Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
According to column 2 of Annex IX "Testing by the inhalation route is appropriate if:
— exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size."
Toxic effects in humans by inhalation of the substance are unlikely because the substance has a very low vapour pressure and the exposure of humans will be low.
Investigations are available that report a rather complete absorption of the test item after oral administration to mammals, see the records WHO 2003 in Section 7.1.1. It is generally accepted that absorption after inhalation exposure is at least that after oral exposure.
Investigations are available that report no relevant metabolisation of the test item after oral absorption. It is therefore concluded that rather the same amount of the test item will be present and will be distributed in the body when the oral or the inhalation route is chosen. Therefore no difference in the systemic toxicity is expected if the oral or the inhalation route is chosen.
The test item is not classified as irritant to eyes. In the acute inhalation toxicity test, only dyspnoea during and shortly after the exposure period (which is likely a sign of discomfort of the rats sitting in the inhalation tubes), and no macroscopic lesions were observed with aerosols of the test item. Therefore no relevant indications were obtained that the test item might cause local lesions to the mucosa of the respiratory tract.
The NOEC for the inhalation route can therefore be derived from the NOELoral, as described in the Guidance Document on Information Requirements Chapter R.8.4.2.
It is considered that this approach is sufficient for a risk assessment.
An inhalation animal experiment is therefore considered not to be justified.
In the ECHA Guidance on Info Requirements Part 7.a of August 2014, p. 294 it is stated "Concerning repeated dose toxicity testing the oral route is the preferred one. However, dependent on the physico-chemical properties of a substance as well as on the most relevant route of human exposure, the dermal or the inhalation route could also be appropriate as specified in REACH Annex VIII and IX."

Dose descriptors for the oral route were derived by a read-across procedure described in Section 7.5.1. These dose descriptors can be used to correct the starting point to obtain dose descriptors for the inhalation route. A read-across approach for the oral route and afterwards to adjust the starting point seems to be more advisable than to read-across directly to an inhalation toxicity study with the source molecule. See Section 3.4 in the document "Analogue approach for sodium phenoxyacetate", attached to the record "Read-across target. 90 day toxicity" in Section 7.5.1.

Cross-referenceopen allclose all
Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
other: compilation of data from the literature
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Objective of study:
absorption
excretion
metabolism
Qualifier:
no guideline required
Principles of method if other than guideline:
Survey and evaluation of the available literature.
The Committee evaluated 43 flavouring agents that are derivatives of phenethyl alcohol and phenoxyethyl alcohol . ... The group also includes four phenoxyethyl alcohol derivatives: phenoxyacetic acid (No. 1026), the sodium salt of a structurally related phenoxyacetic acid (No. 1029), a phenoxyethyl ester (No. 1027) and a phenoxyacetic acid ester (No. 1028). The evaluations were conducted with the Procedure for the Safety Evaluation of Flavouring Agents. None of these agents has previously been evaluated by the Committee.
GLP compliance:
not specified
Details on absorption:
Sodium phenoxyacetate (NaPhA) is easily soluble in water and it dissociates there to the toxicologically relevant anion phenoxyacetate (PhA-) and the physiologically occurring sodium ion.
From the Section on Absorption, distribution and excretion:
"When ingested in traditional foods, in foods to which they have been intentionally added or as hydrolysis products resulting from either condition, phenethyl and phenoxyethyl alcohols, phenylacetaldehyde and phenylacetic and phenoxyacetic acids are rapidly absorbed from the gastrointestinal tract. Once absorbed, the alcohols and aldehydes are rapidly oxidized to yield phenylacetic or phenoxyacetic acid derivatives, which are subsequently excreted in the urine, either free as in the case of phenoxyacetic acid or conjugated as in the case of phenylacetic acid (Williams, 1959; James et al., 1972; Sangster & Lindley, 1986; Hawkins & Mayo, 1986; Caldwell, 1987)."
"Phenoxyacetic acid was fed to male rabbits at a dose of 100–200 mg/kg bw, and some animals also received glycine in amounts corresponding to three equivalents of the acid. In this test, 44–72% of the phenoxyacetic acid was recovered unchanged in the urine within 6 h and 82–105% within 24 h. There was no evidence of conjugation with either glucuronic acid or glycine, even when the diet was supplemented with glycine. A rabbit that received an oral dose of 500 mg of the glycine conjugate of phenoxyacetic acid excreted 30% of the dose unconjugated in the urine after 18 h (Levey & Lewis, 1947).
In another study, 55% of an oral dose of an unspecified amount of phenoxyacetic acid was recovered in the urine of dogs and 61% in the urine of humans. No evidence for glycine or glucuronic acid conjugation was found (Thierfelder & Schempp, 1917)."
Conclusion:
Phenoxyacetic acid and sodium phenoxyacetate are easily and practically completely absorbed after oral administration. The common anion phenoxyacetate is excreted practically completely and unchanged in urine.
Details on excretion:
From the Section on Absorption, distribution and excretion:
"When ingested in traditional foods, in foods to which they have been intentionally added or as hydrolysis products resulting from either condition, phenethyl and phenoxyethyl alcohols, phenylacetaldehyde and phenylacetic and phenoxyacetic acids are rapidly absorbed from the gastrointestinal tract. Once absorbed, the alcohols and aldehydes are rapidly oxidized to yield phenylacetic or phenoxyacetic acid derivatives, which are subsequently excreted in the urine, either free as in the case of phenoxyacetic acid or conjugated as in the case of phenylacetic acid (Williams, 1959; James et al., 1972; Sangster & Lindley, 1986; Hawkins & Mayo, 1986; Caldwell, 1987)."
"Phenoxyacetic acid was fed to male rabbits at a dose of 100–200 mg/kg bw, and some animals also received glycine in amounts corresponding to three equivalents of the acid. In this test, 44–72% of the phenoxyacetic acid was recovered unchanged in the urine within 6 h and 82–105% within 24 h. There was no evidence of conjugation with either glucuronic acid or glycine, even when the diet was supplemented with glycine. A rabbit that received an oral dose of 500 mg of the glycine conjugate of phenoxyacetic acid excreted 30% of the dose unconjugated in the urine after 18 h (Levey & Lewis, 1947). "
"In another study, 55% of an oral dose of an unspecified amount of phenoxyacetic acid was recovered in the urine of dogs and 61% in the urine of humans. No evidence for glycine or glucuronic acid conjugation was found (Thierfelder & Schempp, 1917)."

