2,2'-(ethylenedioxy)diethanol

Endpoint summary

Description of key information

The NOAEL for repeated oral toxicity was determined to be 1522 mg/kg bw/day in rats.

The NOAEC for repeated inhalation toxicity was determined to be 750.865 mg/m3 in rats

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Specific details on test material used for the study:

- Source: Union Carbide Corporation (Texas City, TX)
- Purity: ≥ 99.74%

Species:

rat

Strain:

Fischer 344

Details on species / strain selection:

A pretest health screen was carried out 2 d after arrival, using 5 males and 5 females from the 14-d study, and 10 males and 10 females from the subchronic study. The screen consisted of clinical examination, examination for fecal parasites, viral screen, necropsy, and histology of multiple organs and tissues. They were housed 2/side of divided stainless steel cages mounted on a stainless steel rack. One to two weeks later, they were housed in similar cages but 1/side and this was maintained throughout the study. They were allowed free access to food and water from an automatic system. Environmental temperature was maintained at 19 - 25 °C and relative humidity at 40 - 70%. A 12-h photoperiod was used.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: The rats were approx. 6 weeks of age at first dose.
- Housing: Animals were housed 2/side of divided stainless steel cages mounted on a stainless steel rack. One to two weeks later, they were housed in similar cages but 1/side and this was maintained throughout the study. A layer of Deotized Animal Cage Board (Shepherd Specialty Papers, Inc., Kalamazoo, MI) was kept under each cage and changed at least three times pew week.
- Diet: Ground Purins Certified Rodent Chow #5002 (Ralston Purins Co., St. Louis, MO) was available ad libitum.
- Water: Water (Municipal Authority of Westmoreland County, Greensburg, PA) was provided by an automatic watering system with demand control valves mounted on each rack. Water was available ad libitum.

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 °C
- Humidity: 40-70%
- Photoperiod: 12/12

Route of administration:

oral: feed

Vehicle:

not specified

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Experimental diets were analysed using a gas chromatographic procedure developed at BRRC. Homogeneity of the test substance at each diet concentration was established prior to the start of the study. Stability of the test substance in diets at the 10000 and 50000 ppm concentrations was determined prior to administration of the diets to the animals for the first four preparations. Thereafter, one sample from each preparation (concentration selected sequentially) was retained frozen and analysed in weeks 8 and 13 with one control sample.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

daily

Dose / conc.:

748 mg/kg bw/day (actual dose received)

Remarks:

low dose males (10000 ppm)

Dose / conc.:

848 mg/kg bw/day (actual dose received)

Remarks:

low dose females (10000 ppm)

Dose / conc.:

1 522 mg/kg bw/day (actual dose received)

Remarks:

mid dose males (20000 ppm)

Dose / conc.:

1 699 mg/kg bw/day (actual dose received)

Remarks:

mid dose females (20000 ppm)

Dose / conc.:

3 849 mg/kg bw/day (actual dose received)

Remarks:

high dose males (50000 ppm)

Dose / conc.:

4 360 mg/kg bw/day (actual dose received)

Remarks:

high dose females (50000 ppm)

No. of animals per sex per dose:

- 262 rats (130 males, 132 females) were used
- 30/sex/group in the control and high dose and 20/sex/group in the low and mid dose groups

Control animals:

yes, plain diet

Details on study design:

Fresh diet was prepared and offered to the animals each week. All diet concentrations were prepared by dilution of the premix and mixing for 15 minutes.
Homogeneity of the test substance at each concentration was established prior to the start of the study. Stability of the test material in the diets at 10000 and 50000 ppm was determined prior to dosing after storage in open glass feed jars. Diet concentrations were verified for all dose levels prior to administration of the diets to the animals for the first 4 preparations.

