Reaction mass of 2-(2-(2-butoxyethoxy)ethoxy)ethanol and 3,6,9,12-tetraoxahexadecan-1-ol

Endpoint summary

Description of key information

Half life: 4 -6 hours.

Short description of key information on absorption rate:
Permeability constant 22 ± 8.6ug/cm2/hr.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - dermal (%):

10

Additional information

The main metabolic pathway for metabolism of ethylene glycol monoalkyl ethers is oxidation via alcohol and aldehyde dehydrogenases (ALD/ADH) that leads to the formation of an alkoxy acid. Alkoxy acids are the only toxicologically significant metabolites of glycol ethers that have been detected in vivo. Methoxy acetic acid, a metabolite of ethylene glycol methyl ether, is a known testicular toxicant in rats, and butoxyacetic acid, a metabolite of ethylene glycol butyl ether, causes hemolysis of rodent red blood cells.

In a study to examine the metabolism 2 -(2 -(2-butoxyethoxy)ethoxy)ethanol (TEGBE), the main component of this multi-constituent substance, SD rats were given a single oral dose of 1000mg/kgbw and the urine collected over two 24 hour periods for analysis for a number of expected metabolites. The main metabolite was 2 -(2 -(2 -butoxyethoxy)ethoxy)acetic acid (BEEAA), which accounted for 43% of the original dose. The metabolite butoxyacetic acid was found, the amount accounting for ~4% of the dose of 2 -(2 -(2 -butoxyethoxy)ethoxy)ethanol given. This demonstrates that oxidation of the hydroxyl function is the main metabolic pathway but lesser amounts of the substance are metabolised by cleavage of the ether linkages and also through oxidation of the butyl chain, although metabolites from the latter route could also be due to further oxidation of BEEAA as the secondary metabolites from these two routes are the same. The study also showed that >98% of the dose of 2 -(2 -(2 -butoxyethoxy)ethoxy)ethanol was eliminated within 24 hours demonstrating rapid metabolism (half life ~4 -5 hours) and no potential for bioaccumulation. Around 85% of the dose was collected in the urine within 48 hours, which is considered within the boundaries of what can be considered complete recovery.

In a study to examine the metabolism 2 -(2 -(2-methoxyethoxy)ethoxy)ethanol, SD rats were given a single oral dose of 1000 and the urine collected over two 24 hour periods for analysis for a number of expected metabolites. The dominant metabolite was 2 -(2 -(2-methoxyethoxy)ethoxy)acetic acid, which accounted for 81% of the original dose. Unmetabolised 2 -(2 -(2-methoxyethoxy)ethoxy)ethanol and its glucoronide conjugate, triethylene glycol, methoxyethoxyethoxyacetic acid were also found at levels of 1 -5% . In addition, the metabolite methoxyacetic acid was found, the amount accounting for 0.5% of the dose of 2 -(2 -(2-methoxyethoxy)ethoxy)ethanol given. This demonstrates that oxidation of the hydroxyl function is the dominant metabolic pathway but small amounts of the substance are metabolised by cleavage of the ether linkage. The study also showed that 100% of the dose of 2 -(2 -(2-methoxyethoxy)ethoxy)ethanol was eliminated within 24 hours in the urine.

An in vitro study determined that the permeability of 2-(2-(2-butoxyethoxy)ethoxy)ethanol to human skin is quite low. The permeability co-efficient was determined to be 22 +/-8.6ug/cm2/hr, which is around 0.4% of the skin penetration rate of the shorter chain glycol ether ethylene glycol methyl ether. Exposure to the substance also caused no significant deterioration of skin barrier properties. This is confirmed by QSAR data which indicates that it will have a dermal penetration rate around 10% that of the related substance 2 -butoxyethanol, which is known to have a dermal uptake of around 30%. Using the available data a pro-rata estimate for the dermal uptake of 2 -butoxyethyl acetate is ~5%. However, the dermal LD50 data, which uses 24 hours contact, suggests that penetration over the long term could be significant. As a compromise, a figure of 10% for the absorption rate is considered appropriate.

Discussion on bioaccumulation potential:

The metabolism study showed that the half life of all metabolites was only a few hours and that TEGBE is substantially eliminated within 24 hours of exposure. The study along with the low partition coefficient shows no potential for bioaccumulation.

Discussion on absorption rate:

An in vitro study determined that the permeability of 2-(2-(2-butoxyethoxy)ethoxy)ethanol to human skin is quite low. The permeability co-efficient was determined to be 22 +/-8.6ug/cm2/hr, which is around 0.4% of the skin penetration rate of the shorter chain glycol ether ethylene glycol methyl ether. Exposure to the substance also caused no significant deterioration of skin barrier properties. Using the available data a pro-rata estimate for the dermal uptake of 2 -butoxyethyl acetate is ~5%. However, the dermal LD50 data, which uses 24 hours contact, suggests that penetration over the long term could be significant. As a compromise, a figure of 10% for the absorption rate is considered appropriate. A figure of 10% is also supported by a comparison of the repeat dose toxicity NOAECs for rats by the dermal and oral routes, which differ by a factor of 10 and would suggest an absorption rate therefore of ~10% if the oral absorption is assumed to be 100%.

Based on the permeability limiting the uptake, the following dermal absorption rates would be appropriate for 8 hours continuous exposure:

Exposure (mg/cm2)	Absorption rate
0.1	100%
0.3	59%
1	18%
3	6%
10	2%

From this it can be concluded that any exposure of 1.8mg/cm2 or more over 8 hours would be less than 10% absorbed.

This information suggests that the metabolism of TEGBE will be typical of all of the components of the multi-constituent substance.