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Description of key information

oral
no data available for 2-EHAc
Data from the analogous substance 2-ethylhexan-1-ol:
90 d rat, gavage: NOAEL = 250 mg/kg bw (due to reduced body weight, changed clinical chemistry parameters, organ weights and histopathological findings in higher doses; GLP, comp. to guideline; Astill 1996)
90 d mouse, gavage: NOAEL = 250 mg/kg bw (due to increased organ weights; GLP, comp. to guideline; Astill 1996)
2 yr rat, gavage: NOAEL = 150 mg/kg bw (due to changed body weight and organ weights and clinical signs in higher doses; GLP, comp. to guideline; Astill 1996)
1.5 yr mouse, gavage: NOAEL = 200 mg/kg bw (due to increased mortality and reduced body weight; GLP, comp. to guideline; Astill 1996)
dermal
12 d, rat, open (but immobilised during exposure): NOAEL >= 1070 mg/kg bw/day (Schmidt 1969)
inhalation
20 d rat, vapour: LOAEL = 7.5 mg/L (due to irreversible reduced ovary weights; Schmidt 1969; Val. 3)
Data from the analogous substance 2-ethylhexan-1-ol:
90 d rat, vapour: NOAEL >= 120 ppm = 0.64 mg/L (no effects observed; GLP, OECD 413; Klimisch 1998)

Key value for chemical safety assessment

Additional information

There were only a few limited informations available for the repeated dose toxicity of 2-EHAc itself. However, there were reliable data available from the structural analogon and potential metabolite 2-ethylhexan-1-ol (2 -EH) to assess the repeated dose toxicity of 2-EHAc.

oral

Two reliable subchronic oral gavage rodent studies on 2-EH are available, which were conducted similar to OECD TG 408 (i. e. EPA OTS 798.2650 (90-Day Oral Toxicity in Rodents)) and under GLP. They are reported in the publication of Astill (1996, rat and mouse) and in two study reports of BASF (BASF, 1991, rat, 3 month and BASF, 1991, mouse, 3 month). Local irritation caused forestomach inflammation in rats (and in mice, albeit the incidence and the severity were lower compared to rats). 2-EH was a peroxisome proliferator in rats, but not in mice. The NOEL was 125 mg/kg bw/day in rats and mice. The NOAEL was 250 mg/kg bw/day. Key findings of these studies are outlined below.

Rat study: 90-day oral gavage study using male and female Fischer F344 rats (10 animals per sex and dose) (Astill, 1996 and BASF, 1991, rat, 3 month). The test dose levels were 0, 25, 125, 250, and 500 mg/kg bw/day, based on the results of preliminary 11-day studies.Key results include:

·   Mortalities or clinical findings were not different from controls

·   Food consumption was comparable to controls

·   Body weight gain was reduced in the high dose groups, resulting in decreased terminal weights in males (-7%) and females (-6%); (both p<0.01)

·   Clinico-chemical changes were seen in high dose groups (males: total protein and albumin -13%; females: serum cholesterol -16%)

·   Hematology: reticulocytes were increased (25%) in high dose males and females

·   Organ weights: increased relative weights of liver, forestomach, and kidneys (p<0.01) in male and female groups at 250 and 500 mg/kg bw/day. No weight changes were noted at 25 and 125 mg/kg bw/day

·   Histopathology revealed changes only in high dose animals. Predominantly inflammatory changes in the forestomach which are attributable to the irritation properties of 2 -EH

·   2 -EH at 500 mg/kg bw/day caused peroxisome proliferation, as evidenced by a statistically significant increase of the hepatic cyanide-insensitive palmitoyl coenzyme A activity in male (p<0.001) and female (p<0.05) rats in Week 13

The subchronic NOEL (based on slight changes of relative organ weights) was 125 mg/kg bw/day in male and female rats.The NOAEL was 250 mg/kg bw/day.

Mouse study: 90-day oral gavage study using male and female B6C3F1 mice (10 animals per sex and dose) (Astill 1996 and BASF, 1991, mouse, 3 month). The test dose levels were 0, 25, 125, 250, and 500 mg/kg bw/day, based on the results of preliminary 11-day studies.Key results include:

·   No mortalities or clinical findings differing from controls

·   Food consumption and body weight gain was comparable to controls

·   There were no clinico-chemical or hematological changes at any dose level

·   Organ weight changes: relative weight of liver and forestomach was increased in males and females; a level of statistical significance (p<0.05) was gained in males at 250 and 500 mg/kg bw/day

·   Histopathology revealed slight acanthosis in the mucosa of forestomach in high dose animals (possibly attributable to the irritation properties of 2-EH)

·   2-EH was not a peroxisome proliferator in B6C3F1 mice at up to and including a dose of 500 mg/kg bw/day

The subchronic NOEL (based on slight changes of relative organ weights) was 125 mg/kg bw/day in male and female mice.The NOAEL was 250 mg/kg bw/day.

Based on the results of these subchronic toxicity studies, the dose for subsequent carcinogenicity studies was set at 50 mg/kg bw/day for the absence of treatment-related effects in rats and mice, and 500 and 750 mg/kg bw/day, respectively, in rats and mice as high doses producing minimal toxicity without altering the life span.

Detailed results of the chronic carcinogenicity studies in rats and mice are presented in section on carcinogenicity (IUCLID section 7.7). From these chronic studies a NOAEL for systemic toxicity of 200 mg/kg bw/d was derived for mice (based on increased mortality, reduced body weights, hepatotoxicity in the high dose group) and 150 mg/ kg bw/d for rats (based on increased mortality in the high dose group).

dermal

There is only a limited study available with basic information (Schmidt 1969). One hundred microliters of the undiluted test substance (2 -EHAc; technically pure) was applied twice daily for two hours to 12 cm2 skin areas of 12 albino rats (mean weight 163 g) for 10 days during a 12 day period. The treatment conditions were open, but the animals were immobilised during exposure. The dosage is conform to ca. 1070 mg/kg bw/day. After 28 days of observation animals were sacrificed and subjected to a gross necropsy. No adverse effects were observed and therefore the NOAEL is considered to be >= 1070 mg/kg bw/day.

inhalation

For 2-EHAc, there is only a subacute study available with basic information (Schmidt 1969) which was not conducted according to principles of current guidelines and thus considered not reliable.

Data were also available for the surrogate substance 2 -EH:

No treatment-related effects were noted in an OECD Guideline 413 study (Subchronic Inhalation Toxicity: 90-Day) conducted under GLP conditions and using male and female Wistar rats (10 rats per sex and dose). Exposure levels were 0, 15, 40, and 120 ppm. As there were no effects compared with the control groups in either sex on body weight or body weight gain, clinical signs of toxicity and mortality, haematological and clinical biochemistry parameters, ophthalmological parameters, absolute or relative organ weights including testes, or cyanide-insensitive palmitoyl-CoA oxidation as a parameter to measure hepatic peroxisome proliferation, the NOAEC was 120 ppm, ie. 638 mg/m³ (Klimisch, 1998).

Read across justification to 2-ethylhexan-1-ol for filling data gaps of 2-ethylhexyl acetate:

As indicated by toxicokinetic studies (see chapter on toxicokinetics, metabolism and distribution), 2-ethylhexyl acetate is rapidly hydrolyzed to 2-ethyhexan-1-ol and acetate (acetic acid). Available data on 2-ethyhexan-1-ol is therefore suitable for filling data gaps of 2-ethylhexyl acetate.

Justification for classification or non-classification

There is no study available to assess the repeated dose toxicity of 2 -ethylhexyl acetate. Thus, the data of the potential metabolite 2 -ethylhexanol were used for the assessment of repeated dose toxicity: the oral chronic NOAEL was 200 mg/kg bw in male and female mice in a 2-year carcinogenicity study, based on organ weight changes and mortality at higher doses. The oral subchronic NOAEL was 250 mg/kg bw in male and female Fischer F344 rats and B6C3F1 mice; based on local irritation of the forestomach and increased relative organ weights (stomach, liver in rats and mice; additionally brain, kidneys, testes in rats).

No treatment-related effects were noted in a OECD Guideline 413 study (Subchronic Inhalation Toxicity: 90-Day). The NOAEC was 120 ppm, i. e. 638.4 mg/m³ the highest concentration tested.

No reliable study with repeated dermal application is available.

According to the available test results for 2-EHAc and the analogous substance 2-ethylhexan-1-ol, 2-EHAc has not to be classified for its repeated dose toxicity following 67/548/EEC and GHS requirements, respectively.

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