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Administrative data

Description of key information

In subchronic feeding studies, NOAEL's of approximately 200 and 300 mg/kg/day were established for mice and rats, respectively. Exposure to higher concentrations of 2-EHA was associated with growth retardation, increased liver weight and hepatocyte hypertrophy. In addition, in the highest dose groups decreased food consumption and body weights were observed. At the end of the recovery period (4 weeks), the observed changes had practically disappeared.

Key value for chemical safety assessment

Additional information

In an oral repeated dose toxicity study with B6C3F1-mice (CMA, 1988; similar to OECD 408), groups of ten male and female animals were administered feed containing 0, 0.1, 0.5 or 1.5% (males: 0, 180, 885, 2728 mg/kg bw; females: 0, 205, 1038, 3139 mg/kg bw) 2-EHA for 91-93 consecutive days. Additional groups were assigned to satellite recovery groups and were fed diets containing either 0 or 1.5% 2-EHA for 93 days and then were offered standard diets for 28-29 days. Clinical abnormalities were restricted to alopecia, which was considered unrelated to consumption of the test substance. Body weights were reduced in both males and females in the 1.5% dietary group from the first week through study termination. By day 91, weights were reduced 5% in males and 14% in females. The lower body weights in the 1.5% dietary group paralleled reductions in feed consumption. Feed consumption and body weights were not affected in groups of animals consuming either 0.1% or 0.5% diets. Cholesterol levels were increased among groups of both males and females consuming the 0.5% and 1.5% diets (67% and 25% for the 1.5% and 0.5% males and 77% and 19% for the 1.5% and 0.5% females), while triglyceride levels were reduced to 40% of the control level for 1.5% males and to 17% and 82% of the control for the 1.5 and 0.5% females. Alanine aminotransferase levels were significantly increased (36%) in males consuming the 1.5% diets, but were not associated with any other hepatic enzyme levels. Urea nitrogen was increased 36% for the 1.5% female group, but was lower for all groups of males, and was not associated with any histologic findings. Bilirubin was decreased between 33 and 54% for 0.5% females and the 1.5% males and females. No other significant changes in any clinical chemistry parameter were noted in any group of either males or females. Enlargement of the liver was seen in animals from the 0.5 and 1.5% dose groups. Absolute liver weights in animals fed 1.5% diets were increased 44% in males and 36% in females. At the 0.5% dietary level, liver weights were slightly increased (13%) in males only. When liver weights were expressed relative to body weight, the increases were more pronounced at the 1.5% dietary level (71% in males, 49% in females) due to lower terminal body weights in those groups. Relative to body weight, 0.5% males and females had livers which were 10% and 19% heavier than those in the control group. Other statistically significant changes in absolute or relative organ weights in the 1.5% and 0.5% dietary groups were related to growth retardation early in the animals’ lives or to organ sparing in animals with lower body weights. Histopathology examination of livers revealed hypertrophy of hepatocytes, a decrease in basophilic granularity causing the hepatocytes to appear more eosinophilic, and a decreased incidence of cytoplasmic vacuolization within hepatocytes in animals from the 1.5% and 0.5% dietary groups. Hypertrophy was seen in 10/10 1.5% males, 10/10 1.5% females, and 6/10 0.5% males. Reduction in hepatocyte cytoplasmic vacuolization was seen at the 1.5% and 0.5% dose levels; incidences at 1.5% were 1/10 in both sexes, and 7/10 in males and 5/10 in females at the 0.5% level. Incidence was 10/10 for both control and 0.1% males and females. Renal effects detected histologically included minimal increases in cytoplasmic basophilia of proximal convoluted tubules, absence of brush borders, and enlarged nuclei. These effects were seen only in males at the 1.5% level. Gastric effects included acanthosis and hyperkeratosis of the non-glandular forestomach in 6/10 1.5% male animals. Toxicity seen following 91-94 days of consumption of diets containing 2-EHA was in most instances reversible within 28 days of recovery. In the 1.5% recovery males, cholesterol values were not statistically different from the control group, while somewhat lower values were seen in bilirubin (20%) and triglycerides (27%) in recovery animals relative to control. There were no differences in absolute liver weight following recovery. Slightly increased relative liver weights in the 1.5% female recovery group reflected lower terminal body weights. Histopathology changes observed after 90 days were reversed. Liver effects were restricted to minor hepatocyte hypertrophy in one recovery male and one recovery female. No substance-related renal or gastric effects were observed in recovery groups. Based on this findings, the NOAEL was 0.1% for males and females (ca. 180 and 205 mg/kg bw).

 

In another oral repeated dose toxicity study similar to OECD 408 (CMA, 1988), groups of ten male and female F344 rats were administeredfeed containing 0, 0.1, 0.5 or 1.5% (males: 0, 61, 303, 917 mg/kg bw; females: 0, 71, 360, 1068 mg/kg bw) 2-EHA for 91-93 consecutive days. Additional groups were assigned to satellite recovery groups and were fed diets containing either 0 or 1.5% 2-EHA for 94 days and then were offered standard diets for 27-28 days. Clinical abnormalities during this study consisted of porphyrin tears, porphyrin nasal discharge, alopecia, and urine-stained hair. These abnormalities were transient and were observed without relationship to treatment group. Body weights were reduced in both males and females in the 1.5% dietary group from the first week through study termination. By day 91, weights were reduced 8% in males and 10% in females. The lower body weights in the 1.5% dietary group paralleled reductions in feed consumption. Urine volumes were reduced in females at all treatment levels and specific gravity was increased only in females following consumption of the 1.5% diet. Minor hematological differences involving red blood cells included lower mean corpuscular haemoglobin (1.5% males and females and 0.5% males), mean corpuscular volume (1.5% females), and haemoglobin concentration (0.5% females). None of the changes were accompanied by evidence of anemia. Cholesterol levels were increased among groups of males in a dose-dependent manner (25, 42, and 78% for the 0.1, 0.5, and 1.5% dietary groups, respectively). Increases were also seen for 1.5% males in urea nitrogen (29%) and albumin (16%). Absolute liver weights in animals fed 1.5% diets were increased 32% in males and 19% in females. At the 0.5% dietary level, liver weights were increased 6-7% in both sexes. When liver weights were expressed relative to body weight, the increases were more pronounced at the 1.5% dietary level (44% in males, 33% in females) due to lower terminal body weights in those groups. Relative to body weight, 0.5% males and females had livers which were 6% and 8% heavier than those in the control group. Histopathology examination of livers revealed hypertrophy of hepatocytes and a decreased incidence of cytoplasmic vacuolization within hepatocytes in animals from the 1.5% and 0.5% dietary groups. Hypertrophy was seen in 10/10 1.5% males, 10/10 1.5% females, and 8/10 0.5% males. Reduction in hepatocyte cytoplasmic vacuolization was seen in 1.5% and 0.5% males and 1.5% females; incidences in these groups were 0-2 of 10 compared to 6 to 7 of 10 in respective control groups. Absolute kidney weights were not altered by treatment, but kidney weights relative to body weight were increased 5-13% in the 1.5% male and female groups and the 0.5% female group. Minor increases in relative weight of brain, adrenals and testes in 1.5% animals reflected lower terminal body weights in that group. No renal effects were detected histologically. Toxicity seen following 91-94 days of consumption of diets containing 2-EHA was reversible within 28 days of recovery. Histopathology findings in recovery animals were restricted to minimal bile duct hyperplasia in both control and treatment animals. Hepatocyte hypertrophy and decreased hepatocyte vacuolization, both of which were seen in non-recovery animals, were not observed in recovery animals. No substance-related renal effects were observed in recovery groups. Based on the observed effects, the NOAEL was 0.5% for males and females (ca. 303 and 360 mg/kg bw).

Justification for classification or non-classification

Based on the available data, classification for repeated dose toxicity is not warranted according to EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.