2-hexyloxyethanol

Endpoint summary

Description of key information

No repeated dose toxicity studies for the oral route are available. For the dermal, a GLP study in rabbits, similar to OECD guideline is available. However, the study duration was only 11 days, during which 9 dermal applications were given. For the inhalation route, a 14-week study in rats is available, conducted under GLP and according to OECD guideline 413.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1985

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study was conducted in accordance with GLP and similar to OECD guideline 413.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Principles of method if other than guideline:

NA

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc. Kinston, NY
- Age at study initiation: Approximately 6 week
- Fasting period before study: None
- Housing: Rats were house 2/cage in stainless steel wire-mesh cages
- Diet (ad libitum): Except during exposure
- Water ( ad libitum): Except during exposure
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): Standard conditions
- Humidity (%): Standard conditions
- Air changes (per hr): Standard conditions
- Photoperiod: (12 hrs dark / 12 hrs light):

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: no data

Details on inhalation exposure:

See the attachment-1

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

See the attachment-1

Duration of treatment / exposure:

14 weeks

Frequency of treatment:

6 hours/day/week

Remarks:

Doses / Concentrations:
20 ppm
Basis:
nominal conc.

Remarks:

Doses / Concentrations:
40 ppm
Basis:
nominal conc.

Remarks:

Doses / Concentrations:
85 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

20/sex/exposure group

Control animals:

yes

Details on study design:

- Rationale for animal assignment: Random
- Post-exposure recovery period in satellite groups: Four week recovery period

Positive control:

None

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed prior to, during, and following each exposure for signs of toxic effects. Animals were observed once a day on weekends and holidays during the fourteen-week exposure regimen. Animals held for the four-week recovery period were observed at least once a day.
DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: prior to exposure and weekly thereafter

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
FOOD EFFICIENCY: No

WATER CONSUMPTION: Yes
- Time schedule for examinations: During exposure week 14 and after 4 weeks of recovery
OPHTHALMOSCOPIC EXAMINATION: Yes

- Time schedule for examinations: Prior to exposure and at sacrifice
- Dose groups that were examined: All dose groups


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to sacrifice during exposure week fourteen and after 4 weeks of recovery
- Anesthetic used for blood collection: Yes (identity) Methoxyflurane
- Animals fasted: Yes
- How many animals: 10/sex/exposure group
- Parameters checked in table [No.7,8, 9, 10] were examined.


CLINICAL CHEMISTRY: - Time schedule for collection of blood: Prior to sacrifice during exposure week fourteen and after 4 weeks of recovery
- Anesthetic used for blood collection: Yes (identity) Methoxyflurane
- Animals fasted: Yes
- How many animals: 10/sex/exposure group
- Parameters checked in table [No.1, 2, 3, 4] were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: During exposure week 14 and after 4 weeks of recovery
- Metabolism cages used for collection of urine: Yes
- Parameters checked in table [No.13, 14] were examined.

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Ten rats per exposure group were sacrificed on October 10 (males) and 10 (females), after receiving 66 and 67 exposures, respectively. The 4-week recovery rats, ten males per exposure group and ten females per exposure group were sacrificed after 27 and 28 post exposure days, respectively. The rats were killed by exsanguination via the brachial blood vessels following anesthesia with methoxyflurane. Gross examinations were performed and selected tissues were fixed in 10% neutral buffered formalin for possible future histologic evaluation

HISTOPATHOLOGY: Yes
Histologic evaluation was performed on selected tissues from animals in the high Concentration and control groups. No histologic evaluations were performed on the low and intermediate hexyl CELLOSOLVER groups at the end of either the exposure regimen or the recovery period.

Other examinations:

Organ weights: The brain, liver, kidneys, spleen, lungs, thymus gland, and testes (males only) from all animals were weighed at sacrifice. Organ weights were recorded as absolute weights and as a percentage of both body weight and brain weight.

