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Any other information on results incl. tables

Incidence of eosinophilic cytoplasmic inclusions in nasal turbinates

 

MALES (out of 5 animals)

 

Severity	Control	Low dose	Mid dose	High dose
Trace	2	2	2	3
Slight	0	0	0	1

 

FEMALES (out of 5 animals)

 

Severity	Control	Low dose	Mid dose	High dose
Trace	3	3	1	2
Slight	0	0	0	3

Applicant's summary and conclusion

Conclusions:

Well conducted study according to GLP and EU guidelines. The highest dose did not induce systemic toxicity but 0.27 and 1.1 induced local irritation.

Executive summary:

In a 28 -day study conducted according to guideline, male and female rats were exposed to 0.09, 0.27 or 1.1mg/l of 2 -(2'-ethoxyethoxy)ethanol in an inhalation chamber for 6 hours per day, 5 days per week. There were no changes indicative of a systemic effect at any of the doses tested. Changes indicative of mild local respiratory tract irritation were seen in rats exposed at 0.27mg/liter or 1.1mg/liter, and a slight increase in eosinophilic inclusions in the olfactory epithelium of the nasal mucosa at 1.1mg/liter. No effects indicative of mild local irritation were observed at 0.09mg/liter. In conclusion, the NOAEL for systemic effects can be established at 1.1mg/liter and for local effects at 0.09mg/liter.