Conclusion: PhAA is easily and practically completely absorbed after oral administration and is excreted practically completely and unchanged in urine (of rabbits).
Metabolites identified:
no
Details on metabolites:
From the Section on Absorption, distribution and excretion:
"When ingested in traditional foods, in foods to which they have been intentionally added or as hydrolysis products resulting from either condition, phenethyl and phenoxyethyl alcohols, phenylacetaldehyde and phenylacetic and phenoxyacetic acids are rapidly absorbed from the gastrointestinal tract. Once absorbed, the alcohols and aldehydes are rapidly oxidized to yield phenylacetic or phenoxyacetic acid derivatives, which are subsequently excreted in the urine, either free as in the case of phenoxyacetic acid or conjugated as in the case of phenylacetic acid (Williams, 1959; James et al., 1972; Sangster & Lindley, 1986; Hawkins & Mayo, 1986; Caldwell, 1987)."
"Phenoxyacetic acid was fed to male rabbits at a dose of 100–200 mg/kg bw, and some animals also received glycine in amounts corresponding to three equivalents of the acid. In this test, 44–72% of the phenoxyacetic acid was recovered unchanged in the urine within 6 h and 82–105% within 24 h. There was no evidence of conjugation with either glucuronic acid or glycine, even when the diet was supplemented with glycine. A rabbit that received an oral dose of 500 mg of the glycine conjugate of phenoxyacetic acid excreted 30% of the dose unconjugated in the urine after 18 h (Levey & Lewis, 1947). "
"In another study, 55% of an oral dose of an unspecified amount of phenoxyacetic acid was recovered in the urine of dogs and 61% in the urine of humans. No evidence for glycine or glucuronic acid conjugation was found (Thierfelder & Schempp, 1917)."

Conclusion: PhAA is easily and practically completely absorbed after oral administration and is excreted practically completely and unchanged in urine (of rabbits).

Cited reports and publications:

- Caldwell, J. (1987) Human disposition of [14C]-ORP/178. Unpublished report. Private communication. Submitted to WHO by Flavor and Extract Manufacturers’ Association of the United States.Cited by WHO 2003.

- Hawkins, D.R. & Mayo, B.C. (1986) Plasma kinetics of [14C]-ORP/178 in the rat. Unpublished report. Private communication. Submitted to WHO by Flavor and Extract Manufacturers’ Association of the United States.Cited by WHO 2003.

- Howes, D. Absorption and metabolism of 2-phenoxyethanol in rat and man. Cosmet.Toiletries, 103, 75, 1988. Cited by WHO 2003.

- James, M.O., Smith, R.L., Williams, R.T. & Reidenberg, M. (1972) The conjugation of phenylacetic acid in man, sub-human primates and some non-primate species. Proc. R. Soc. London B, 182, 25–35.Cited by WHO 2003.