Statistics:

Results of quantitative continuous variables (such as body weight changes) were intercompared among the three concentration groups and one control group by use of Bartlett's homogeneity of variance (Sokal and Rohlf, 1969), analysis of variance (ANOVA) (Sokal and Rohlf, 1969), and Duncan's multiple range tests (Snedecor and Cochran, 1967). The latter was used to delineate which exposure groups differed from the control, when F from the analysis of variance was significant. If Bartlett's test indicated heterogeneous variances, all groups were compared by ANOVA for unequal variances (Welch or Brown and Forsythe, 1974) followed if necessary by t-tests. Corrected Bonferroni probabilities were used for t-test comparisons. Statistical procedures for hematologic continuous variables were similar and details of the procedures can be found
in the Clinical Pathology Report (Appendix 2). The fiducial limit of 0.05 (two-tailed) was used as the critical level of significance for all comparisons.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

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

effects observed, treatment-related

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY: The principal sign observed in males that was considered to be exposure related was a urogenital wetness in the 71 ppm group. Urogenital wetness was also observed in female rats, but in a dose-related manner among all hexyl CELLOSOLVE*-exposed groups. On a daily basis, the urogenital wetness was principally observed after the exposure rather than in the morning (before the exposure). The urogenital wetness was primarily observed beginning during week 6 of the study and continued until the termination of exposures. Also, beginning about week 9 and continuing until the termination of exposures, rats of the 71 ppm group were observed lying on their sides during the daily exposures. There were no significant signs observed during the recovery period.
There were no mortalities during the study.


BODY WEIGHT AND WEIGHT GAIN: Consistent statistically significant decreases in body weight gain were observed in the 71 ppm males (weeks 5-12) and females (weeks 5-14), and in the 41 ppm females (weeks 6-12). There were no exposure-related decreases in body weight gain observed in any group during the recovery period. There were no statistically significant differences in absolute body weight for any of the groups at the end of the exposure or recovery period


FOOD AND WATER CONSUMPTION: Statistically significant Increases in food and water consumption were observed in the 71 ppm males at the end of the exposure regimen (day 93). A significant increase in food consumption was observed in the 71 ppm females at the end of both the exposure regimen (day 94) and the recovery period (day 122). Other statistically significant differences were considered to be spurious as they were observed in the 20 ppm group with no effects observed in the 41 ppm group, i.e., no dose-response effect

OPHTHALMOSCOPIC EXAMINATION: There were no exposure-related ocular effects observed during the study.

HAEMATOLOGY: There were no biologically significant alterations were observed in hematology parameters for rats monitored at 14 weeks or following a four week recovery period.


CLINICAL CHEMISTRY: There were no biologically significant alterations were observed in serum chemistry parameters for male rats monitored at 14 weeks or following a four week recovery period.
However, decreases in transaminases (AST and ALT) and sorbitol dehydrogenase (SDH), and Increases in alkaline phosphatase (ALP) were observed at the end of the exposure period for
female rats exposed to 71 ppm hexyl CELLOSOLVER vapor. No similar effects were observed on these enzyme levels at the end of the recovery period for female rats exposed to 71 ppm of hexyl CELLOSOLVER vapor. However, there was a statistically significant increase in gamma-glutamyl -transferase for the 71 ppm females at the end of the recovery period.

URINALYSIS: There were no biologically significant alterations were observed in urinalysis parameters for rats monitored at 14 weeks or following a four week recovery period.

ORGAN WEIGHTS: There were two organs for which possible exposure-related effects were observed. For males, statistically significant increases in absolute and relative kidney weights were observed for the 41 and 71 ppm groups at the end of the exposure regimen. A statistically significant Increase in the kidney/body weight ratio was also observed for the 20 ppm males. Similar effects were not observed for males after the recovery period. Females of the 71 ppm group exhibited slight Increases in absolute and relative kidney weights, with the kidney/body weight value achieving statistical significance. Absolute and relative liver weights were statistically significantly increased for females of the 71 ppm group at the end of the exposure regimen.

