Distillation residue, butyl alcohols production, rectification

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1996-12-31

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The need for further investigations is re-evaluated after registration when more information is expected to be available on the exposure pattern and on the properties of the target substance and potential analogue substances. Oncogenicity studies performed with the main constituent of the registered substance, 2-ethylhexanol. Studies performed with Fischer F344 rats and B6C3F1 mice followed the current U.S. EPA Good Laboratory Practice Guidelines. In the absence of proper toxicokinetic or metabolism study with the registered substance this study serves as a good surrogate studies: a) it represents the effects of the only identified and quantified consituent of the substance, since the consituents of this registered UVCB-substance cannot be recognized and its composition varies to the degree that composition cannot be fixed. b) studies have been performed following U.S. EPA Good Laboratory Practice. c) they provide information on metabolism and metabolites of 2-ethylhexanol and information what also is predicted to happen when this registered UVCB-substance is metabolized.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Prechronic toxicity studies on 2-ethylhexanol in F344 rats and b6C3F1 mice.

Author:

Astill B.D., K. Deckardt, Chr. Gembardt, R-Gingell, D.Guest, J.R. Hodgson, W.Mellert, S.R. Murphy and T.R. Tyler

Year:

1996

Bibliographic source:

Fundamental and applied toxicology 29, 31-39 (1996)

Report date:

1996

Reference 2

Reference Type:

publication

Title:

Oncogenicity testing of 2-ethylhexanol in Fischer 344 rats and B6C3F1 mice

Author:

Astill B.D., R. Gingell, D.Guest, J. Hellwig, J.R. Hodgson, K. Kuettler, W.Mellert, S.R. Murphy, R.L. Sielken jr and T.R. Tyler

Year:

1996

Bibliographic source:

Fundamental and applied toxicology 31, 29-41

Report date:

1996

Materials and methods

Objective of study:

metabolism

Principles of method if other than guideline:

Oncogenicity (76 weeks in mice, 104 weeks in rats) and subchronic studies (13 weeks both in mice and rats) also discussed and studied the metabolites of 2-ethylhexanol.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-ethylhexan-1-ol

EC Number:

203-234-3

EC Name:

2-ethylhexan-1-ol

Cas Number:

104-76-7

Molecular formula:

C8H18O

Details on test material:

- Name of test material (as cited in study report): 2-ethylhexanol
- Molecular formula (if other than submission substance): C8H18O
- Molecular weight (if other than submission substance): 130.23 g/mol
- Substance type: branched-chain primary alcohol
- Physical state: liquid
- Analytical purity: >99.0% purity (Gas chromatography)
- Stability: gas chromatographic analysis of dose samples indicated that under the conditions of dose formulation preparation and for the duration of the daily dosing period, the aqueous emulsion of 2-ethylhexanol was stable, homogenous, and within +-10% of nominal concentrations at all dose levels.Homogeneity ensured by 1-min high-speed sonication with ultra-turrax sonicator and maintained with magnetic stirring during dosing. Samples were prepared daily in batches of 150ml per study group.

Radiolabelling:

yes

Remarks:

1-14C

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test animal species: Fischer 344 rats and B6C3F1 mice

TEST ANIMALS
- Source:not disclosed, age: rats 33-35 days upon arrival, mice 43-44 days upon arrival.
- Age at study initiation: 42 days rats, 44 days mice
- Weight at study initiation: rats: males 103g (86-128) and females 81g (64-95), mice: males 23g (21-26) and females 19g (17-23)
- Fasting period before study: 16-20 hours
- Housing: following U.S. EPA GLP: rats housed singly in suspended stainless steel wire mesh cages and mice singly in plastic cages arranged in racks.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%):30-70
- Air changes (per hr): not disclosed
- Photoperiod (hrs dark / hrs light): 12 hours

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Remarks:

Cremophor EL

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): daily
- Mixing appropriate amounts with (Type of food): cavage solution in Cremophor LE
- Justification for vehicle choice: most stable dose formulation and minimized tract irritation and inflammation.

VEHICLE
- Justification for use and choice of vehicle (if other than water): not disclosed
- Concentration in vehicle: 11-day study: 1000 and 1500 mg/kg bw ; 13-week study: 25, 125, 250 and 500 mg/kg bw. Oncogenicity: rats 50, 150, 500 mg/kg bw and mice 0, 50, 200 and 750 mg/kg bw.
- Amount of vehicle (if gavage): 10ml/kg bw or 1ml in mice 3ml in rats (solution of 0,005% Cremophor EL)
- Lot/batch no. (if required):not disclosed
- Purity: not disclosed

HOMOGENEITY AND STABILITY OF TEST MATERIAL: see test material details.

Duration and frequency of treatment / exposure:

5 times a week

Doses / concentrations

Remarks:

Doses / Concentrations:
Prechronic: 11-day study 1000 and 1500 mg/kg bw 13-week study 25, 125, 250 and 500 mg/kg bw. Oncogenicity: rats 50, 150, 500 mg/kg bw and mice 0, 50, 200 and 750 mg/kg bw.

No. of animals per sex per dose / concentration:

Prechronic study: 10 males and females, rats and mice.
Oncogenic study: 50 males and females, rats and mice.

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

Not required

Results and discussion

Preliminary studies:

The target organs of 2-ethylhexanol in rodents are the liver, the kidney, the central nervous system and the mucosa of respiratory and gastrointestinal tracts, depending on the route of administration.

Main ADME results

Main ADME results 1

Type:

metabolism

Results:

54% recovered after 24 hours, 76% recovered within 4 days

Main ADME results 2

Type:

excretion

Results:

Metabolites excreted in urine were mostly glucuronides of oxidative products of 2-ethylhexanol

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Absorption was not studied but clearance in urine was reported to be 54% within 24 hours, absorption and metabolism must be fast.

Details on excretion:

Metabolites excreted in urine were mostly glucuronides of oxidative products of 2-ethylhexanol.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Metabolites excreted in urine were mostly glucuronides of oxidative products of 2-ethylhexanol (% of radiolabel in urine free, % as glucuronide):
2-ethylhexanoic acid (9%, 48%), 5-hydroxy-2-ethylhexanoic acid (4.2%, 2.0%), 6-hydroxy-2-ethylhexanoic acid (1.35%, 12.0%) and 2-ethyladipic acid (7.6%, 15.3%). Only traces of 2-ethylhexanol was found in urine.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results