- Levey, S. & Lewis, H.B. The metabolism of phenoxyacetic acid, its homologues, and some monochlorophenoxyacetic acids. New examples of oxidation. J. Biol. Chem., 168, 213–221,1947. Cited by WHO 2003.

- Sangster, S.A. & Lindley, M.G. (1986) Metabolism and excretion of ORP/178 in man. Unpublished report. Private communication. Submitted to WHO by Flavor and Extract Manufacturers’ Association of the United States.Cited by WHO 2003.

- Thierfelder, H. & Schempp, E. Behaviour of benzoylpropionic acid, phenethyl alcohol and phenoxyacetic acid in the body of men and dogs. Arch. Ges. Physiol., 167, 280–288, 1917. Cited by WHO 2003.

- Williams, R.T. Book: Detoxication Mechanisms - The Metabolism and Detoxication of Drugs, Toxic Substances and Other Organic Compounds, 2nd Ed., London, Chapman & Hall. 1959. Cited by WHO 2003.

Executive summary:

From WHO 2003, Section on Absorption, distribution and excretion:

"When ingested in traditional foods, in foods to which they have been intentionally added or as hydrolysis products resulting from either condition, phenethyl and phenoxyethyl alcohols, phenylacetaldehyde and phenylacetic and phenoxyacetic acids are rapidly absorbed from the gastrointestinal tract. Once absorbed, the alcohols and aldehydes are rapidly oxidized to yield phenylacetic or phenoxyacetic acid derivatives, which are subsequently excreted in the urine, either free as in the case of phenoxyacetic acid or conjugated as in the case of phenylacetic acid (Williams, 1959; James et al., 1972; Sangster & Lindley, 1986; Hawkins & Mayo, 1986; Caldwell, 1987)."

"Phenoxyacetic acid was fed to male rabbits at a dose of 100–200 mg/kg bw, and some animals also received glycine in amounts corresponding to three equivalents of the acid. In this test, 44–72% of the phenoxyacetic acid was recovered unchanged in the urine within 6 h and 82–105% within 24 h. There was no evidence of conjugation with either glucuronic acid or glycine, even when the diet was supplemented with glycine. A rabbit that received an oral dose of 500 mg of the glycine conjugate of phenoxyacetic acid excreted 30% of the dose unconjugated in the urine after 18 h (Levey & Lewis, 1947). "

"In another study, 55% of an oral dose of an unspecified amount of phenoxyacetic acid was recovered in the urine of dogs and 61% in the urine of humans. No evidence for glycine or glucuronic acid conjugation was found (Thierfelder & Schempp, 1917)."

Conclusion: Phenoxy acetic acid and sodium phenoxyacetate are easily and practically completely absorbed after oral administration. The common anion phenoxyacetate is excreted practically completely and unchanged in urine (of rabbits).

Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2002
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The source study is a reliability 2 study, and the analogue approach is transparent.
Justification for type of information:
The sodium phenoxyacetate metabolic pathway analogue approach is presented.
The description of this analogue approach - in a more extensive and structured form - is attached.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
1.1. Analogue Hypothesis
The target substance (to be registered) is sodium phenoxyacetate (NaPhA). The source substance is phenoxyethanol. Phenoxyethanol is the metabolic precursor of phenoxyacetate.
The hypothesis is that systemic toxicity caused by oral dosing of PhE to mammals comprise at least the toxicity that would be obtained after oral dosing of NaPhA. The dose descriptor NOAEL for PhE can be transcribed as a worst case to NaPhA.
For more details see the attached justification.

1.2. Applicability domain (AD) of the analogue approach
The approach is suitable for read-across of systemic effects observed in toxicity studies with mammals. Primarily oral toxicity studies are concerned, 1) because the practically complete absorption of the source and the target substance is known, and 2) because haematotoxicity, caused by the not yet metabolised source substance PhE, was observed especially after dermal exposure to rabbits.
The applicability of the approach to toxicity endpoints using the dermal or the inhalation route needs some caution.

The read-across approach is not suitable for ecotoxicity endpoints, because PhE is readily biodegradable to CO2 in aqueous media and no stable metabolite PhA- is formed in ecosystems as in the case of mammalian systems.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Sodium phenoxyacetate
Synonyms: Acetic acid, 2-phenoxy-, sodium salt (1:1); etc.
Abbreviated to: NaPhA (or NaPhAA)
CAS-No.: 3598-16-1
Molecular Formula: C8H7NaO3
Molecular mass: 174.13
Smiles Code: c1(OCC(=O)[O-])ccccc1.[Na+]
Physical state: Solid.