The liver/body weight ratio was also significantly increased for the 41 ppm group females. However, there were apparent dose-related Increases in absolute and relative liver weights for all exposed groups of females at the end of the exposure regimen. Absolute and relative liver weights were also significantly increased at the end of the recovery period for the 71 ppm females. For males, statistically significant Increases in relative (both to body and brain weight) liver weights were observed for the 71 ppm group. However, dose-related increases were evident for the liver/brain weight data for hexyl-CELLOSOLVER -exposed males. Liver/body weight ratios were statistically significantly increased for the 41 and 71 ppm males at the end of the recovery period.



GROSS PATHOLOGY: There were no gross lesions found that were attributable to Hexyl CELLOSOLVE* vapor exposure.


HISTOPATHOLOGY: There were no histologic lesions observed that were attributable to Hexyl CELLOSOLVE* vapor exposure.

Dose descriptor:

NOAEL

Effect level:

41 ppm

Sex:

male/female

Basis for effect level:

other: overall effects

Critical effects observed:

not specified

None

Conclusions:

Based on the data from this study, 41 ppm is considered to be the concentration at which no biologically significant toxic effects were observed. Although the toxic effects observed at 71 ppm were generally mild, the spectrum of body weight, clinical chemistry, and organ weight effects, some of which persisted into the recovery period, are considered to be treatment related and thus to be biologically relevant in assessing potential health effects from this material.

Executive summary:

Four groups, each consisting of 20 Fischer 344 rats per sex, were exposed for 6 hours per day, 5 days per week, for 14 weeks to the vapor of ethylene glycol hexyl ether) at target concentrations of 0 (control), 20, 40, or 85 ppm and followed by 4 week recovery period.. Actual mean concentrations obtained for this study were 20, 41, and 71 ppm ethylene glycol hexyl ether.

 

Rats were received from breeding Laboratories. Rats were kept for acclimatization for 5 days. At study initiation rats were of approximately 9 weeks old. Rats were housed 2/cage in stainless steel cages with wire mash bottoms. Rats were provided ad libitum feed and municipal water except during exposure. The animals were kept on a 12-hour photoperiod throughout the study.

 

Monitors for toxic effects included clinical observations, body weight, food and water consumption, ophthalmology, hematology, clinical chemistry, urinalysis, organ weights, and macroscopic and microscopic tissue evaluations.

  

The principal sign observed in males that was considered to be exposure related was a urogenital wetness in the 71 ppm group. Urogenital wetness was also observed in female rats, but in a dose-related manner among ethylene glycol hexyl ether-exposed groups. On a daily basis, the urogenital wetness was principally observed after the exposure rather than in the morning (before the exposure). The urogenital wetness was primarily observed beginning during week 6 of the study and continued until the termination of exposures. Also, beginning about week 9 and continuing until the termination of exposures, rats of the 71 ppm group were observed lying on their sides during the daily exposures. There were no significant signs observed during the recovery period. There were no mortalities during the study.

 

Consistent statistically significant decreases in body weight gain were observed in the 71 ppm males (weeks 5-12) and females (weeks 5-14), and in the 41 ppm females (weeks 6-12). There were no exposure-related decreases in body weight gain observed in any group during the recovery period. There were no statistically significant differences in absolute body weight for any of the groups at the end of the exposure or recovery period.

 

Statistically significant Increases in food and water consumption were observed in the 71 ppm males at the end of the exposure regimen (day 93). A significant increase in food consumption was observed in the 71 ppm females at the end of both the exposure regimen (day 94) and the recovery period (day 122). Other statistically significant differences were considered to be spurious as they were observed in the 20 ppm group with no effects observed in the 41 ppm group, i.e. no dose-response effect.

