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

Endpoint summary

Description of key information

Oral: LD50 [(R)-2-(4-hydroxyphenoxy)-propanoic acid] > 2000 mg/kg bw, rat, OECD 401, Lheritier 1988
Oral: LD50 [(R)-2-(4-hydroxyphenoxy)-propanoic acid] > 5000 mg/kg bw, rat, OECD 420, Henderson 1981
Inhalation: LC50 (4h) [(R)-2-(4-hydroxyphenoxy)-propanoic acid] > 1.84 mg/L, OECD 403, Young 1996

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

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 until 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 401. The fact that the study is used for read-across purposes triggers reliability rating 2.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

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
- Summary. Sprague-Dawley rats; however, Ico rats bred by Iffa-Credo are also reported as "Wistar/Furth/Ico strain" in the literature (Trouillas J, Girod C, Claustrat B, Cure M & Dubois MP (1982), Am J Pathology 109(1): 57 -70)
- Source: Iffa-Credo, Les Oncins, 69210 L'Arbresle, France
- 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

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

Preliminary study:

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

Sex:

male/female

Dose descriptor:

LD0

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Mortality:

none at any dose

Clinical signs:

other: No behavioral abnormalities detected throughout the 14-day observation period

Gross pathology:

No macroscopic anomalies observed at terminal sacrifice

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)-, sodium salt (2R) (CAS 133647-88-8) 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 Na+ 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 sodium ions in the target substance, is expected to have no toxicological consequences as sodium salts are typically less toxic in comparison to the free acids based on a comparison of data for sodium salts and the free acids of a number of simple organic acids and as the amount of Na+ applied in a limit test is still more than 5 times lower than the value derived from published LD50 values for NaCl.

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

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral toxicity of sodium (2R)-2-(4-hydroxyphenoxy)propanoate is estimated to be > 2000 mg/kg bw by read across.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Only two studies were available, which were carried out according to guidelines and under GLP.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Study period:

1995-09-22 until 1995-10-24

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study on structural analogue (free acid) according to OECD guideline 403. The fact that the study is used for read-across purposes triggers reliability rating 2.

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1150 (Acute inhalation toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd, CH-4415 Fuellinsdorf, Switzerland
- Strain: Albino Wistar rat, Han-Ibm (outbred), SPF quality
- Age at study initiation: Males 7 weeks, females 10 weeks
- Weight at study initiation: Males 180.0 - 190.9 g, females 180.6 - 185.2 g
- Fasting period before study: No
- Housing: in groups of 5, in Makrolon type-IV cages
- Diet: pelleted standard Kliba 343 rat maintenance diet ad libitum (Pelleted standard Kliba 343 rat maintenance diet ad libitum, Batch no 65/95, Kliba Muehlen A.G., CH-4303 Kaiseraugst, Switzerland)
- Water: community tap water Fuellinsdorf ad libitum
- Acclimation period: 18 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 40 - 70%
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 1995-09-22 To: 1995-10-24

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Remarks:

flow-past exposure

Vehicle:

clean air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Chamber design based on fluid dynamic modelling of test atmosphere flow; provides a constant stream of fresh test article past the animals' noses, to prevent rebreathing (Cannon WC, Blanton EF & McDonald KE (1983): The flow-past chamber: An improved nose-only exposure system for rodents, Am. Ind. Hyg. Assoc. J. 44(12): 923-928)
- Exposure chamber volume: not stated, low-volume tubular system
- Method of holding animals in test chamber: restraint tubes, to ensure nose-only exposure
- Source and rate of air: compressed air, 48 L/min
- Method of conditioning air: filtering
- System of generating particulates/aerosols: RBG-1000 aerosol generator feeding a micronising Jet-Mill; resulting aerosol passed through Ni-63 charge neutralizer
- Method of particle size determination: Mercer stainless-steel 7-stage cascade impactor (model 02-130, In-Tox Products Inc. Albuquerque, USA), flow rate 1 L/min; gravimetric determination of material deposited on each stage (weighing collector steel slips)
- Treatment of exhaust air: no data
- Temperature: 21.3 +/- 0.4 °C (HMI 32 Vaisala temperature + humidity indicator, N=10)
- Humidity: 19.6 +/- 5.1 % (HMI 32 Vaisala temperature + humidity indicator, N=10)
- Oxygen concentration 21.0 +/- 0.05 % vol (Oxopac RD, Draegerwerk Zurich, N=10)
- Pressure in air chamber: slightly positive