Phenoxyacetic acid
Abbreviated to: PhAA
CAS: 122-59-8
Molecular formula: C8H8O3
Molecular mass: 152.149
SMILES: O=C(O)COc1ccccc1
Physical state: Solid.

NaPhA and PhAA are dissociated in water at pH > ca. 4. Therefore the common anion phenoxyacetate (PhA-) and the cations Na+ and H+ also occur.

Phenoxyethanol
Synonyms: 2-phenoxyethanol; ethyl glycol monophenol ether; ethylene glycol monophenyl ether; phenoxytol; 1-hydroxy-2-phenoxyethane; (2-hydroxyethoxy) benzene
Abbreviated to: PhE; (PE)
CAS-No.: 122-99-6
Molecular Formula: C8-H10-O2
Molecular mass: 138.165
Smiles Code: c1(ccccc1)OCCO
Physical form: Oily, slightly viscous liquid at room temperature

2.1. Purity / Impurities
- NaPhA: The registered substance has a purity >96 %. Impurities are sodium chloride and water. Purity is therefore not a relevant factor for the analogue approach, to provide data for systemic toxicity endpoints only.
- PhAA: Purity is not relevant, as PhA- is the major metabolite of PhE and no studies will be proposed with PhAA. Purity is therefore not a relevant factor for the analogue approach.
- PhE: The analytical purity of the test substances used for the key studies on repeated dose toxicity and developmental toxicity were 99.9 % or above. The purity is considered high enough to not impede the analogue approach.


3. ANALOGUE APPROACH JUSTIFICATION
Supporting physical-chemical properties, toxicokinetics and metabolism of the analogues
For more details see the attached justification.
Conclusion:
Phenoxyacetic acid and sodium phenoxyacetate are easily and practically completely absorbed after oral administration. The common anion phenoxyacetate is excreted practically completely and unchanged in urine.
Phenoxyethanol PhE is rapidly and rather completely absorbed after oral dosing. PhE is rapidly metabolised predominantly to PhA- and rapidly excreted mainly as unchanged PhA-. More than 90 % of an oral dose of 2-phenoxyethanol was excreted in the urine of rats as phenoxyacetic acid within 24 h.
PhE is well absorbed through the skin, but not completely. Remarkable is that PhE is metabolised to PhA- after dermal exposure slower and to a lower extent than after oral exposure, which is explained by an extensive first-pass metabolism in the liver. The slower and lower metabolisation of PhE with the dermal route is explaining the qualitatively different toxic effects (haematotoxicity) observed by action of the unmetabolised PhE after dermal application (compared to the oral route), especially in the rabbit.


Analogue approach for the oral route
For more details see the attached justification.
A NOAEL of 369 mg PhE / kg bw (taken from the Japanese 90-day oral key study for rats, MHLW 2003) can be used to read-across to the worst case NOAEL of 376 mg NaPhA / kg bw.
The overall transcription factor is 1.15 if the unit 'mg test substance per kg body weight' is selected.

4. DATA MATRIX
A data matrix is not relevant for this metabolic pathway analogue approach, because the molecule PhE and the anion PhA- are related by metabolism and not by chemical structure or molecular weight or by common physico-chemical properties.
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Species:
rat
Route of administration:
oral: drinking water
Key result
Dose descriptor:
NOAEL
Effect level:
376 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
haematology
histopathology: non-neoplastic
Remarks on result:
other: The NOAEL of 369 mg/kg/d was transcribed to the NOAEL of the target substance by applying a transcription factor of 1.02. See the attached analogue approach.
Dose descriptor:
NOAEL
Effect level:
665 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
haematology
histopathology: non-neoplastic
Remarks on result:
other: The NOAEL of 369 mg/kg/d was transcribed to the NOAEL of the target substance by applying a transcription factor of 1.02. See the attached analogue approach.
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
10 000 other: mg PhE/L drinking water
System:
urinary
Organ:
bladder
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
10 000 other: mg PhE/L drinking water
System:
haematopoietic
Organ:
erythrocyte development
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Conclusions:
A read-across from the toxicity results of the substance 2-phenoxyethanol to the target substance sodium phenoxyacetate was performed. A NOAEL for an oral 90-day toxicity study with rats of 376 mg sodium phenoxyacetate per kg body weight and day was obatined.
Executive summary:

A read-across from the toxicity results of the substance 2-phenoxyethanol to the target substance sodium phenoxyacetate was performed. A NOAEL for an oral 90-day toxicity study with rats of 376 mg sodium phenoxyacetate per kg body weight and day was obtained.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion