2-phenoxyethanol

Endpoint summary

Description of key information

2-Phenoxyethanol displayed low acute oral toxicity in rats.
2-Phenoxyethanol displayed very low acute dermal toxicity tested in rats and rabbits.
2-Phenoxyethanol displayed no effects following inhalation exposure in rats.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

no

Remarks:

GLP was not compulsory at the time the study was performed

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): 2-phenoxyethanol (technical grade)
- Physical state: colourless liquid
- Analytical purity: ca. 80% 2-phenoxyethanol
- Composition of test material, percentage of components: 2-phenoxyethanol, (ca. 80% 2-phenoxyethanol, ca. 18% monophenyldiglycol, ca. 0.5% monophenyltriglycol)
- Lot/batch No.: substance number: 82/135
- Expiration date of the lot/batch: May 1983

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Germany
- Age at study initiation: ca. 12 weeks
- Weight at study initiation (mean): 188 g (males), 180 g (females)
- Fasting period before study: 16 h, but water was available
- Diet (e.g. ad libitum): conventional laboratory
- Water (e.g. ad libitum): drinking water
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 6.81, 14.70, 31.60, 50.00 %
- Amount of vehicle (if gavage): 10 mL/kg b.w.
- Other: 0.5 % aqueous carboxymethyl cellulose solution

Doses:

681, 1470, 3160, and 5000 mg/kg b.w.

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs (once daily)

Sex:

female

Dose descriptor:

LD50

Effect level:

1 840 mg/kg bw

95% CL:

1 010 - 2 960

Sex:

male

Dose descriptor:

LD50

Effect level:

4 070 mg/kg bw

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 740 mg/kg bw

95% CL:

1 910 - 4 050

Mortality:

All animals dosed with 681 mg/kg b.w. survived the 14 d observation period. All males survived a treatment of 1470 mg/kg b.w., whereas 2 out of 5 female rats died. At a dose level of 3160 mg/kg b.w., 2 males and 4 females died, respectively. At the highest dose level 3 male and all female animals died. In all treatment groups, the latest time point where death occurred was observation day 1. Generally females were more susceptible to 2-phenoxyethanol compared to males.
Increasing dose resulted in increased mortality.

Clinical signs:

other: Dyspnoea; apathy; abnormal position; staggering; atony; deficiency in pain and cornea reflex; coma-like state; spastic gait; rough fur; exsiccosis; exophthalmoses; general poor condition

Gross pathology:

Animals that died during the study course revealed following signs at necropsy:
Congestion; lungs which were slightly inflated; sporadically reddened glandular stomach

Dose [mg/kg b.w.]	Number of dead/ all animals were investigated	Time of death	Observations
Males
681	0	--	dyspnoea; apathy; abnormal position; staggering; atony; paresis
1470	0	--	dyspnoea; apathy; abnormal position; staggering; atony; deficiency in pain and cornea reflex; coma-like state;
3160	2	1 d	dyspnoea; apathy; abnormal position; staggering; atony; deficiency in pain and cornea reflex; coma-like state;
5000	3	1 d	dyspnoea; apathy; abnormal position; staggering; atony; deficiency in pain and cornea reflex; coma-like state; spastic gait; rough fur; exsiccosis; exophthalmoses; general poor condition
LD50value	4070 mg/kg b.w.
Females
681	0	--	dyspnoea; apathy; abnormal position; staggering; atony; paresis
1470	2	1 d	dyspnoea; apathy; abnormal position; staggering; atony; deficiency in pain and cornea reflex; coma-like state;
3160	4	1 d	dyspnoea; apathy; abnormal position; staggering; atony; deficiency in pain and cornea reflex; coma-like state;
5000	5	1 h (3 animals); 1 d (2 animals)	dyspnoea; apathy; abnormal position; staggering; atony; deficiency in pain and cornea reflex; coma-like state; exsiccosis; exophthalmoses; general poor condition
LD50value	1840 mg/kg b.w.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

CLP: acute toxicity Cat. 4

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 840 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

06 Sep 2005 - 17 Feb 2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: OECD 412

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Landesamt für Umwelt, Wasserwirtschaft und Gewerbeaufsicht, Mainz

Test type:

other: sub-acute inhalation toxicity

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): 2-phenoxyethanol
- Physical state: liquid/ colourless, clear
- Analytical purity: > 99.9 core peak-area% (GC)
- Lot/batch No.: 41183068E0
- Expiration date of the lot/batch:
- Stability under test conditions: The stability under storage conditions over the exposure period was guaranteed by the sponsor and the sponsor holds the responsibility
- Storage condition of test material: room temperature, under N2, in the dark

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany
- Age at study initiation: about 7 weeks
- Weight at study initiation: males: ca. 227 g, females: ca. 163 g
- Housing: animals were housed singly in makrolon-wire cages (type MD III, Becker & Co., Castrop-Rauxel, FRG (floor area about 800 cm²)
- Diet (e.g. ad libitum): milled mouse/rat laboratory diet “GLP”, (Provimi Kliba SA, Kaiseraugst, Basel Switzerland)
- Water (e.g. ad libitum): tap water
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 06 Sep 2005 To: 28 Sep 2005

