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EC number: 203-988-3 | CAS number: 112-59-4
OECD 422, diet: NOAEL = 300mg/kg (based on liver and body weight effects), Dow 2004
6 weeks, gavage: LOAEL 891mg/kg (based on reduced body weight), Eastman Kodak, 1982, RA substance DEGBE
OECD 408, drinking water, 90 -days: NOAEL = 250mg/kg (based on liver and body weight effects), Johnson et al. 2005, RA substance DEGBE
90 days, dermal: NOAEL = 2000mg/kg (highest dose tested), LOAEL for local effects = 200mg/kg, Auletta et al. 1993, RA substance DEGBE
5 weeks, vapour: NOAEC = 18ppm, app. 0.12mg/L (highest dose tested), Dow 1981, RA substance DEGBE
OECD 414, vapour, 90 days: NOAEC = 14ppm, app. 0.09 mg/L (highest dose tested), BASF 1992, RA substance DEGBE
OECD 413, vapour, 90 days: NOAEC = 41ppm, app. 0.25mg/L (based on liver and body weight effects), Dow, 1985, RA substance EGHE
Corrected for differences in molecular weight (146 vs. 190 g/mol) between EGHE and DEGHE results in a NOAEC for DEGHE of 0.33 mg/L.
Analyses of all test diets from the first mix of the main study revealed mean concentrations ranging from 92.5 to 104% of targeted concentrations.
Analyses of the low dose female and high dose male diets indicated that the diets were homogeneous. Analyses confirmed that the 10% premix was stable for 14 days and that the test diets were stable for 8 days at concentrations ranging from 0.120 to 0.359%, which encompass the range of dietary concentrations used in the study.
4 intubation errors reported in high dose, 2 in mid dose and one in low dose group. Top dose may have exceeded MTD.
In a 6 week sub-acute gavage study that broadly followed the standards for such tests pertaining at the time, standard toxicological end points were studied for rats in doses up to 3564mg/kg bw/day. Significant toxicity was seen in the high dose group, suggesting that the MTD may have been exceeded. The only effects seen in the low dose group were equivocal changes in the kidney (proteinaceous casts and hemosiderin) and changes attributed to the dosing method (stomach hyperkeratosis). Possible effects were reported on body weight reduction in this group (8%) but since there was some discrepancy in the reporting of this (other data indicated no significant change at the low dose) this could not be interpreted definitively. The lowest dose of 891mg/kg bw /day was therefore identified as a no effect level.
In a well reported 90 day sub-chronic guideline and GLP drinking water study, standard toxicological end points, supplemented by additional examinations, were studied for Fischer 344 rats in doses up to 1000mg/kg. Multiple, albeit mild, effects were seen in the high dose group. The only treatment related effect seen in the mid dose group were equivocal changes (decreases of around 2 -3%) in erythron (RBC count, Hgb and Hct) that were statistically significant to unusually high concurrent controls but within historical control ranges.
This dose level of 250mg/kg/day was therefore considered to be the no adverse effect level.
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.
Measured concentrations in atmosphere.
Aerosol particles were not detected in the inhalation atmosphere.
In a 90 day guideline and GLP inhalation study rats were exposed in 3 dose groups up to the maximum saturated vapour pressure of 2 -(2 -butoxyethoxyethanol). Satellite recovery groups were also included for all 3 dose groups and the controls. No adverse effects were seen in any dose group. The NOAEL was therefore 14ppm (94mg/m3), the maximum concentration tested.
Changes in males not deemed of toxicological significance as not associated with changed histology. However, since change in females was associated with histological change, this was deemed significant. However, it is difficult to postulate a toxic effect which would cause a liver increase in one sex and a decrease in the other. The authors postulated that the changes in females could be indicative of a minimal degreee of liver toxicity but could equally be secondary adaptive physiological responses not directly linked to treatment.
In a 5 week GLP inhalation study rats were exposed to a concentrations of 2 -(2 -butoxyethoxyethanol) up to and including the saturated vapour pressure. The only effect of note which was both statistically significant and biologically plausible was a slight increase (+6%) in liver weight in high dose females. Vacuolisation also occurred in the livers of these female animals, but this change was also seen in all control, low and mid dose animals. In the absence of further differences, the change in liver weight was considered adaptive. Additionally, inhalation exposure for 90-days did not lead to changes in female livers. The NOAEC was set to 18 ppm.
Females appeared to be more susceptible than males to concentration-dependent irritation at the application site. Effects at the highest dosage were desquamation, atonia, eschar and necrosis.
In a well conducted study designed to assess the sub-chronic and reproductive toxicity of 2 -(2 -butoxyethoxy)ethanol to rats, the test substance was administered by the dermal route for 13 weeks to the maximum practical concentration attainable of 2ml/kg. The only effect of note was dermal irritation at the site of repeated application which occured at all doses, albeit very slight at the low dose and only in males at towards the end of the study. Irritancy was more marked in females than males and produced some necrosis at the highest dose. There were no other adverse findings noted.
There is no sub-chronic or chronic study available for 2-(2-hexyloxyethoxy)ethanol (DEGHE). A Combined Repeated Dose Toxicity Study oral with the Reproduction/Developmental Toxicity Screening Test (OECD 422) was conducted with DEGHE (Dow, 2004). This study differs from a 90 d study according to OECD guidelines in the level of detail in the study design and in the group size. Although the exposure duration of an OECD 422 may be similar for female animals (54 days), it is shorter for the male animals and the level of information derived from the study is different to that from a 90 d study. To cover the endpoint "sub-chronic toxicity", a read-across was conducted to the related analogues ethylene glycol hexyl ether (EGHE) and diethylene glycol butyl ether (DEGBE). A read across justification document has been attached to the corresponding enpoints and to chapter 13.
Data generated with DEGHE
Dietary administration of 100, 300, or 1000mg/kg DEGHE to CD rats in a combined repeated dose / Reproduction toxicity screening test according to OECD guideline 422 resulted in slight treatment-related decreases in body weights of males and females given 1000 mg/kg/day(DOW, 2004). Decreased maternal body weights persisted throughout the gestation and lactation phases of the study. Females given 1000 mg/kg/day had treatment-related increases in serum ALT and ALP activities, along with increases in relative liver weight. These effects corresponded with treatment-related histopathologic changes in the liver that consisted of very slight panlobular hepatocyte hypertrophy. Males given 1000 mg/kg/day had treatment-related increases in relative liver weight, which corresponded with the histological alteration of very slight periportal hepatocyte hypertrophy. At 1000 mg/kg/day, other findings of lesser significance included slightly increased blood urea nitrogen and decreased absolute thymus weights in females, decreased urine pH and increased relative kidney weights in males. Additional histopathologic findings of minor toxicological significance at 1000 mg/kg/day included very slight diffuse acinar hypertrophy of the submandibular salivary gland in males, and very slight atrophy of the mesenteric adipose tissue in females. There were no adverse effects of DEGHE on neurological function.
Based on these results, the no-observed-effect level (NOEL) for general toxicity was 300 mg/kg/day.
Data generated with DEGBE
Sub-acute inhalation toxicity[SW1] was assessed in an older study comparable to OECD 412(DOW, 1981). 15 Fischer 344 rats per sex and dose were exposed for 5 weeks to 2, 6, and 18 ppm DEGBE vapour via whole body inhalation. Observations included body and organ weights, ophthalmoscopic examinations, haematology, clinical chemistry, urinalysis, gross, and histopathology. The only effect of note which was both statistically significant and biologically plausible was a slight increase (+6%) in liver weight in high dose females. Vacuolisation also occurred in the livers of these female animals, but this change was also seen in all control, low and mid dose animals. In the absence of further differences, the change in liver weight was considered adaptive. Additionally, inhalation exposure for 90-days did not lead to changes in female livers. The NOAEC was set to 18 ppm.
In a well-documented study similar to OECD 407, ten male rats per group received 891, 1781, or 3564mg/kg DEGBE via gavage on five days each week for six weeks(Eastman Kodak, 1982). Body weight, clinical signs, haematology, and clinical chemistry was assessed. A histopathologic examinations was performed. Six high dose animals died, four of these as a result of intubation errors. The total number of red blood cells, haemoglobin and mean corpuscular haemoglobin concentration were decreased in the mid and high dose animals, while the mean corpuscular volume and the mean corpuscular haemoglobin were increased. Liver and spleen weights were increased at the two highest doses, which was accompanied by read pulp hypocellularity in the four surviving high dose animals. There were no histopathological changes in the liver. There were discrepancies in the reported body weights. As a conservative approach, it is assumed that terminal body weight was reduced in all dose groups. The NOAEL is therefore below 871 mg/kg.
In a sub-chronic study according to OECD 413 and GLP, 10 Wistar rats per sex and dose were exposed to 2, 6, and 14 ppm DEGBE vapour(BASF AG, 1992)via whole body inhalation. Satellite recovery groups were also included for all 3 dose groups and the controls. No adverse effects were seen in any dose group. Liver weights were increased in the high dose recovery group males only. In the absence of histopathological changes and no effect on liver weight in all other groups or females, this change was not considered adverse. The NOAEL was therefore set to 14ppm (94mg/m3), the maximum dose tested.
A 90 day sub-chronic OECD408 guideline and GLP drinking water study was carried out using Fischer 344 rats using doses of 50, 250 and 1000mg/kg/day of DEGBE(Johnson, et al., 2005). End points studied included cage side and detailed clinical observations, body weight, food and water consumption, ophthalmic observations, haematology, clinical chemistry, urine analysis and neurobehavioural observations (functional observation battery). Sperm analysis was also performed. Multiple, albeit mild, effects were seen in body and organ weights, water and food consumption and in the haematology, clinical chemistry and urine analysis the high dose group. In the histopathology, the only finding attributed to treatment was in female livers in the high dose groups where slight or very slight lesions were recorded (foci of aggregates of macrophages/histiocytes, which are common in F344 rats and were observed in greater numbers in the high dose females). Very slight hypertrophy of periportal hepatocytes was also seen in 6 high dose females. No treatment related histopathological effects were found in the bone marrow or spleen in any cohort. The only treatment related effect seen in the mid dose group were equivocal changes (decreases of around 2 -3%) in erythron (RBC count, Hgb and Hct) that were statistically significant to unusually high concurrent controls but within historical control ranges. The mid dose level of 250mg/kg/day was therefore considered the no adverse effect level.
In a well conducted study designed to assess the sub-chronic and reproductive toxicity of DEGBE to SD male and female rats, the test substance was administered by the dermal route for 13 weeks at doses of 200, 600, 2000mg/kgbw/day (Auletta, et al., 1993). The top dose used was the maximum practical concentration attainable. The lower concentrations were diluted in water to give a constant application volume but the top dose was applied neat. 10 animals were used per sex per dose. The only significant effect of note was dermal irritation at the site of repeated application which occurred at all doses, albeit very slight at the low dose and only in males towards the end of the study. Irritancy was more marked in females than males and produced some necrosis at the highest dose. There were no other adverse findings noted. The NOAEL for local skin irritation was <200mg/kgbw/day. The NOAEL for all other effects was >2000mg/kgbw/day.
Data generated with EGHE
In a 90-day sub-chronic GLP inhalation study similar to OECD 413, 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 vapours of ethylene glycol hexyl ether at target concentrations of 0 (control), 20, 40, or 85 ppm(DOW, 1985). Exposure was followed by a four week recovery period for half the animals. Actual mean concentrations obtained for this study were 20, 41, and 71 ppm EGHE. Examinations included regular assessments of clinical signs, body weight, food consumption, and water consumption. Prior to sacrifice, blood and urine samples were collected and analysed.Gross examination and histopathology was performed. There were no histopathological changes caused by exposure to EGHE. 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). Body weights were significantly decreased for high and mid dose animals. Decreases in body weight and increases in female liver weights observed at 41ppm were considered to be adaptive (and not adverse) since there were no correlative changes in histopathology or serum chemistry. Liver weights were increased in a dose dependent manner and stayed elevated in the 71ppm group at the end of the recovery period. 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. This change was not seen after the recovery period. However, there was a statistically significant increase in gamma-glutamyl -transferase for the 71 ppm females at the end of the recovery period. The changes are difficult to interpret since levels of 3 out of 4 enzymes were decreased and only 1 out of 4 was increased. Based on these data, 41 ppm (245 mg/m3) is considered to be NOAEC.
Systemic effects were generic (body weight decrease, liver effects) and occured at high concentrations only. None of the studies presented above gives any indication that DEGHE causes specific target organ toxicity. Consequently, clasification for this endpoint is not required according to (CLP) Regulation (EC) No. 1272/2008.
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