 

There were no exposure-related ocular effects observed during the study. There were no biologically significant alterations were observed in hematology parameters for rats monitored at 14 weeks or following a four week recovery period. There were no biologically significant alterations were observed in urinalysis parameters for rats monitored at 14 weeks or following a four week recovery period. There were no biologically significant alterations were observed in serum chemistry parameters for male rats monitored at 14 weeks or following a four week recovery period.

However, decreases in transaminases (AST and ALT) and sorbitol dehydrogenase (SDH), and Increases in alkaline phosphatase (ALP) were observed at the end of the exposure period for female rats exposed to 71 ppm ethylene glycol hexyl ether vapor. No similar effects were observed on these enzyme levels at the end of the recovery period for female rats exposed to 71 ppm of ethylene glycol hexyl ether vapor. However, there was a statistically significant increase in gamma-glutamyl-transferase for the 71 ppm females at the end of the recovery period.

 

Increased absolute and/or relative liver and kidney weights in both sexes of the 71 ppm group and, to a lesser extent, in the 41 ppm group. However, there were no exposure-related macroscopic or microscopic abnormalities found in this study. There were no exposure-related effects on the potential primary target tissues for glycol ethers of blood and testes. The changes observed at 41 ppm and below were not considered to be biologically significant, while the effects observed at 71 ppm, although not severe, were considered to be related to exposure to ethylene glycol hexyl ether vapor and thus to have biological relevance.

Based on the data from this study, 41 ppm is considered to be the concentration at which no biologically significant toxic effects were observed. Although the toxic effects observed at 71 ppm were generally mild, the spectrum of body weight, clinical chemistry, and organ weight effects, some of which persisted into the recovery period, are considered to be treatment related and thus to be biologically relevant in assessing potential health effects from this material.

 

 

 

 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

245 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: This study was conducted in accordance with GLP and similar to OECD guideline 410. However, the study duration was only 11 days.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Principles of method if other than guideline:

Information not available

GLP compliance:

yes

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc. Kinston, NY
- Age at study initiation: Approximately 22 week
- Fasting period before study: None
- Housing: Rats were house 1/cage in stainless steel wire floors
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: Approximately 2 week


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 61°F and 70°F
- Humidity (%): 40-70 %
- Air changes (per hr): Standard conditions
- Photoperiod: (12 hrs dark / 12 hrs light)

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on exposure:

see the attachment-1

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

Nine applications were given over a period of 11 days.

Frequency of treatment:

6/hours/day

Remarks:

Doses / Concentrations:
44 mg/kg/bw/day
Basis:
nominal per unit body weight

Remarks:

Doses / Concentrations:
222 mg/kg/bw/day
Basis:
nominal per unit body weight

Remarks:

Doses / Concentrations:
444 mg/kg/bw/day
Basis:
nominal per unit body weight

No. of animals per sex per dose:

5/sex/group

Control animals:

yes

Details on study design:

- Rationale for animal assignment: Random
- Post-exposure recovery period in satellite groups: None

Positive control:

no data

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes


DETAILED CLINICAL OBSERVATIONS: Yes
Time schedule for examinations: Daily

DERMAL IRRITATION (if dermal study): Yes
Time schedule for examinations: Daily
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were measured immediately prior to the f i r s t dose (Day 1), one week after the first dose (Day 8), and on the day of sacrifice (Day 12).


FOOD CONSUMPTION: Yes
Food consumption data were collected for a l l animals on days 3, 5, 7, 8, 10, and 12

FOOD EFFICIENCY: No



WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to necropsy
- Anaesthetic used for blood collection: Yes (identity) Injections of T 61 euthansia solution
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in table [No 13,14.] were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to necropsy
- Anaesthetic used for blood collection: Yes (identity) Injections of T 61 euthansia solution
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in table [No.15, 16] were examined.


URINALYSIS: Yes
- Time schedule for collection of urine: prior to necropsy
- Metabolism cages used for collection of urine: No
- Animals fasted: Yes
- Parameters checked in table [No.17, 18] were examined.


NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
At the end of treatment, all rabbits were sacrificed by caudal ear vein injections of T61 Euthanasia Solution. Prior to sacrifice, body weights were obtained to allow expression of relative organ weights. A complete necropsy was performed on each animal. The liver, kidneys, adrenals, brain, and heart of all rabbits and the testes of all males were weighed at the time of
necropsy.

Other examinations:

Organ weights: The liver, kidneys, adrenals, brain, and heart of all rabbits and the testes of all males were weighed at the time of necropsy.

Statistics:

Food consumption, body weight, and organ weight data were intercompared for the dose and control groups by use of Levene's test for homogeneity of variances, by analysis of variance, and by pooled variance t-tests. The t-tests were used, i f the analysis of variance was significant, to delineate which groups differed from the control group. If Levene1s test indicated heterogeneous variances, the groups were compared by an analysis of variance for unequal variances followed,
if necessary, by separate variance t - tests. Non-parametric data were analyzed by the Kruskal-Wallis test or, if necessary, by the Wilcoxon rank sum test as modified by Mann-Whitney,
Frequency data were compared using Fisher's exact tests where appropriate. All statistical tests, except the frequency comparisons were performed using BMDP Statistical Software (Dixon, 1985). The frequency data tests are described in Biometry (Sokal, R. R. and Rohlf, F. J. W. H. Freeman and Company: San Francisco, 1969). The fiducial limit of 0.05 was used as the critical level of significance for all tests.

Clinical signs:

effects observed, treatment-related

Dermal irritation:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY: Treatment-related signs of toxicity observed during the study included emaciation, cold extremities, and not eating in three of 5 females from the high dose group. One female in the high dose group died on Day 9 and a second female from this treatment group was sacrificed moribund on Day 10.
Treatment area effects, other than the Draize scored erythema and edema, included dose-related increases in the incidence and/or severity of lichenification , and necrosis, observed in the mid and high dose groups of both sexes. Exfoliation occurred in all male and most female animals at all dosage levels, and fissuring occurred in most animals at the mid and high dose treatment groups for both sexes. Ecchymosis was observed for one male from the mid dose treatment group. Excoriation was noted in two males from the high dose group only, and ulceration was recorded in one male and two females from the high dose group. These lesions principally occurred during the second week of dosing. Erythema in the treatment area scored as barely perceptible (Grade 1) or well defined (Grade 2) was observed after the first day of treatment with test material for most males in the mid and high dose treatment groups (4/5 and 5/5 respectively). Erythema was first observed in the low dose treatment group of males on Day 4. The incidence of males scored with erythema at some time during the study was 4/5, 5/5, and 5/5 for the low, mid, and high dose groups, respectively with the highest incidence and severity recorded on Days 7 and 8. Edema in male rabbits treated with Hexyl CELLOSOLVE was more prominent than erythema in the male animals from the mid and high dose treatment groups. Well defined (Grade 2) to moderate (Grade 3) edema was recorded for all males in the high dose group by Day 5 with barely perceptible edema scored for two animals on Day 3. Edema was observed in 1/5 males in the mid dose group on Day 3 and all animals by Day 4. The majority of the scores for these animals were well defined (Grade 2) or moderate (Grade 3) throughout the remainder of the study. Edema, like erythema, tended to be scored higher in the middle of the study (Days 7 and 8). No edema was observed in males from the low dose group at any time during the study.

BODY WEIGHT AND WEIGHT GAIN: Weight loss (a mean of -182 g) was observed for males in the high dose group during the first week of the study compared to a weight gain of 35 g for controls. Although a slight weight gain was observed for the males in the high dose group between Days 8 and 12, the mean weight for this group was 154 g lower than the initial weight on Day 12. No treatment-related effects body weight or body weight gain was noted in males from either the low or mid dose treatment groups. Females from the high dose group also lost weight during the first week of the study with a moderate recovery observed between Days 8 and 12. The mean body weight was less than the Day 1 weights for the females from the high dose group by 523 and 403 grams, respectively on Days 8 and 12 of the study compared to gains of 27.8 and 51.5 grams observed for controls at these time intervals. No treatment-related effects were noted in females from either the low or mid dose treatment group.


