Propanoic acid, 2-(4-hydroxyphenoxy)-, potassium salt (1:1), (2R)-

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

key study

Study period:

1988-02-02 to 1988-05-05

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study on structural analogue (free acid) according to OECD guideline. The fact that the study is used for read-across purposes triggers reliability rating 2.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(R)-2-(4-Hydroxyphenoxy)propanoic acid

IUPAC Name:

(R)-2-(4-Hydroxyphenoxy)propanoic acid

Constituent 2

Reference substance name:

Propanoic acid, 2-(4-hydroxyphenoxy)-, (2R)-

IUPAC Name:

Propanoic acid, 2-(4-hydroxyphenoxy)-, (2R)-

Constituent 3

Reference substance name:

94050-90-5

Cas Number:

94050-90-5

IUPAC Name:

94050-90-5

Constituent 4

Reference substance name:

(R)-2-(4-hydroxyphenoxy)propanoic acid

EC Number:

407-960-3

EC Name:

(R)-2-(4-hydroxyphenoxy)propanoic acid

IUPAC Name:

407-960-3

Details on test material:

- Name of test material (as cited in study report): Hydroxy-4 phénoxy-2 propionique acide H.P.P.A
- Molecular formula: C9H10O4
- Molecular weight: 182.17
- Physical state: fine white powder
- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Isomers composition: no data
- pH of 20% w/v suspension in 10% gum Arabic aqueous suspension: 2.7 at 21.6°C

Test animals

Species:

rat

Strain:

other: Ico rats: OFA.SD (IOPS Caw); Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 5-7 weeks
- Weight at study initiation: 195-218 g (males), 161-179 g (females)
- Fasting period before study: 15-20 hours
- Housing: Preliminary study: 2 per cage, polycarbonate cages type FI; main study: 5 per cage, polycarbonate cages type MI
- Diet (ad libitum): Rat-mouse pelleted complete maintenance diet, U.A.R. formule "A.04 CR" (U.A.R., Villemoisson sur Orge, 91360 Epinay sur Orge, France)
- Water (ad libitum): softened and filtered drinking water
- Acclimation period: minimum 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 30 - 70 % relative humidity
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12 hours

IN-LIFE DATES: From: 1988-02-02 To: 1988-02-24

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: gum Arabic, 10 % w/v aqueous dispersion

Details on oral exposure:

VEHICLE
- Concentration in vehicle: Preliminary study: 5, 10, and 20 % w/v suspension; main study: 20 % w/v suspension
- Amount of vehicle (if gavage): 10 ml/kg bw
- Justification for choice of vehicle: requested by study monitor
- Purity: no data
- pH of 20% w/v suspension in vehicle: 2.7
- pH of pure vehicle (10% w/v gum Arabic aqueous suspension): 4.4

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg bw

DOSAGE PREPARATION (if unusual): suspension maintained on magnetic stirrer

Doses:

Preliminary study: 500, 1000, 2000 mg/kg bw
Main study: 2000 mg/kg bw

No. of animals per sex per dose:

Preliminary study: 2
Main study: 5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: days -1, 1, 8, and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs (15 min, 1, 2, 4 h after application, then daily), body weight, macropathology (liver, heart, kidneys, lungs)

Statistics:

No calculation of LD50, since no mortalities were observed
Body weight: mean, standard variation, coefficient of variation; Student test to compare treated and control groups

Results and discussion

Preliminary study:

No mortality observed in either males or females (2 per sex) at 500, 1000, and 2000 mg/kg bw

Effect levels

Effect levels 1

Sex:

male/female

Dose descriptor:

LD0

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Effect levels 2

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Mortality:

none at any dose

Clinical signs:

No behavioral abnormalities detected throughout the 14-day observation period

Body weight:

Comparable to controls during the 14-day observation period

Gross pathology:

No macroscopic anomalies observed at terminal sacrifice

Any other information on results incl. tables

No deaths, clinical signs, or macropathological findings were observed in either sex at the limit test dose (2000 mg/kg bw) with the source substance, the free acid (R)-2-(4-hydroxyphenoxy)-propanoic acid (CAS 94050-90-5).

The acute oral toxicity of the target substance propanoic acid, 2-(4-hydroxyphenoxy)-, potassium salt (2R) (CAS 1184648-08-5) is determined by read-across from the limit test with the free acid. The analogue approach is based on the facts that source and target contain the identical molecular structure and the same functional groups (except the K+ counterion), form a pH-dependent equilibrium, and the salt is rapidly converted to the free acid under the acidic conditions in the stomach. Upon neutralization in the duodenum (with a large excess of sodium ions), source and target become fully indistinguishable in their bioavailability and metabolic fate.

The only difference, the presence of equimolar quantities of potassium ions in the target substance, is expected to have no toxicological consequences, since the quantity of K+ administered with a limit test dose (2000 mg/kg bw) of the target substance amounts to only 26% of a conservative estimate for the oral LD50 of potassium ions, derived from KCl data.

As a conclusion, the acute oral toxicity of propanoic acid, 2-(4-hydroxyphenoxy)-, potassium salt (2R) is estimated to be > 2000 mg/kg bw.

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The acute oral toxicity of potassium (R)-2-(4-hydroxy-phenoxy)-propionate is estimated to be > 2000 mg/kg bw by read across.