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose/head only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Generator systems:
- Continuous infusion pumps PERFUSOR (B. Braun) for test group 1
- Piston metering pumps (Sarstedt DESAGA) for test group 2 and 3
- Two-component atomizers (stainless steel, Schlick mod. 970)
- Glass mixing stages (BASF)
- Glass cyclonic separators (BASF)

Generation procedure:
For each concentration the test substance was supplied to a two-component atomizer at a constant rate by means of a metering pump. The aerosol was generated with compressed air in a mixing stage with conditioned dilution air and passed via the cyclonic separator into the inhalation system. Due to the vapor pressure of the test substance, in all test groups mixtures of vapor and liquid aerosol are tested. The theoretical vapor concentration is up to 40 mg/m3.

TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.)
The target concentration of 40 mg/m3 in test group 1 was the saturation vapor concentration. At this concentration, part of the test substance might condensate in the atmosphere, thus liquid aerosols might be formed. To demonstrate the aerosol formation, two cascade impactor measurements were carried out. These resulted in MMADs between 2.9 and 3.7 μm with GSDs of 4.3 and 4.5. The amount of test substance that was trapped by the cascade impactor was approximately 20 % of that measured in the atmosphere, which was in the expected range for condensation effect. Due to the long sampling time (150 min), the condensation on the cascade stages during the sampling period might be much more pronounced in this group than in the other groups. Therefore, the particle size measurements in test group 1 were considered not to reflect the real particle size distribution, but to describe the liquid aerosol formation in the test atmosphere.
Cascade impactor measurements in the test groups 2 and 3 resulted in MMADs between 0.5 and 1.3 μm that were well within the respirable range. The calculated mass fractions of particles below 3 μm aerodynamic size ranged between 72.0 and 85.2%. The EACD (effective aerodynamic cut-off diameter 50%) of the last impactor stage is 1.2 μm. MMAD values below 1.2 μm are gained by extrapolation outside the effective measuring range of the impactor. Therefore the real value may lie between the calculated one and 1.2 μm.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

> 6 h

Remarks on duration:

6 hours per day, 5 days per week for 14 days (10 exposures)

Concentrations:

0, 40, 200, 1000 mg/m³ (nominal)
Measured absolute concentration (mean +/-SD): 48.2+/-4.8; 246+/-20; 1070+/-55

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days exposure period without post exposure observation period
- Frequency of observations and weighing: once each working day
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: examination of blood

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 1 000 mg/m³ air (nominal)

Mortality:

No deaths were recorded throughout the study up to and including the maximal dose.

Clinical signs:

other: In none of the test groups clinical signs of toxicity were observed.

Body weight:

Treatment related influence on body weight development or food consumption was found in the high concentration group on study day 7.

Gross pathology:

Clinical pathology examinations revealed no treatment-related changes in either males or females. 14 days of aerosol inhalation of the test substance led to histopathologic findings in the respiratory tract. The respiratory epithelium in the nasal cavity was the target tissue in high and mid concentration males and females. In the very anterior part signs of degeneration and metaplasia were noted, whereas in the more posterior parts hyperplasia was observed. Inflammatory cell infiltrates were seen in the mid and top concentration groups as a reaction to treatment. These findings are thought to be substance-related and the top concentration groups were slightly more affected. In the larynx (level I) in the area of the very sensitive epithelium at the base of the epiglottis, three male animals of the high concentration group showed a minimal to slight hyperplasia of the respiratory epithelium. This finding is also considered to be substance-related.

Other findings:

- Organ weights: In males of the mid and top concentration the absolute lung weight (up to 20.4%) and in males of the top concentration the relative lung weight (up to 19.3%) were statistically significantly increased.
- Histopathology: In the lungs there was an increase in thickness of small and terminal bronchi and increased numbers of mucous cells in larger bronchi of mid and top concentration males and females.
- Potential target organs: upper respiratory tract

Interpretation of results:

GHS criteria not met

Conclusions:

CLP: not classified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

1 000 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

according to guideline

Guideline:

other: Draft IRLG (Interagency Regulatory Liaison Group) Guidelines for Selected Acute Toxicity Tests (August. 1979)

Deviations:

no

GLP compliance:

no

Remarks:

GLP was not compulsory at the time the study was performed

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): 2-phenoxyethanol, "Cosmetical grade"
- Physical state: liquid
- Analytical purity: Not given, however assumed to be ca. 92% 2-phenoxyethanol, ca. 8% Diethylenglykolmonophenylether (cosmetical grade)
- Lot/batch No.: sample number: 2219-93

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Plummers Rabbit Ranch
- Weight at study initiation: 2500- 2780 g

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5-5.6 mL

Duration of exposure:

24 h

Doses:

2 mL/kg (corresponding to 2214 mg/kg bw; based on a density of 1.107 g/mL)

No. of animals per sex per dose:

4

Control animals:

no

Details on study design:

Test was performed on abraded skin only.
- Duration of observation period following administration: 14 days

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 214 mg/kg bw

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 214 mg/kg bw

Additional information

Oral:

In the key study, i.e. an oral toxicity study according to OECD 401 (BASF AG, 1982), 2 -phenoxyethanol showed low acute oral toxicity in the rodent species rat (LD50 female approximately 1840 mg/kg bw). Generally, males were less susceptible to 2-phenoxyethanol than females (LD50 male 4070 mg/kg). Administration of high oral doses to rats induced dyspnoea, apathy, abnormal position, staggering, atony, deficiency in pain and cornea reflex, coma like state, spastic gait, rough fur, exsiccosis, exophthalmoses and general poor condition. In the CLH report on the Proposal for Harmonised Classification and Labelling for Phenoxyethanol (June 2018), the LD50 values were corrected by the purity of the test substance (i.e. 80%), resulting in 1472 mg/kg for females and 3256 mg/kg for males or 2192 mg/kg bw for both gender combined.

In the second key oral toxicity study conducted according to OECD 401 (Sasol, 1983), the LD50 value for male and female rats was determined to be 1850 mg/kg bw. The purity of the test substance was > 99%.

In the CLH report on the Proposal for Harmonised Classification and Labelling for Phenoxyethanol (June 2018), the available data for the registered substance were assessed and also both key studies were taken into account. Two additional studies – included here as supporting studies – were also considered relevant. In the study carried out in 1980 (non-guideline and non-GLP) with Sprague Dawley rats, the LD50 was 1394 mg/kg bw in males and 2579 mg/kg bw in females (Hill Top Research Inc. 1980; 80-479-21). In the 1970s acute range-finding study (not guideline or GLP) in rats, the LD50 value of 1439 mg/kg bw given was for males and females combined (OECD SIDS 2004).

Overall, the results of these four studies give a range of LD50 values in rats between 1394 – 3256 mg/kg bw and were considered for classification and determination of the Acute Toxicity Estimate (ATE). The other oral acute toxicity studies in rats provided were considered to have at least some deficiencies in their reporting, making them less reliable for classification purposes. However, the LD50 values were considered as broadly in line with those of the described studies above.

The lowest LD50 value of 1394 mg/kg bw was  used as the Acute Toxicity Estimate (ATE).

 

Dermal:

There are two dermal acute toxicity studies with only basic data given. Based on these studies

2-phenoxyethanol has a low dermal toxicity: In rats, acute dermal toxicity was tested up to a concentration of 24575 mg/kg bw. In this test, mortalities occurred 21 to 48 h post-dosing (no further details given) (Davies 1970). The LD50 in rat was calculated to be 14391 mg/kg bw.

In rabbits, no mortality was noted at the limit dose of 2.0 mL/kg bw (corresponding to 2214 mg/kg bw) tested on abraded skin only (Doyle 1980). The only effect observed in two rabbits was a local erythema and desquamation at the dosing site, which was reversible within 3 days after dosing. Desquamation was observed in one rabbit from observation days 3-14. Thus, the LD50 was > 2214 mg/kg bw.

 

Inhalation:

Several acute Inhalation Risk Tests (IRT) of minor relevance were available. Rats were exposed to saturated vapour for 7 or 8 hours, respectively (BASF AG 1963, Union Carbide Corp., 1982). If the vapour pressure of 0.014 hPa, respectively 0.01 hPa both at 20°Care taken into account, this corresponds to an atmospheric concentration of 80 resp. 57 mg/m³ by calculation. No deaths or clinical signs were observed. The low inhalation toxicity of 2-phenoxyethanol in rat was confirmed by a Guideline subacute aerosol inhalation study performed according to GLP (BASF AG, 2007; 36I0498/01187). No mortalities were seen in rats head/nose only exposed up to a nominal dose of 1000 mg/m³ (1070 +/- 55 mg/m³ measured absolute concentration) for 14 days (6 hours per day, 5 days per week). No deaths were recorded and in none of the test groups were clinical signs of toxicity observed throughout the study up to and including the maximal dose (LC₅₀ ≥ 1000 mg/m³).

If one looks at analytically measured concentrations in the 14 day inhalation study in rats, the calculated values are in line with the 14 day NOAEC of 40 mg/m³ (nominal) respectively 48 mg/m³ analytically determined. At this concentration the vapour fraction was about 80% and the rest was aerosol. This allows the conclusion that the LC50 of phenoxyethanol vapour is clearly above the saturated vapour concentration at room temperature after a single 8 hour exposure and even if exposure is prolonged to 14 days.

Justification for classification or non-classification

Acute oral toxicity:

CLP: Cat. 4 / EU: Xn R22

In the CLH report on the Proposal for Harmonised Classification and Labelling for Phenoxyethanol (June 2018), the registered substance was determined to meet the criteria for classification in acute oral toxicity category 4 (300 < ATE ≤ 2000).

 

Acute dermal toxicity:

CLP: not classified / EU: not classified

 

Acute inhalation toxicity:

Testing up to 1000 mg/m3 displayed no effects.

CLP: not classified / EU: not classified

In the CLH report on the Proposal for Harmonised Classification and Labelling for Phenoxyethanol (June 2018), no classification of the registered substance is proposed for acute toxicity by the inhalation route, since the registered substance has not been tested above 1 mg/l and there were no deaths below this concentration.