Observations and examinations performed and frequency:

- Detailed clinical observations were conducted weekly and daily observations were made for overt clinical signs.
- Rats were given ophthalmoscopic observations (indirect ophthalmoscopy) before dosing and at the end of the dietary dosing period.
- Body weights and food consumption were measured at weekly intervals. Body weight gains were calculated at each weighing period for the time since initial (day 0) body weight measurement.
- Blood was collected on day 30, immediately following the end of dietary dosing, and at the end of the recovery period for hematology and serum chemistry (10 animals/sex/group).
- The following blood parameters were measured or calculated: hemoglobin concentration, erythrocyte count, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, total and differential leukocyte count.
- The following elements were measured or calculated in serum: glucose, urea nitrogen, albumin globulin, total protein creatinine, bilirubin (total, conjugated and unconjugated), phosphorus, Ca++, Na+, K+, CI-, aspartate and alanine aminotransferases, alkaline phosphatase, gamma-glutamyl transferase, creatine kinase, lactate and sorbitol dehydrogenases.
- The following urine values were determined: volume, pH, specific gravity, colour, microscopy, blood, protein, ketones, glucose, bilirubin and urobilinogen.

Sacrifice and pathology:

20 rats/sex/group were sacrificed at the end of the dosing period, and 10 rats/sex from the control and high-dose groups were sacrificed after the recovery periods and subjected to necropsy examination for any signs of gross pathology. The following organs were removed and weighed: liver, kidneys, heart, spleen, brain, adrenal glands, testes, and ovaries. A further number of tissues and organs were removed and processed for histological examination.

Other examinations:

- Examination for fecal parasites was conducted using a cellophane tape test and by zinc sulfate flotation from cecal contents obtained at neropsy on 5 animals per sex. Histopathology was performed on 3 sacrificed animals/sex. At least the following tissues were examined: liver, kidneys, trachea, lungs, heart, spleen, salivary glands, submandibular lymph notes, and nasal cavities.
- Each rat was uniquely numbered by ear notch and toe-clipping. Only rats with body weights within +/-20% of the population mean for each sex were used.

Statistics:

Data for continuous, parametric variables were intercompared for the dose and control groups using Levene's test for homogneity of variances, by analysis of variance, and by pooled variance t-tests. Frequency data were compared using Fisher's exact tests where appropriate. All statistical tests, except the frequency comparisons were performed using BMDP Statistical Software. The fiducial limit of 0.05 was used as the critical level of significance for all tests.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight depression compared to controls occurred in males from the high dose group throughout the study and in females during the latter weeks of the study. Body weights for males from the recovery group were similar to controls after the 6-week period but females did not show recovery of body weight. In fact, the largest difference from the control value occurred during the recovery period for the females. Based on the larger magnitude of change in the high dose group than was observed for the other dose groups, the body weight differences were considered related to treatment. A transient decrease from control in cumulative body weight gain was observed for the animals from both sexes in the middle weeks of the study. Due to the unusual pattern of weight differences, the relationship to treatment of these decreases was unclear.

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Haematology measurements, including decreased erythrocytes and haematocrit in males from the high and mid dose groups and decreased haemoglobin and increased MCV in the high dose group only, were altered at the 13-week measurement period. These changes were considered to be of questionable biological significance based on a lack of similar effect in the females, the small magnitude of the changes, and the lack of corresponding effects in other cell indexes.

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

Decrease in urine pH at all dose levels in males and the mid and high dose levels in females and an increase in urine volume in males from the high dose group were considered to be related to TEG treatment.

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):

Observations of small increases in kidney weight (high dose group females) and kidney weight relative to body weight (all groups of males and mid and high dose group females) were considered to be probably treatment related. Based on the lack of any other significant toxic effects, particularly the lack of histologic evidence of renal injury, hyperplasia, or hypertrophy, the altered urine measurements were considered to be most likely related to excretion of the large amounts of test material (or metabolites) during the course of this study.

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Dose descriptor:

NOAEL

Effect level:

20 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

organ weights and organ / body weight ratios

urinalysis

Key result

Dose descriptor:

NOAEL

Effect level:

1 522 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

organ weights and organ / body weight ratios

urinalysis

Dose descriptor:

NOAEL

Effect level:

1 699 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

organ weights and organ / body weight ratios

urinalysis

Key result

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

1 522 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

Please refer to chapter 13 for the read-across justification.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEC

Remarks:

mouse

Effect level:

750.865 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Remarks on result:

other: Result read-across source CAS No. 25322-68-3

Remarks:

Corrected for molecular weight.

Dose descriptor:

NOAEC

Remarks:

rat

Effect level:

750.865 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Remarks on result:

other: Result read-across source CAS No. 25322-68-3

Remarks:

Corrected for molecular weight.

Key result

Critical effects observed:

no

Reference 2

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

The objective of this study was to determine and evaluate the toxic effects in rats which may occur from 9 days of repeated, whole body, inhalation exposure to the test substance as aerosol.

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

2.48 µm

Geometric standard deviation (GSD):

1.6

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

9-day exposure during 2-week period

Frequency of treatment:

6 h/d

Dose / conc.:

500 mg/m³ air (nominal)

Remarks:

Equivalent to a mean analytical concentration of 494 mg/m3

Dose / conc.:

2 000 mg/m³ air (nominal)

Remarks:

Equivalent to a mean analytical concentration of 2011 mg/m3

Dose / conc.:

5 000 mg/m³ air (nominal)

Remarks:

Equivalent to a mean analytical concentration of 4824 mg/m3

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Observations and examinations performed and frequency:

Clinical observations, ophthalmological examinations, body and organ weights, haematalogic and serum clinical chemistry evaluations, urinalysis.

Sacrifice and pathology:

Macroscopic and microscopic evaluations.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Clinical signs of toxicity at 4824 mg/m3 included ataxia, prostration, unkempt fur, labored breathing (males only), ocular discharge, swollen periocular tissue, perinasal and periocular encrustation and blepharospasm in both sexes. At 494 mg/m3 and 2011 mg/m3, there were swollen periocular tissues and perinasal encrustations.

Mortality:

mortality observed, treatment-related

Description (incidence):

Exposure of rats to a respirable aerosol of the test substance at a mean analytical concentration of 4824 mg/m3 for 6 h/d resulted in mortality after 2 - 4 days of exposure.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Statistically significant decreases in body weight and body weight gains were also seen in animals exposed to 4824 mg/m3. At 2011 mg/m3, there were statistically significant decreases in body weights in males from exposure Day 5. Females from the 2011 mg/m3 exposure concentration group and rats of both sexes from the 494 mg/m3 exposure concentration group had body weights and body weight gains that were not significantly different from the controls.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

For exposed rats that survived the exposure regimen, food consumption was statistically increased in an exposure concentration-related fashion for females only at 494 and 2011 mg/m3.

Food efficiency:

not examined

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

effects observed, treatment-related

Description (incidence and severity):

Water consumption was statistically significantly increased in both sexes at 2011 mg/m3 and in females at 494 mg/m3.

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

The only statistically significant haematological effect occurred in females from the 2011 mg/m3 group which included slight increases in erythrocyte count and slight decreases in corpuscular volume.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Notable clinical chemistry findings were increased activities of alanine aminotransferase at 2011 mg/m3 and alkaline phosphatase at 494 and 2011 mg/m3, and slight increases in blood urea nitrogen and inorganic phosphorous in females from the 494 and 2011 mg/m3 exposure concentration groups.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

Urinalysis showed statistically significant increases in urine volume and decreases in osmolality, pH, and N-acetyl-ß-D-glucosaminidase activity at 2011 mg/m3, with a trend for changes in these values at 494 mg/m3.

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 liver and kidney weights were increased in females from the 2011 mg/m3 exposure concentration group and increased relative (as percentage of body weight) weights were measured for both organs at 2011 mg/m3. There was no histological evidence of liver or kidney injury noted in animals from any exposure concentration group.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Hyperinflation of the lungs was observed during necropsy in 5 males and 10 females from the 4824 mg/m3 exposure concentration group. The most notable gross pathological findings from treated rats were unkempt fur, swollen eyelids with periocular and perinasal discharge and crusting, and multifocal or diffuse colour change due to congestion and hemorrhage of various organs and tissues.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

The most prominent microscopic lesion found in the 4824 mg/mg exposure concentration group involved congestion and, occasionally hemorrhage of many organs and tissues. The pituitary, nasal mucosa, brain and lungs were affected in many of the rats of both sexes. Congestion of the kidneys and hemorrhage in the thymus were also relatively common in the females. The only microscopic lesion was minimal to mild alveolar histiocytosis, which was in excess of that for the controls at 2011 mg/m3, but not at 494 mg/m3.

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Dose descriptor:

LOAEC

Effect level:

494 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical biochemistry

clinical signs

food consumption and compound intake

organ weights and organ / body weight ratios

water consumption and compound intake

Critical effects observed:

yes

Lowest effective dose / conc.:

494 mg/m³ air (analytical)

System:

hepatobiliary

Organ:

liver

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

Reference 3

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

The objective of this study was to determine and evaluate the toxic effects in rats which may occur from 9 days of repeated, nose-only, inhalation exposure to the test substance as aerosol.

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Specific details on test material used for the study:

- Source: Union Carbide Corporation, Texas City, TX
- Bacth no.: TS-2051109
- Purity: 99.9%
- Appearance: clear liquid

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, (Portage, MI)
- Weight: The body weight range on the day of first exposure was 257.8 g to 332 g for males and 168.5 to 242 g for females.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Approximately 35 days
- Housing: The animals were individually housed in stainless steel, wire mesh cages (22.5 x 15.5 x 18.0 cm). Cages were changed and sanitized at least once every 2 weeks.
- Diet: Ground Lab Diet (The Richmond Standard, Certified Rodent Diet, PMI Feeds, inc.) was available ad libitum, except during exposures.
- Water: Tap water (ad libitum)
- Acclimation period: Approximately 3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25 °C
- Humidity (%): 40-70%
- Photoperiod: 12/12 (05:00 - 17:00)

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

ca. 1.3 µm

Remarks on MMAD:

The MMAD were 1.2, 1.4 and 1.3 microns for the 100, 500 and 1000 mg/m3 groups, respectively, with daily GSD values ranging from 1.25 to 1.39 for all groups.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

9 days

Frequency of treatment:

6 h/d

Dose / conc.:

100 mg/m³ air (nominal)

Remarks:

Equivalent to a mean gravimetric concentration of 102 mg/m3

Dose / conc.:

500 mg/m³ air (nominal)

Remarks:

Equivalent to a mean gravimetric concentration of 517 mg/m3

Dose / conc.:

1 000 mg/m³ air (nominal)

Remarks:

Equivalent to a mean gravimetric concentration of 1036 mg/m3

No. of animals per sex per dose:

Control: 15 males, 15 females
100 mg/m3: 10 males, 10 females
500 mg/m3: 10 males, 10 females
1000 mg/m3: 15 males, 15 females

Control animals:

yes, concurrent no treatment

Observations and examinations performed and frequency:

Clinical observations, ophthalmic examinations, body and organ weights, food and water consumption, haematologic and serum clinical chemistry evaluations, protein fractions, urinalysis, urine chemistry

Sacrifice and pathology:

necropsy, microscopic evaluations

Clinical signs:

no effects observed

Description (incidence and severity):

No exposure-related clinical signs were observed in the male or female animals.

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No changes in body weights for the males or females or body weight gains for the males in any substance-treated group. A non-statistical significant decrease in the female body weight gains of the 500 and 1000 mg/m3 groups was observed in the intervals days 8 - 9 and 9 - 12.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No changes in food consumption measurements for the males and females in any exposure groups were noted.

Food efficiency:

not examined

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

no effects observed

Description (incidence and severity):

No changes in water consumption measurements for the males and females in any exposure groups were noted.

Ophthalmological findings:

no effects observed

Description (incidence and severity):

There were no ophthalmic lesions found in this study which were attributed to the test substance exposure.

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No exposure-related organ weight changes in the males or females were observed.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No clinical pathology findings were related to exposures.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No gross or microscopic lesions in any of the exposed animals.

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Dose descriptor:

NOAEC

Effect level:

1 036 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

750.865 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated oral toxicity:

In a BRRC study (1990), male and female rats were given orally (feed) doses ranging from 0 - 3849 mg/kg over a study period of 13 weeks. Small increases in kidney weight (high dose group females) and kidney weight relative to body weight (all groups of males and mid and high dose group females) were considered to be probably treatment related. Hematology measurements were altered at the 13-week measurement period. These changes were considered to be of questionable biological significance based on a lack of similar effect in the females, the small magnitude of the changes, and the lack of corresponding effects in other cell indexes. Decrease in urine pH at all dose levels in males and the mid and high dose levels in females and an increase in urine volume in males from the high dose group were considered to be related to TEG treatment. Based on the lack of any other significant toxic effects, particularly the lack of histologic evidence of renal injury, hyperplasia, or hypertrophy, the altered urine measurements were considered to be most likely related to excretion of the large amounts of test material (or metabolites) during the course of this study. NOAELs were found to be 1522 mg/kg for male animals and 1699 mg/kg for female animals.

Repeated dermal toxicity:

Repeated dermal application of 2 mL/rabbit of the test substance for 6 weeks did not result in any toxicity or macro- or microscopic changes (EPA, 1993).

Repeated inhalation toxicity:

In a 9-day inhalation study by Ballantyne (2006), ten Sprague-Dawley rats per sex per dose were exposed whole body to 494, 2011 and 4824 mg/m3 for 6 hours/day to aerosol TEG. Mortalities occurred at 4824 mg/m3 between exposure days 2 and 5. Nonspecific indications of toxicity at 2011 mg/m3 were signs of irritation, decreased body weight and increased food and water consumption; evidence of hepatic dysfunction was indicated by increased serum alkaline phosphatase and alanine aminotransferase activities, but liver histology was normal. Fluid imbalance was suggested by increases in water consumption, blood urea nitrogen, relative kidney weight and urine volume, with decreased urine osmolality, pH and N-acetyl-beta-D-glucosaminidase activity. At 494 mg/m3 there were minimal signs of irritation, increased water consumption and slightly increased alkaline phosphatase; histology of the kidney was normal. Thus, in this 9 day repeated aerosol whole body exposure study a No-Observed-Effect-Level (NOEL) could not be established. Since preening of the fur at these high aerosol concentrations exposures might have led to a confounding factor from the resultant oral intake, another 9 day repeated aerosol study was conducted (Ballantyne 2006), but by nose-only exposure of Sprague-Dawley rats for 6 hours/day to TEG aerosol concentrations of 0, 102, 517 and 1036 mg/m3. In this study there were no clinical signs, no effects on food and water consumption, and no biochemical or histological evidence of hepatorenal dysfunction. By the end of the exposure period, male and female rats of the 1036 mg/m3 group had body weights lower than those of the controls, but not with statistical significance. Since there were no statistically significant effects on any monitors, 1036 mg/m3 is considered to be a threshold for toxicity by nose-only exposure to TEG aerosol. In view of a NOAEC of > 1000 mg/kg/day (limit test) in the 9 days study, no study of longer duration has been initiated.

Read-across with PEG 200

Further evidence is obtained from a 90 days inhalation studies in mice and rats with polyethylene glycol 200 (PEG 200), a mixed material which contains approximately 17% TriEG, 29% TetraEG and 25% PentaEG. All components are expected to behave toxicologically in a very similar manner.

Chemical System Laboratory (CSL; 1981) reported a 13-week inhalation study with Fischer 344 rats. Groups of 72 animals were whole body exposed 6 hours per day, 5 days a week to 0.1 mg/L or 1 mg/L PEG 200 in aerosol form. The control group was treated with air. Groupswere divided into three subgroups: (a) 6-week exposure group of 24 animals, (b) 13-week exposure group of 24 animals, (c) a group of 24 animals to be held for 30 days after the 13-week exposure. The exposed and control animals were observed daily for toxic signs and death. The animals used were weighed individually at approximately 2-week intervals.At necropsy, tissues were examined and pathological and haematological parameters were evaluated. It was concluded thatPEG 200 produced no positive effects in rats at the 100 and 1000 mg/m3 concentrations over the 13 weeks of exposure used in this study.

Chemical System Laboratory (CSL; 1981) reported another 13-week inhalation study but with B6C3F1 mice. Groups of 30 animals were whole body exposed 6 hours per day, 5 days a week to 0.1 mg/L or 1 mg/L PEG 200 in aerosol form. The control group was treated with air. Groupswere divided into three subgroups: (a) 6-week exposure group of 10 animals, (b) 13-week exposure group of 10 animals, (c) a group of 10 animals to be held for 30 days after the 13-week exposure. The exposed and control animals were observed daily for toxic signs and death. The animals used were weighed individually at approximately 2-week intervals.At necropsy, tissues were examined and pathological parameters were evaluated. It was concluded thatPEG 200 also produced no positive effects in mice at the 100 and 1000 mg/m3 concentrations over the 13 weeks of exposure used in this study.

Justification for classification or non-classification

Based on the available information classification for repeated dose toxicity is not warranted in accordance with EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008.