2-hexyloxyethanol

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted as per compliance to Good Laboratory Practices TSCA Standards; Federal Register 48(230): 5397-53944, November 29, 1983.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Objective of study:

other: pharmacokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.8320 (Oral/dermal pharmacokinetics)

Principles of method if other than guideline:

not applicable

GLP compliance:

yes

Radiolabelling:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazleton-Dutchland
- Age at study initiation: 9-10 weeks of age
- Weight at study initiation: 2-3 kg
- Fasting period before study: not specified
- Housing: individually housed in Roth-type metabolism cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

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

Route of administration:

intravenous

Vehicle:

physiological saline

Details on exposure:

In the intravenous studies, EGHE and 14C-EGHE were diluted in 0.9% (w/v) NaCl in water. The dose solution was delivered gravimetrically to each animal in a study. In intravenous studies, the dose solution was delivered using a syringe with a sawed-off needle into an indwelling cannula over a period of 2 minutes. The dose volume was followed by the same volume of 0.9% NaCl to clear the cannula, then the cannula was plugged.

Duration and frequency of treatment / exposure:

single

Remarks:

Doses / Concentrations:
10 and 1 mg/kg

No. of animals per sex per dose / concentration:

6 animals

Control animals:

not specified

Positive control reference chemical:

not applicable

Details on study design:

- Dose selection rationale: based on acute and probe study
- Rationale for animal assignment: random

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, plasma, blood, cage washes
- Time and frequency of sampling: Urine was collected on dry ice in 6- to 12-hr intervals and feces in 24-hr intervals. Urine samples were assayed immediately for 14c and the remaining volumes were stored at approximately -80°C until chemical analysis was conducted by HPLC. Feces were frozen at approximately -20°C until analyzed. Expired 14CO2, was collected at 12-hour intervals and stored at approximately -20°C until analyzed for 14C

Statistics:

The pharmacokinetic description of the fate of absorbed l4C-EGHE w as derived using best-fit parameter estimates for the plasma. The parameters
estimated included: rate constant of absorption, ka; rate constant of elimination, ke; volume of distribution, Vd; half-lives (t1/2) of absorption and elimination and area under the plasma concentration (AUC) versus time.

Preliminary studies:

not applicable

Details on absorption:

no data

Details on distribution in tissues:

no data

Details on excretion:

The disposition of radioactivity following 10 and 0.1 mg/kg doses of EGHE/14C-EGHE to male NZW rabbits was that the total recovery of dose in excreta fractions, carcass and the cage wash was approximately 95 to 100% in the two dose groups.
A majority of the dose was eliminated in the urine (approximately 80%) while less than 2% was eliminated in the feces (largely in the first day of exposure).
There were no marked difference in rates or extents of urinary elimination observed between the two dose groups. In general, most of the dose recovered in the urine was eliminated in the first 24 hours after dosing, after which little additional urinary elimination of the dose occurred.

Test no.:

#1

Toxicokinetic parameters:

Cmax: (10 mg/kg): 42.491 µg/g

Test no.:

#1

Toxicokinetic parameters:

Tmax: (10 mg/kg): 0 minutes

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: (10 mg/kg): Half-life of distribution: 40.232 min

Test no.:

#1

Toxicokinetic parameters:

AUC: (10 mg/kg): AUC(48): 3598.5 µg/g.min

Test no.:

#1

Toxicokinetic parameters:

AUC: (10 mg/kg): AUC(∞): 4241.3 µg/g.min

Test no.:

#1

Toxicokinetic parameters:

other: (10 mg/kg): Distribution rate constant k(d): 0.017229 min(-1)

Test no.:

#1

Toxicokinetic parameters:

other: (10 mg/kg): Elimination rate constant k(e): 0.00036001 min (-1)

Test no.:

#1

Toxicokinetic parameters:

other: (10 mg/kg): Apparent volume of distribution Vd: 32610 ml

Test no.:

#1

Toxicokinetic parameters:

other: (10 mg/kg): Systemic clearance Cl(tot): 11.74 ml/min

Test no.:

