2-(2-(2-butoxyethoxy)ethoxy)ethanol

Endpoint summary

Additional information

Epidemiological data.

-NIOSH (NOES Survey 1981-1983) has statistically estimated that 25,310 workers (50 of these are female) are potentially exposed to triethylene glycol monobutyl ether or (2-(2-(2-butoxyethoxy)ethoxy)ethanol) in the US. Occupational exposure to triethylene glycol monobutyl ether may occur through inhalation and dermal contact with this compound at workplaces where triethylene glycol monobutyl ether is produced or used (SRC). Monitoring and use data indicate that the general population may be exposed to triethylene glycol monobutyl ether via ingestion of contaminated drinking water, and dermal contact with products containing triethylene glycol monobutyl ether.

- The substance2-(2-(2-butoxyethoxy)ethoxy)ethanolis an analogue of the test substance used in the study of Saavedra D, Arteaga M, Tena M,1997. In a case controlled study, exposure of pregnant females to methoxyethanol was associated with a specific phenotype of developmental facial abnormalities in offspring. Whilst exposure was not quantified, the description of the operations suggests that exposures, which took place in in the 1970’s was extensive and by multiple routes of exposure.

- The substance2-(2-(2-butoxyethoxy)ethoxy)ethanol is an analogue of the test substance used in the study of Cook RR, Bodner KM, Kolesar RC et al,1982.

In a cross–sectional study of workers exposed to methoxyethanol during the manufacturing and packaging operations in the early 1980’s, no gross abnormalities or meaningful differences were noted in haematogical or fertility parameters. Exposures ranged from approximately 0.5-2ppm (8hr TWA). The number of subjects examined in the study was relatively small however.

- The substance2-(2-(2-butoxyethoxy)ethoxy)ethanol is an analogue of the test substance used in the study of Welch LS, Schrader SM, Turner TW et al1989. A study of shipyard painters exposed to methoxyethanol and ethoxyethanol showed clear evidence of oligospermia and azoospermia once confounding by smoking was controlled for. Many other sperm parameters showed evidence for effects but not to levels of statistical significance. The was significant evidence that exposure to methoxyethanol causes a small shift towards anaemia and a more substantial reduction in polymorphnuclear leukocyte counts in a small proportion of workers. The OR calculated for the oligospermia amongst non smokers was 1.85, but the 95% interval of 0.6-5.6 suggested caution is needed in interpreting risk from this figure.

- The substance2-(2-(2-butoxyethoxy)ethoxy)ethanol is an analogue of the test substance used in the study of El-Zein RA, Abdel-Rahman SZ, Morris DL et al,2002.

In a case controlled study, exposure of pregnant females to methoxyethanol was associated with a specific and characteristic phenotype of developmental facial abnormalities in offspring that was not seen in controls. Persistent cytogenetic damage was also observed exclusively in all 6 in utero exposed offspring but not in controls. Whilst exposure was not quantified, the description of the operations suggests that exposures, which took place in in the 1970’s was extensive and by multiple routes of exposure.

Health surveillance data.

Two cases of dermatitis herpetiformis (DH) temporally related to the use of a cleaning solution containing 2 -butoxyethanol (2BE) have been reported. Analysis of the mixture showed the presence of 2 -butoxyethanol amongst a number of other materials. Patch testing was carried out with the individual chemicals at the same concentration than in the mixture, except for 2BE which was diluted to avoid irritation). There was no reported reaction to 2 -butoxyethanol or 2-(2-(2-butoxyethoxy)ethoxy)ethanolthe subject of this dossier) is expected to exhibit very similar toxicity in the patch tests whereas some of the other chemicals caused an adverse response.

Direct observations.

- In the experiment, human abdominal whole skin (dermis plus epidermis) samples were assessed in vitro. Skin samples were mounted in a glass diffusion apparatus that exposed 2.54 sq. cm of epidermal area for chemical absorbtion determinations. Samples were tested for integrity (tritiated water diffusion through the skin prior to exposure), diffusion of glycol ethers through the skin, and epidermal damage after chemical exposures (increase in tritiated water diffusion following exposure). The three compounds crossed human epidermis at molar rates 170-330 times slower than the corresponding monoethylene glycol ethers. The skin damage ratio for TGME, however, was comparable to that of ethylene glycol monomethyl ether, indicating that the diffusion barrier function of the skin was slightly diminished after 12 hours of exposure.

