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Diss Factsheets

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Non-GLP, non-guideline animal experimental study, published in peer reviewed literature, minor restrictions in reporting but otherwise adequate for assessment. Read-across justification: The available toxicological data for the target and source substances is outlined in the data matrix (Annex I). The toxicological properties of the target substance are related mainly to acetic acid/acetate since the anhydride components of the substance are hydrolytically unstable. When the target substance comes in contact with water or moisture a complete hydrolysis will take place to form no other hydrolysis products than acetic acid/acetate and adipic acid. Thus, the use of data from acetic acid and adipic acid is justified to evaluate toxicological properties of the target substance. Furthermore, data from acetic anhydride is used in the assessment. Experimental data obtained with the source substances indicate that the substances has low oral (LD50 > 1780 – 3310 mg/kg bw) and inhalation (LC50 1680 - 7700 mg/m3) acute toxicity. Furthermore, the acetic acid and acetic anhydride are irritating to skin at concentration < 25% and corrosive to skin at ≥ 25%. Acetic anhydride and acetic acid are not tested for sensitisation due corrosive properties; adipic acid did not show any evidence of sensitising in an animal study. The source substances did not show positive response in genetic toxicity studies available. Repeated toxicity studies via oral route conducted for acetic acid showed NOAEL values ≥ 210 mg kg bw/day and via inhalation route for acetic anhydride 4.2 mg/m3.. Reproduction toxicity studies conducted for acetic acid did not show any adverse effects on reproduction at the highest concentration tested (1600 mg/kg bw/day).

Data source

Reference
Reference Type:
publication
Title:
On the pharmacokinetics of the ethanol metabolite acetate: Elimination from the blood and cerebrospinal fluid
Author:
Freundt KJ
Year:
1973
Bibliographic source:
Drug Res. 23: 949-951

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
The distribution and elimination kinetics of acetate were determined from concentrations in plasma and cerebral spinal fluid following single intravenous doses of sodium acetate.
GLP compliance:
not specified

Test material

Constituent 1
Reference substance name:
Sodium acetate
EC Number:
204-823-8
EC Name:
Sodium acetate
Cas Number:
127-09-3
IUPAC Name:
sodium acetate
Details on test material:
- Name of test material (as cited in study report): Sodium acetate, analytical grade (Merck, Darmstadt)
- No further details
Radiolabelling:
no

Test animals

Species:
dog
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight: 15-25 kg
- Diet: Altromin dry pellets ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- maintained under constant conditions

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
intravenous
Vehicle:
other: Ringer solution
Duration and frequency of treatment / exposure:
Single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
3-6mmol/kg
No. of animals per sex per dose / concentration:
Total of 5 (sex not reported)
Control animals:
no
Details on dosing and sampling:
The dose was injected into the left femoral vein at a rate of 48 mmol/min. Blood samples for the determination of acetate using an enzymic method were withdrawn from the right femoral vein.

Results and discussion

Preliminary studies:
Background concentrations of acetate in plasma and cerebral spinal fluid were determined in man, dog and rabbit. Concentrations (mean±SD) in plasma were 0.065±0.007 (n=9), 0.090±0.012 (n=15) and 0.088±0.022umol/mL (n=5) for man, dog and rabbit respectively; concentrations in cerebral spinal fluid were 0.091±0.007 and 0.089±0.013 in man and dog respectively.

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
At plasma pH (7.4) only about 0.23% of the acetate was unionised and able to permeate across a lipid barrier. Over a 60 min period during which plasma concentrations of acetate were maintained at 22 umol/mL, the maximum concentration in cerebral spinal fluid (CSF) was approximately 20x lower than in plasma; the permeability (min-1) for distribution from plasma into CSF was 0.002±0.0009. The elimination half life from CSF was 14.6± 5.9 min.
Details on excretion:
Elimination half lives were 3.0±0.5, 4.0±0.3, 4.1±0.4 and 5.0±0.5 minutes at doses of 3, 4, 5 and 6 mM/kg, respectively.

Metabolite characterisation studies

Metabolites identified:
no

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Acetate is rapidly eliminated. Elimination half lives were 3.0±0.5, 4.0±0.3, 4.1±0.4 and 5.0±0.5 minutes at doses of 3, 4, 5 and 6 mM/kg, respectively