TEST ATMOSPHERE
- Nominal concentration: Weight loss of test substance piston in dust generator, divided by airflow: 9.67 mg/L air
- Gravimetric concentration: Sampling on Gelman A/E, 47 mm glass fiber filters in stainless steel Gelman (Ann Arbor, USA) filter sampling device, airflow 1.2 L/min: 1.86 +/- 0.31 mg/L air (N=4)
- Analytical concentration: Sampling glass fiber filters from gravimetric determination, extracted with 3 x 10 mL methanol, analyzed with HPLC: 1.84 +/- 0.31 mg/L air (N=4)
- Brief description of analytical method used: HPLC, Nucleosil C-18 AB 5 micrometer column, eluents: 0.2% phosphoric acid / acetonitrile (9+1 and 1+9, respectively), step gradient, detection: UV 280 nm, quantitation with 5-point calibration curve
- Samples taken from breathing zone: yes

VEHICLE
- none

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Cumulative weight % less than Effective Cut-off Diameters (ECD) plotted vs. ECD, analysis with probit software program (Biosoft, Cambridge, UK)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 4.67 +/- 2.85 micrometer

Analytical verification of test atmosphere concentrations:

yes

Remarks:

elution and HPLC quantitation

Duration of exposure:

4 h

Concentrations:

1.84 +/- 0.31 mg/L air, highest technically achievable concentration

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: mortality and clinical signs: hourly during exposure (grossly abnormal signs only, animals in restraint tubes), once after exposure, thereafter daily
- Frequency of weighing: days 1 (before exposure), 4, 8, 15 (day of necropsy)
- Necropsy of survivors performed: yes, lungs fixed by instillation (4% formaldehyde in neutral phosphate buffer), trachea, larynx and head with nasopharyngeal tissues fixed in same formaldehyde solution
- Other examinations performed: no organ weights, no histopathology

Statistics:

None (only one exposure concentration, no mortality observed)

Preliminary study:

no

Sex:

male/female

Dose descriptor:

LC0

Effect level:

1.84 mg/L air (analytical)

Based on:

act. ingr.

Exp. duration:

4 h

Remarks on result:

other: Highest technically achievable concentration

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 1.84 mg/L air (analytical)

Based on:

act. ingr.

Exp. duration:

4 h

Remarks on result:

other: Highest technically achievable concentration

Mortality:

None in either sex

Clinical signs:

other: None detected in any animal at any time point

Body weight:

Slight weight loss (<4 g) in some animals on day 4 (2/5 males, 1/5 female). Normal weight gain thereafter.

Gross pathology:

Several or isolated reddish foci on seminal vesicles in 3/5 males. No other macroscopical findings.

No deaths and no clinical signs were observed in either sex after 4 hours of inhalation exposure to the highest technically achievable concentration (1.84 +/- 0.31 mg/L air) of the source substance, the free acid (R)-2-(4-hydroxyphenoxy)-propanoic acid (CAS 94050-90-5).

The acute inhalation toxicity of the target substance propanoic acid, 2-(4-hydroxyphenoxy)-, sodium salt (2R) (CAS 133647-88-8) is determined by read-across from the limit inhalation 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 Na+ counterion), form a pH-dependent equilibrium, and both are rapidly converted to the sodium salt in plasma (due to the large excess of sodium ions), which makes both substances indistinguishable in their bioavailability and metabolic fate.

The only difference, the presence of equimolar quantities of sodium ions in the target substance, is expected to have negligible toxicological consequences, since the quantity of Na+ administered per hour during inhalation of a limit concentration (5000 mg/m3 of the target substance) is several times lower than Na+ taken up when reaching the LC50 value determined for NaCl.

As a conclusion, the acute inhalation LC50 of propanoic acid, 2-(4-hydroxyphenoxy)-, sodium salt (2R) is estimated to be > 1840 mg/m3.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute inhalation LC50 of sodium (2R)-2-(4-hydroxyphenoxy)propanoate is estimated to be > 1.84 mg/L based on read-across from the above study. But as there is no sign of any clinical effect at the highest technically achievable concentration in that test it is highly likely that the real LC50 level is even higher than the limit concentration for classification purposes. Based on these findings and as the sodium content up to the limit value is expected to have negligible toxicological consequences the substance is not classified for acute inhalation toxicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute toxicity of sodium (2R)-2-(4-hydroxyphenoxy)propanoate, (CAS 133647-88-8) was determined by read-across from acute toxicity studies conducted with the free acid, namely (R)-2-(4-hydroxyphenoxy)propanoic acid (CAS 94050-90-5).

 

Acute Oral Toxicity:

Two oral toxicity studies conducted according to guidelines and under GLP are available for the source substance, (R)-2-(4-hydroxyphenoxy)-propanoic acid (CAS 94050-90-5). For the purpose of classification and labelling, the most conservative value (Lheritier 1988) has been selected. The study is considered complete, reliable and adequate for the purposes of risk assessment, classification and labelling. The LD50 in male and female rats was determined to be >2000 mg/kg bw, since no mortality, clinical signs, or macropathological findings were observed in the limit test with the source substance, the free acid (R)-2-(4-hydroxyphenoxy)-propanoic acid.

The acute oral toxicity of the target substance propanoic acid, 2-(4-hydroxyphenoxy)-, sodium salt (2R) (CAS 133647-88-8) 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 Na+ 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 sodium ions in the target substance, is expected to have no toxicological consequences as sodium salts are typically less toxic in comparison to the free acids based on a comparison of data for sodium salts and the free acids of a number of simple organic acids and as the amount of Na+ applied in a limit test is still more than 5 times lower than the value derived from published LD50 values for NaCl.

As a conclusion, the acute oral toxicity of propanoic acid, 2-(4-hydroxyphenoxy)-, sodium salt (2R) is estimated to be≥2000 mg/kg bw. The value is carried forward for the purpose of risk assessment, classification and labelling.

 

Acute Inhalation Toxicity:

Only a single inhalation toxicity study conducted according to guideline OECD 403 and under GLP is available for the source substance, (R)-2-(4-hydroxyphenoxy)-propanoic acid (CAS 94050-90-5). The study is considered complete, reliable and adequate for the purposes of risk assessment, classification and labelling. The LC50 in male and female rats upon 4-hour nose-only exposure to the test substance dust was determined to be > 1.84 +/- 0.31 mg/L air (analytical, highest achievable concentration), since no mortality and no clinical symptoms were observed with the source substance, the free acid (R)-2-(4-hydroxyphenoxy)-propanoic acid.

The acute inhalation toxicity of the target substance propanoic acid, 2-(4-hydroxyphenoxy)-, sodium salt (2R) (CAS 133647-88-8) is determined by read-across from the limit inhalation 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 Na+ counterion), form a pH-dependent equilibrium, and both are rapidly converted to the sodium salt in plasma (due to the large excess of sodium ions) after uptake via the lungs, which makes both substances indistinguishable in their bioavailability and metabolic fate.

The only difference, the presence of equimolar quantities of sodium ions in the target substance, is expected to have negligible toxicological consequences, since the quantity of Na+ administered per hour during inhalation of a limit concentration (5000 mg/m3 of the target substance) is several times lower than Na+ taken up when reaching the LC50 value determined for NaCl.

As a conclusion, the acute inhalation LC50 of propanoic acid, 2-(4-hydroxyphenoxy)-, sodium salt (2R) is estimated to be > 1840 mg/m3. 

Justification for selection of acute toxicity – oral endpoint
For the purpose of classification and labelling, the most conservative value has been selected.

Justification for selection of acute toxicity – inhalation endpoint
Only one study was available, which was carried out according to guidelines and under GLP.

Justification for classification or non-classification

Acute Oral Toxicity

The key value selected for the acute oral toxicity, LD50 ≥ 2000mg/kg bw does not lead to classification, according to the criteria in Regulation (EC) No. 1272/2008, Annex I, Part 3, 3.1.2.

Acute Inhalation Toxicity

The key value selected for the acute inhalation toxicity, LC50 > 1.84 mg/L. Substances having an LC50 in the range from 1.0 to 5.0 mg/L are classified into Hazard Category 4 according to No. 1272/2008, Annex I, Part 3, 3.1.2., which may also be applicable for this test item. For classification purposes it should however be considered that there is no sign of any clinical effect at the highest technically achievable concentration of 1.84 mg/L in the respective test. Furthermore, the substance has no acute oral toxicity with a LD50 >5000 mg/kg in the oral toxicity study (Henderson 1981). Based on the evidence of very low acute toxicity and using expert judgment the substance is not classified for acute inhalation toxicity.

Acute Dermal Toxicity

No experimental data are available which are suitable for the purposes of classification and labelling.