- In a suicide attempt, a 50-year woman ingested 250-500 ml of a window cleaner containing 12 % of 2 -butoxyethanol, corresponding to about 0.5 to 1 g/kg bw. On admission to the intensive care unit, the patient was comatose. Biochemically she presented with metabolic acidosis, hypokalaemia, a rise in serum creatinine level and a markedly increased urinary excretion of oxalate crystals. The patient made a full recovery after 7 days. Acute exposure of a human to 0.5-1g/kg of 2-butoxyethanol cause marked but fully reversible effects.

- A case history report described a 19 year old male who ingested between 2 -4.2g/kg of 2 -butoxyethanol in the form of a commercial degreaser preparation which also contained other chemicals such as monoethanolamine and potassium hydroxide. The patient exhibited neurotoxicity and acidosis and at one stage was considered critically ill. There was no evidence of renal or hepatic toxicity though. Some residual neurological deficits persisted after recovery from this severe intoxication but it was difficult to attribute this entirely to this substance as the patient was already on strong medication for depression, attention deficit hyperactivity disorder and post-traumatic stress disorder secondary to child abuse.

-A case report of a deliberate ingestion of a mixture containing 10-30 % of 2 -butoxyethanol was reported. A 51-year-old woman ingested 8 ounces of this mixture (corresponding to an estimate dose of 24-72g of EGBE and range of 0.4 – 1.2 g/kg bw) in a suicide attempt. Clinical symptoms were metabolic acidosis and mental status depression. The patient was treated with ethanol therapy and recovered without apparent sequelae. No signs of hematotoxicity were noticed.

-In an attempted suicide, a 23-year-old woman had ingested about 500 ml of a mixture containing 2 -butoxyethanol (2BE) (12.7 %) and of ethanol (3.2 %) (about 57 g of 2BE corresponding to a dose of about 1g/kg bw). Upon admission, the subject was in a comatose state, had breathing difficulties was in metabolic acidosis and had a 2BE blood concentration of EGBE 432 mg/l which fell to 302mg/l. 2 hr after admission. A fall in haemoglobin from 11.9 g/dl on admission to 8.9 g/dl on the second day, together with the appearance of haematuria was noticed. The half-life of 2BE in the blood was 210 min. Butoxyacetic acid concentration in the urine peaked 4 hr after dialysis treatment was initiated.

-A case study reported the findings from an 18 year old male who ingested on two separate occasions 360 -480mls of a glass cleaner containing 22% 2 -butoxyethanol. Approximately 10hrs after the first ingestion the patient developed severe CNS depression, metabolic acidosis, haematuria and mild elevation of hepatic enzymes. The second ingestion was approximately 10 days after discharge. Following this exposure, the patient failed to show the delayed severe CNS depression or profound metabolic acidosis. Clinically significant hemolytic anaemia, oxaluria, ethylene glycol production or renal problems were not present. The patient recovered without sequelae on both occasions.

-An examination of children poisoning looked at 24 cases over two years where 2 -butoxyethanol (2BE) ingestion occured through the accidental consumption of glass cleaners. The ingested cleaners contained 2BE in concentrations ranging from 0.5 % to 9.9 %. The child cases ranged from 7 months to 9 years old. The quantities ranged from 5 to 300 mL - 24 children. All the cases were asymptomatic on presentaion. In most cases treatment was by simple dilution and in only two was gastric lavage used. The authors concluded that a pediatric oral exposure to a dose of 1ml of 2BE did not require aggressive intervention.

- Repeat inhalation exposure to very high levels of methoxyethanol vapour at the workplace caused severe CNS depression and some evidence of adverse impact on haematologic parameters. In all 5 cases complete recovery was observed.

-A study using human volunteers showed that methoxyethanol is readily absorbed through the skin both as a vapour and liquid. Dermal uptake of vapour was estimated to account for up to 55% of total uptake. Dermal uptake of liquid is sufficiently great (2.9mg/cm2/hr) that exposure of even a relatively small area of skin for a short period of time (eg palm of hand for 15 mins) is likely to outweigh exposure by inhalation over a whole day.

- Repeat dermal contact to methoxyethanol by two male workers caused adverse but reversible changes to blood parameters and toxic encephalopathy.