#1

Toxicokinetic parameters:

half-life 2nd: (10 mg/kg): Half-life of elimination: 1925.4 min

Test no.:

#2

Toxicokinetic parameters:

Cmax: (1.0 mg/kg): 5.0998 µg/g

Test no.:

#2

Toxicokinetic parameters:

Tmax: (1.0 mg/kg): 0 minutes

Test no.:

#2

Toxicokinetic parameters:

half-life 1st: (1.0 mg/kg): Half-life of distribution: 16.917 min

Test no.:

#2

Toxicokinetic parameters:

AUC: (1.0 mg/kg): AUC(48): 288.73 µg/g.min

Test no.:

#2

Toxicokinetic parameters:

AUC: (1.0 mg/kg): AUC(∞): 357.38 µg/g.min

Test no.:

#2

Toxicokinetic parameters:

other: (1.0 mg/kg): Distribution rate constant k(d): 0.040973 min(-1)

Test no.:

#2

Toxicokinetic parameters:

other: (1.0 mg/kg): Elimination rate constant k(e): 0.00029278 min (-1)

Test no.:

#2

Toxicokinetic parameters:

other: (1.0 mg/kg): Apparent volume of distribution Vd: 43640 ml

Test no.:

#2

Toxicokinetic parameters:

other: (1.0 mg/kg): Systemic clearance Cl(tot): 12.777 ml/min

Test no.:

#2

Toxicokinetic parameters:

half-life 2nd: (1.0 mg/kg): Half-life of elimination: 2367.5 min

Metabolites identified:

no

Details on metabolites:

3-9 peaks were observed, none of which corresponded to EGHE. These peaks were probably considered metabolites of EGHE, of which at least three of which appear to be major urinary metabolites.

none

Conclusions:

Interpretation of results: low bioaccumulation potential based on study results
Under the conditions of the study, the results in rabbits indicate that while EGHE has a large potential for systemic absorption, it is rapidly and extensively eliminated from the plasma by metabolic conversion to multiple metabolite species.

Executive summary:

The absorption, distribution, metabolism and elimination of ethylene glycol monohexyl ether (EGHE) following single intravenous dose was investigated in rabbits. In New Zealand White rabbits, intravenous doses of 10 and 1 mg/kg EGHE given to male rabbits were metabolized rapidly, so that EGHE levels were less than 1% of the total plasma radioactivity by 1 hour post-dosing. About 80% of the radioactivity was recovered in the urine, with less than 2% in the feces. Because the rabbits were housed in open metabolism cages, the recoveries of radioactivity in CO2 and organic volatile fractions could not be assessed; however, over 90% of the dose was recovered in the intravenous studies. The results in rabbits indicate that, while EGHE has a large potential for systemic absorption, it is rapidly and extensively eliminated from the plasma by metabolic conversion to multiple metabolite species.

Reference 2

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted with compliance to Good Laboratory Practices TSCA Standards; Federal Register 48(230): 5397-53944, November 29, 1983.

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:

EPA OPP 85-3 (Dermal Penetration)

Principles of method if other than guideline:

not applicable

GLP compliance:

yes

Radiolabelling:

yes

Remarks:

C14- Labeled EGHE

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazleton-Dutchland, denver ,PA
- Age at study initiation: 9-10 weeks
- Weight at study initiation: 2 - 3 kgs
- Housing: Open rack-type metabolism cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum):Ad libitum
- Acclimation period:5 days


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

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Duration of exposure:

48 hour experimental period

Doses:

Percutaneous Male-10mg/kg
Percutaneous Female-10mg/kg

No. of animals per group:

5 animals per group

Control animals:

no

Details on study design:

APPLICATION OF DOSE: 10mg/kg EGHE to male and female rabbits.

TEST SITE
- Preparation of test site: The dose material was applied to the skin using a syringe and needle
- Area of exposure: Occluded with polyethylene sheeting held in place woth waterproof surgical tape and covered with stretch adhesive bandage tape.

SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: yes:

SAMPLE COLLECTION
- Collection of blood: 1,2,4,8,12,24,30,36 and 48 hours
- Collection of urine and faeces: Done

Details on in vitro test system (if applicable):

not applicable

Signs and symptoms of toxicity:

not specified

Dermal irritation:

no effects

Absorption in different matrices:

Refer to attachment

Total recovery:

Refer to attachment

Conversion factor human vs. animal skin:

not applicable

none

Conclusions:

The results in rabbits indicates that EGHE (Ethylene glycol hexyl ether) has a large potential for systemic absorption, it is rapidly and extensively eliminated from the plasma by metabolic conversion to multiple metabolite species.

Executive summary:

New Zealand White rabbits were used to access Skin Penetration and Pharmacokinetics of Ethylene Glycol Monohexyl Ether (EGHE). Intravenous doses of 10 and 1 mg/kg EGHE given to male rabbits were metabolized rapidly, so that EGHE levels were less than 1% of the total plasma radioactivity by 1 hour post-dosing. About 80% of the radioactivity was recovered in the urine, with less than 2% in the feces. Because the rabbits were housed in open metabolism cages, the recoveries of radioactivity in C02and organic volatile fractions could not be assessed; however, over 90% of the dose was recovered in the intravenous studies. After cutaneous dosing of 10 mg/kg EGHE to male and female rabbits, about 75% of the dose was recovered; the remainder of the dose may have been lost because the organic volatile fraction could not be collected. No sex differences in the disposition of EGHE were observed. EGHE penetrated the skin rapidly, and the radioactivity was widely distributed. Most of the radioactivity was eliminated in the urine (55-65%) with minimal recovery in feces. The cutaneous bioavailability, based on total radioactivity, was greater than 65%; however, EGHE was extensively metabolized so that it accounted for less than 10% of the total radioactivity by 1 hour post-dosing. In nearly all urine fractions no EGHE was detected, but up to nine metabolite peaks were found.

No marked accumulation of EGHE was observed in a variety of tissues and organs that were analyzed.

The results in and rabbits indicate that, while EGHE has a large potential for systemic absorption, it is rapidly and extensively eliminated from the plasma by metabolic conversion to multiple metabolite species.

 

Reference 3

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted as per compliance to Good Laboratory Practices TSCA Standards; Federal Register 48(230): 5397-53944, November 29, 1983.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Objective of study:

other: pharmacokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.8320 (Oral/dermal pharmacokinetics)

Principles of method if other than guideline:

not applicable

GLP compliance:

yes

Radiolabelling:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Sprague Dawley, Inc.
- Age at study initiation: 11-12 weeks old
- Weight at study initiation: not specified
- Fasting period before study: not specified
- Housing: group housed during acclimation and individually housed in Roth-type metabolism cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

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

Route of administration:

intravenous

Vehicle:

physiological saline

Details on exposure:

In the intravenous studies, EGHE and 14C-EGHE were diluted in 0.9% (w/v) NaCl in water. The dose solution was delivered gravimetrically to each animal in a study. In intravenous studies, the dose solution was delivered using a syringe with a sawed-off needle into an indwelling cannula over a period of 2 minutes. The dose volume was followed by the same volume of 0.9% NaCl to clear the cannula, then the cannula was plugged.

Duration and frequency of treatment / exposure:

single

Remarks:

Doses / Concentrations:
25 and 2.5 mg/kg

No. of animals per sex per dose / concentration:

4 animals

Control animals:

not specified

Positive control reference chemical:

not applicable

Details on study design:

- Dose selection rationale: based on acute study
- Rationale for animal assignment: random

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, plasma, blood, cage washes
- Time and frequency of sampling: Urine was collected on dry ice in 6- to 12-hr intervals and feces in 24-hr intervals. Urine samples were assayed immediately for 14c and the remaining volumes were stored at approximately -80°C until chemical analysis was conducted by HPLC. Feces were frozen at approximately -20°C until analyzed. Expired 14CO2, was collected at 12-hour intervals and stored at approximately -20°C until analyzed for 14C

Statistics:

The pharmacokinetic description of the fate of absorbed l4C-EGHE w as derived using best-fit parameter estimates for the plasma. The parameters
estimated included: rate constant of absorption, ka; rate constant of elimination, ke; volume of distribution, Vd; half-lives (t1/2) of absorption and elimination and area under the plasma concentration (AUC) versus time.

Preliminary studies:

not applicable

Details on absorption:

no data

Details on distribution in tissues:

no data

Details on excretion:

A majority of the dose was eliminated in the urine (approximately 65 to 75%) while less than 10% was eliminated as CO2 and less than 5% was eliminated in the feces (largely in the first day of exposure in C02 and feces fractions).
There was no marked difference in rates or extents of urinary elimination between the two dose groups. In general, most of the dose recovered in the urine was eliminated in the first 6 hours after dosing.

Test no.:

#1

Toxicokinetic parameters:

Cmax: (25 mg/kg): 129.25 µg/g

Test no.:

#1

Toxicokinetic parameters:

Tmax: (25 mg/kg): 0 minutes

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: (25 mg/kg): Half-life of distribution: 15.213 min

Test no.:

#1

Toxicokinetic parameters:

AUC: (25 mg/kg): AUC(48): 8153.2 µg/g.min

Test no.:

#1

Toxicokinetic parameters:

AUC: (25 mg/kg): AUC(∞): 8153.2 µg/g.min

Test no.:

#1

Toxicokinetic parameters:

other: (25 mg/kg): Distribution rate constant k(d): 0.04562 min(-1)

Test no.:

#1

Toxicokinetic parameters:

other: (25 mg/kg): Elimination rate constant k(e): 0.00080246 min (-1)

Test no.:

#1

Toxicokinetic parameters:

other: (25 mg/kg): Apparent volume of distribution Vd: 1013 ml

Test no.:

#1

Toxicokinetic parameters:

other: (25 mg/kg): Systemic clearance Cl(tot): 0.8129 ml/min

Test no.:

#1

Toxicokinetic parameters:

half-life 2nd: (25 mg/kg): Half-life of elimination: 863.78 min

Test no.:

#2

Toxicokinetic parameters:

Cmax: (2.5 mg/kg): 9.1632 µg/g

Test no.:

#2

Toxicokinetic parameters:

Tmax: (2.5 mg/kg): 0 minutes

Test no.:

#2

Toxicokinetic parameters:

half-life 1st: (2.5 mg/kg): Half-life of distribution: 17.301 min

Test no.:

#2

Toxicokinetic parameters:

AUC: (2.5 mg/kg): AUC(48): 619.25 µg/g.min

Test no.:

#2

Toxicokinetic parameters:

AUC: (2.5 mg/kg): AUC(∞): 619.25 µg/g.min

Test no.:

#2

Toxicokinetic parameters:

other: (2.5 mg/kg): Distribution rate constant k(d): 0.040065 min(-1)

Test no.:

#2

Toxicokinetic parameters:

other: (2.5 mg/kg): Elimination rate constant k(e): 0.00067483 min (-1)

Test no.:

#2

Toxicokinetic parameters:

other: (2.5 mg/kg): Apparent volume of distribution Vd: 1507 ml

Test no.:

#2

Toxicokinetic parameters:

other: (2.5 mg/kg): Systemic clearance Cl(tot): 1.017 ml/min

Test no.:

#2

Toxicokinetic parameters:

half-life 2nd: (2.5 mg/kg): Half-life of elimination: 1027.1 min

Metabolites identified:

no

Details on metabolites:

2-7 peaks were observed, none of which corresponded to EGHE and these peaks were considered to probably be metabolites of EGHE, of which at least three of which appear to be major urinary metabolites.

none

Conclusions:

Interpretation of results: low bioaccumulation potential based on study results
The results in rats indicate that while EGHE has a large potential for systemic absorption, it is rapidly and extensively eliminated from the plasma by metabolic conversion to multiple metabolite species.

