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

Acute Toxicity: inhalation

Administrative data

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 to 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. 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:

1996

Report date:

1996

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 3

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

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): D-(+)-2-(4-Hydroxyphenoxy)-Propionic acid
- Substance type: Pure test substance
- Physical state: Solid
- Analytical purity: 93.7% of active ingredient
- Impurities (identity and concentrations): no data

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- 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
- 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

Administration / exposure

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)

Results and discussion

Preliminary study:

no

Effect levels

Effect levels 1

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

Effect levels 2

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.

Any other information on results incl. tables

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)-, potassium salt (2R) (CAS 1184648-08-5) 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 K+ 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 potassium ions in the target substance, is expected to have limited toxicological consequences, since the quantity of K+ administered per hour during inhalation of a limit concentration (5000 mg/m3 of the target substance) amounts to approx. 99% of a non-lethal intravenous and ca. 58% of a lethal intravenous K+ infusion rate determined for KCl.

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

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The acute inhalation LC50 of potassium (R)-2-(4-hydroxy-phenoxy)-propionate 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. This is supported by another LC50 measurement reported in UBE Industries Ltd., Tokyo, Japan (2002): Safety Data Sheet of R-HPPA (CAS 94050-90-5), Version 1, 2002/07/15 with LC50 > 5.2 mg/L (inh. rat). Based on these findings and as the potassium content up to the limit value is expected to have limited toxicological consequences the substance is not classified for acute inhalation toxicity.