- Repeat exposure of male workers to high concentrations of methoxyethanol (>25ppm) causes adverse effects on the blood. Thewhite blood cells are affected in all exposed individuals and the red blood cells in a significant minority. These adverse effects are thought to be due to toxicity to the bone marrow. Such exposures also caused toxic encephalopathy, manifest as tremors and lethargy, in a significant minority of those exposed.

- Accidental exposure of two adult males to a single oral dose of around 1300mg/kg caused weakness and nausea accompanied by respiratory distress. A marked metabolic acidosis developed plus marked oxaluria in one patient. Both patients made full and uneventful recoveries within 4 weeks.

- Repeat exposure of a male worker to airborne concentrations of methoxyethanol (average 35 ppm) and dermal contact through methoxyethanol soaked cleaning rags caused a depression in both wide and red blood cell counts and a macrocytic anaemia. This effect was reversed within 3 months of removing the individual from exposure.

Sensitisation data (humans).

-In a human volunteer insult patch test skin sensitisation study using 2 -(2 -ethoxyethoxy)ethanol, 25 healthy adult healthy volunteers were subjected to nine occlusive 48 -72hr patch applications of 0.02ml of test substance. This was followed by a resting period and a challenge patch to evaluate sensitisation potential. Under these experimental conditions, 2 -(2 -ethoxyethoxy)ethanol did not induce any primary or cumulative irritation, nor any cutaneous sensitisation reaction.

-In a very old study, 2 -(2 -ethoxyethoxy)ethanol was applied repeatedly to the forearms of human volunteers under non occlusive conditions for a period of 10 days. Repeated application of the test substance produced some evidence of a reversible irritant response in a small number of individuals but there was no evidence of a sensitisation response.

Exposure related observations in humans: other data

- In a 48hr occlusive patch irritation study in Japanese subjects, 0.05ml of 50% (w/w) 2 -(2 -ethoxyethoxy)ethanol induce irritation observed as erythema, edema or vesicles in most subjects. Similar results were seen with other tested substances such as propylene and dipropylene glycol.

-The substance 2-(2-(2-butoxyethoxy)ethoxy)ethanolis an analogue of the test substance used in the study of Shih TS, Hsieh AT, Liao GD, Chen YH, Liou SH , 2000.A study was carried out to examine the effect of occupational exposure to 2-methoxethanol on haematology and reproductive toxicity (specifically effect on sperm) found some evidence for depression of blood parameters (specifically erythropoietic effects). However, whilst there was statistically significant differences between control and exposed groups, average values at exposures of 4 to 4.3ppm remained within normal ranges. Significant differences seen in males were not seen in female groups and vica versa. Significant differences between the two populations (exposed and not exposed) was not always seen in analysis for trend. No effects were seen on sperm parameters.

- The substance2-(2-(2-butoxyethoxy)ethoxy)ethanolis an analogue of the test substance used in the study of Shih TS, Hsieh AT, Chen YH, Liao GD, Chen CY, Chou JS, Liou SH, 2003.

A study was carried out to examine the association between occupational full shift exposure and haematological effects and their reversibility before and after implementation of exposure risk reduction measures. 29 exposed and 90 none exposed workers were recruited. Whole shift personal exposures were measured and urinary levels of methoxyacetic acid where determined. Haematological parameters were assessed on blood samples taken at the end of the exposure periods (3 in a 6 month period). Exposure to 42ppm average levels of methoxyethanol produced significant changes to blood parameters. Many, but not all parameters showed recovery to normal levels when exposures had reduced to 2.65ppm and 0.55ppm. However, the study shows that the correlation between the exposed group personal monitoring air exposure values and the biological monitoring parameters was far from linear. In particular, whilst the air exposure values for the male exposed group dropped from 41.9ppm to 0.55ppm between the start and end of the study (~70 fold) , the level of methoxyacetic acid (MAA) measured in urine only fell from 57.7 to 13.5 mg MAA/g creatinine (~4 fold). Since the control group measurements were 0.19ppm and 1.02 mg MAA/g creatinine, this does suggest that a significant element of the internal dose resulted from internal exposure, especially in the August group. This means that this study cannot be reliably used to determine the no effect level for 2-methoxyethanol exposure in humans (using haematological parameters as the measure of effect.)