Executive summary:

The absorption, distribution, metabolism and elimination of ethylene glycol monohexyl ether (EGHE) following single intravenous doses were investigated in rats. In male Fischer 344 rats, intravenous doses of 25 and 2.5 mg/kg EGHE were metabolized rapidly, such that EGHE was less than 1% of the total radioactivity in the plasma by 8 hours post-dosing. The remaining plasma radioactivity was eliminated mostly in the urine (~65-75%) with minimal amounts of radioactivity recovered in feces or CO2 and organic volatile fractions. The results in rats indicate that while EGHE has a large potential for systemic absorption, it is rapidly and extensively eliminated from the plasma by metabolic conversion to multiple metabolite species.

Reference 4

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted with compliance to Good Laboratory Practices TSCA Standards; Federal Register 48(230): 5397-53944, November 29, 1983.

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:

EPA OPP 85-3 (Dermal Penetration)

Principles of method if other than guideline:

not applicable

GLP compliance:

yes

Radiolabelling:

yes

Remarks:

C14- Labeled EGHE

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Sprague Dawley, Inc.
- Age at study initiation: 11-12 week
- Housing: Roth-type metabolism cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period:5 days


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

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Duration of exposure:

48 hour experimental period

Doses:

25 mg/kg EGHE Percutaneous- Male
25 mg/kg EGHE Percutanesous- Female

No. of animals per group:

5 animals per group

Control animals:

no

Details on study design:

APPLICATION OF DOSE: 25 mg/kg EGHE to male and female rats

TEST SITE
- Preparation of test site: The dose material was applied to the skin using a syringe and needle
- Area of exposure: Occluded with polyethylene sheeting held in place woth waterproof surgical tape and covered with stretch adhesive bandage tape.

SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: yes:

SAMPLE COLLECTION
- Collection of blood: 1,2,4,8,12,24,30,36 and 48 hours
- Collection of urine and faeces: Done

Details on in vitro test system (if applicable):

not applicable

Signs and symptoms of toxicity:

not specified

Dermal irritation:

no effects

Absorption in different matrices:

Refer to attachment

Total recovery:

Refer to attachment

Conversion factor human vs. animal skin:

no data

none

Conclusions:

The results in rats indicates that EGHE (Ethylene glycol hexyl etherP) was extensively metabolized, so that it accounted for only 5-50% of the total plasma radioactivity.

Executive summary:

Fischer 344 rats were used to access Skin Penetration and Pharmacokinetics of Ethylene Glycol Monohexyl Ether (EGHE). Intravenous doses of 25 and 2.5 mg/kg of EGHE given to the animals and were metabolized rapidly, such that EGHE was less than 1 % of the total radioactivity in the plasma by 8 hour post dosing. The remaining plasma radioactivity was eliminated mostly in the urine (nearly 65 -75%) with minimal amounts of radioactivity recovered in feces or CO2 and organic volatile fractions. After cutaneous dosing of 25 mg/kg EGHE to male and female rats, over 95% of the dose was recovered and no sex differece in EGHE disposition was observed. EGHE penetrated the sin rapidly and was widely distribute. In contrast to the intravenous route, less radioactivity was recovered in the urine (nearly 20 -30%), but significant amounts were found in feces and the organic volatile fraction (over 20 and 10%, respectively).

The cutaneous bioavailability was greater than 75% in rats when total radioactivity was measured; however, EGHE was extensively metabolized, so that it accounted for only 5 -50% of the total plasma radioactivity. EGHE was not found in urine fractions, but up to 7 urinary metabolite peaks were observed. There was no marked accumulation of radioactivity in liver, kidney, lund or a variety of other tissues and organs that were analyzed.

Description of key information

Short description of key information on bioaccumulation potential result: 
The pharmacokinetics of Ethylene Glycol Hexyl Ether (EGHE) folllowing a single intravenous exposure to Fischer 344 rats and New Zealand rabbits was evaluated
Short description of key information on absorption rate: 
The skin penetration and pharmacokinetics of ethylene glycol hexyl ether (EGHE) folllowing a single cutaneous exposure to Fischer 344 rats and New Zealand rabbits was evaluated

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

75

Absorption rate - inhalation (%):

100

Additional information

Several pharmacokinetics studies and skin penetration studies have been conducted with Ethylene Glycol Hexyl Ether (EGHE) in rats and rabbits.The results in both species indicate that, while EGHE has a large potential for systemic absorption, it is rapidly and extensively eliminated from the plasma by metabolic conversion to multiple metabolite species. After cutaneous dosing of EGHE to rats and rabbits, EGHE penetrated the skin rapidly and was widely distributed. The cutaneous bioavailability was greater than 75% in rats and greater than 65% in rabbits. However, EGHE was extensively metabolized. There was no marked accumulation of EGHE in liver, kidney, lung or a variety of other tissues and organs that were analyzed.

Discussion on bioaccumulation potential result:

The absorption, distribution, metabolism and elimination of ethylene glycol monohexyl ether (EGHE) following single intravenous dose was investigated in rats and rabbits. In male Fischer 344 rats, intravenous doses of 25 and 2.5 mg/kg EGHE were metabolized rapidly, such that EGHE was less than 1% of the total radioactivity in the plasma by 8 hours post-dosing. The remaining plasma radioactivity was eliminated mostly in the urine (~65-75%) with minimal amounts of radioactivity recovered in feces or CO2 and organic volatile fractions. In New Zealand White rabbits, similar results were obtained. Intravenous doses of 10 and 1 mg/kg EGHE given to male rabbits were metabolized rapidly, so that EGHE levels were less than 1% of the total plasma radioactivity by 1 hour post-dosing. About 80% of the radioactivity was recovered in the urine, with less than 2% in the feces. Because the rabbits were housed in open metabolism cages, the recoveries of radioactivity in C02 and organic volatile fractions could not be assessed; however, over 90% of the dose was recovered in the intravenous studies. The results in rats and rabbits indicate that, while EGHE has a large potential for systemic absorption, it is rapidly and extensively eliminated from the plasma by metabolic conversion to multiple metabolite species.

Discussion on absorption rate:

The absorption, distribution, metabolism and elimination of ethylene glycol monohexyl ether (EGHE) following single cutaneous dose were investigated in rats and rabbits. After cutaneous dosing of 25 mg/kg EGHE to male and female rats, over 95% of the dose was

recovered and no sex difference in EGHE disposition was observed. EGHE penetrated the skin rapidly and was widely distributed. In contrast to the intravenous route, less radioactivity was recovered in the urine (~20-30%), but significant amounts were found in feces and the organic volatile fraction (over 20 and 10%, respectively). The cutaneous bioavailability was greater than 75% in rats when total radioactivity was measured; however, EGHE was extensively metabolized, so that it accounted for only 5-50% of the total plasma radioactivity. EGHE was not found in urine fractions, but up to 7 urinary metabolite peaks were observed. There was no marked accumulation of radioactivity in liver, kidney, lung or a variety of other tissues and organs that were analyzed.

After cutaneous dosing of 10 mg/kg EGHE to male and female rabbits, about 75% of the dose was recovered; the remainder of the dose may have been lost because the organic volatile fraction could not be collected. No sex differences in the disposition of EGHE were observed. EGHE penetrated the skin rapidly, and the radioactivity was widely distributed. Most of the radioactivity was eliminated in the urine (55-65%) with minimal recovery in feces. The cutaneous bioavailability, based on total radioactivity, was greater than 65%;

However, EGHE was extensively metabolized so that it accounted for less than 10% of the total radioactivity by 1 hour post-dosing. In nearly all urine fractions no EGHE was detected, but up to nine metabolite peaks were found. No marked accumulation of EGHE was observed in a variety of tissues and organs that were analyzed.

The results in rats and rabbits indicate that, while EGHE has a large potential for systemic absorption, it is rapidly and extensively eliminated from the plasma by metabolic conversion to multiple metabolite species.