FOOD CONSUMPTION: A trend toward reduced food consumption was observed for males during the first week of the study with reductions of 2.5%, 6.5% and 35.62 for the low, mid, and high dose treatment groups, respectively when compared to control values. Only the reduction in the high dose group was statistically significant. During the second week of the study, only the high dose group showed reduction in food consumption (17.62). This difference was not statistically significant. Females in the mid and high dose treatment groups showed reductions in food consumption of 7.9% and 69.7% for the first week of the study, with a 6.6% and 44.3% reduction for the second week of the study when compared to control values. The high level reduction for the first week of the study was the only value that was statistically significant.

HAEMATOLOGY: Male and female rabbits receiving 444 mg/kg/day of Hexyl CELLOSOLVE had
Statistically significant decreased erythrocyte counts (23.8% and 21.7% decreases from control, respectively), hemoglobin concentration (17.9% and IA.3% decreases, respectively), and hematocrit (.6.3% and 12.7% decreases, respectively). MCV values were increased by 11.2% for both male and female high dose animals, although only the increase in the value for males was
Statistically significant. Female rabbits in the 222 mg/kg/day group had a decreased hematocrit value (7.1% decrease) which was statistically significant. A trend for these alterations was observed in all exposure groups in males, and at least the two highest dose groups for females.

CLINICAL CHEMISTRY: There were no other treatment-related changes in serum clinical chemistry measurements for either males or females in any dose group

URINALYSIS: There were no other treatment-related changes in serum urinalysis measurements for either males or females in any dose group.

ORGAN WEIGHTS: No treatment-related differences in absolute or relative organ weights were observed for males or females from any treatment group. Males from the high dose group had elevated brain weights relative to body weight which resulted from the lower body weights for this group.


GROSS AND HISTOPATHOLOGY: Treatment-related gross and microscopic findings in rabbits surviving to the end of the study were limited to the treated skin. Microscopically, the treated skins of the majority of the rabbits in all of the Hexyl CELLOSOLVE treated groups were characterized by ancanthosis, hyperkeratosis and dermatitis. The dermatitis was ulcerative in nature in the most severely affected rabbits (primarily individual rabbits in the mid and high dose groups), and epidermal/dermal necrosis was present in the treated skins of a small number of rabbits in the high dose group. The histologic changes present in the treated skins were similar for the male and female rabbits on study. In the 2 females from the high dose group that died, gross and microscopic findings in the treatment area were similar to those in the animals that were sacrificed. No cause of death was obvious from these evaluations.

Dose descriptor:

LOAEL

Effect level:

44 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: local skin irritation

Dose descriptor:

NOAEL

Effect level:

222 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: systemic effects

Critical effects observed:

not specified

None

Conclusions:

Based on the results of this study the LOAEL for local effects is 44 mg/kg bw/day and the NOAEL for systemic effects is 222 mg/kg bw/day.

Executive summary:

New Zealand White rabbits (5/sex/group) were exposed to undiluted ethylene glycol hexyl ether by occluded cutaneous contact at doses of 0, 44, 222, or 444 mg/kg body weight/day (0, 0.05, 0.25, or 0.5 ml/kg/day). Nine applications (6 hours/day) were given over an 11-day period. A control group had water applied to the treatment site at a dose of 0.5 ml/kg/day.

 

Monitors effects included clinical observations, body weights, food consumption, hematology, clinical chemistry, urinalysis, organ weights, gross and histopathology.

 

Survivors were sacrificed the day following the final application of test material or water. One female in the high dose group died on Day 9 and a second female from this treatment group was sacrificed moribund on Day 10. The cause of death could not be determined from the evaluations performed in this study. No overt indications of treatment-related toxicity were observed, however, and death may have resulted from stress due to the skin irritation and dosing procedures used. Barely perceptible erythema was observed in male rabbits in the 44 mg/kg/day dose group. Barely perceptible to well-defined erythema was observed in males from the mid and high dose treatment levels. Graded erythema showed a dose-response relationship ranging from barely perceptible in the low dose group to moderate in the high dose group for female rabbits. Edema, scored as barely perceptible to moderate, was recorded for male rabbits in the mid and high dose levels. Graded edema showed a dose-response relationship ranging from barely perceptible in the low dose group to severe in the high dose group for females. Some individual variation in response to the irritant properties of the test material was observed. There was a tendency for the erythema and edema observed in this study to be of higher incidence and severity in the middle dosing days (particularly Days 7 and 8). Since no applications were given on Days 6 and 7, the cause of this effect is unclear.

 

The results of this study indicated that repeated percutaneous exposure of ethylene glycol hexyl ether to rabbits resulted in dose related local skin irritation at doses of 44 mg/kg/day and above.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

222 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Additional information

In a 2-week dermal toxicity study New Zealand White rabbits were exposed to undiluted ethylene glycol hexyl ether by occluded cutaneous contact at doses of 44, 222, or 444 mg/kg body weight/day. Nine applications (6 hours/day) were given over an 11-day period. Monitors effects included clinical observations, body weights, food consumption, hematology, clinical chemistry, urinalysis, organ weights, gross and histopathology. One female in the high dose group died on Day 9 and a second female from this treatment group was sacrificed moribund on Day 10. The cause of death could not be determined from the evaluations performed in this study. No overt indications of treatment-related toxicity were observed, however, the death may have resulted from stress due to the skin irritation and dosing procedures used. The results of this study indicated that repeated percutaneous exposure of ethylene glycol hexyl ether to rabbits resulted in dose related local skin irritation at doses of 44 mg/kg/day and above. No systemic effects were observed at the mid and low dose levels. Hence, the LOAEL for local effects is 44 mg/kg bw/day and the NOAEL for systemic effects is 222 mg/kg bw/day.

In a repeated dose inhalation study, four groups, each consisting of 20 Fischer 344 rats per sex, were exposed for 6 hours per day, 5 days per week, for 14 weeks to the vapors of ethylene glycol hexyl ether at target concentrations of 0 (control), 20, 40, or 85 ppm and followed by 4 week recovery period. Actual mean concentrations obtained for this study were 20, 41, and 71 ppm ethylene glycol hexyl ether). Based on the data from this study, 41 ppm (245 mg/m3) is considered to be NOAEC. At this concentration no biologically significant toxic effects were observed. Decreases in body weight and increases in male kidney and female liver weights occurring at this concentration were considered to be adaptive (and not adverse) since there were no correlative changes in histopathology or serum chemistry. The changes in liver enzymes in animals exposed to 71 ppm (425 mg/m3) are difficult to interpret since levels of 3 out of 4 enzymes were decreased and only 1 out of 4 was increased. Whereas the effects on the kidney were not dose-dependent, liver weights increased in a dose-dependent manner and were not reversed after 4 weeks of recovery in animals exposed to 71 ppm. No effects on red blood cells or histologic changes in the liver or kidney were noted at concentrations up to and including the highest concentration tested (71 ppm or 425 mg/m3).

 

Repeated dose toxicity: inhalation - systemic effects (target organ) digestive: liver

Repeated dose toxicity: dermal - systemic effects (target organ) other: skin

Justification for classification or non-classification

The no observed adverse effect levels for systemic effects induced by ethylene glycol hexyl ether exceed the values triggering classification. Therefore, no classification for prolonged exposure is required.