2-methyl-4-phenylbutan-2-ol

Endpoint summary

Description of key information

Acute oral toxicity: LD50 (female) = >2000 mg/kg bw (OECD 425/GLP)

Read-across to PEA (CAS No. 60 -12 -8) - Acute inhalation toxicity: LC50 male/female = > 4.63 mg/L (nominal concentration) (Equivalent or similar to OECD 403/GLP)

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

Study period:

09 June 2017 to 27 October 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

GLP compliance:

yes (incl. QA statement)

Test type:

up-and-down procedure

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Yinghai (Cangzhou) Aroma Chemical Company Ltd.;CP008-170101
- Expiration date of the lot/batch: 30-06-2018
- Purity: 99.7%

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: INTOX PVT. LTD.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 9 to 11 weeks
- Weight at study initiation: 181 g to 194 g
- Fasting period before study:
- Housing: Animals were housed in room number AR-06, in the experimental animal facility of INTOX PVT. LTD., maintained under appropriate barriers.
Animals were housed in sterilised solid bottom polypropylene cages [size: 42 cm (L) x 29 cm (W) x 19 cm (H)] with stainless steel grill tops, facilities for food and water bottle, and with bedding of clean and sterilised paddy husk. Cages were suspended on movable stainless steel racks.
- Diet: Altromin' brand extruded pelleted rat feed manufactured by M/s Altromin Spezialfutter GmbH & Co. KG, Germany, and supplied by ATNT Laboratories, Mumbai was provided ad libitum.
- Water: Potable water passed through 'Aquaguard' water filter was provided ad libitum in sterilized bottles with stainless steel sipper tubes.
- Acclimation period: six to twenty days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25°C
- Humidity (%): 30 to 70%
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark.


IN-LIFE DATES: From: To:

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

The test item at the concentrations of 2000 mg/kg bw, was administered to each rat by a single oral gavage. The test item was administered by oral gavage to each rat as a single dose using a suitably graduated syringe and a stainless steel intubation needle (size: 16G). The dosage volume administered to individual rat is as tabulated above and was adjusted according to its most recently recorded body weight

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 females

Control animals:

no

Details on study design:

On the day of dosing, all animals were observed for signs of toxicity and death, periodically during the first 24 hours with special attention given during the first 4 hours (i.e. at 10 minutes, 30 minutes, 1 hour, 2 and 4 hours following dosing) and thereafter they were observed once a day for 14 days post dosing. The appearance, progress and disappearance of these signs were recorded.

The body weights of rats were individually recorded at one day prior to dosing (day -1), on the day of dosing (day 0, fasting body weight), on day 7 and at termination on day 14. Weight gain and group mean values were computed over day -1 body weights

At end of the study, all surviving animals were weighed and humanely sacrificed by carbon dioxide asphyxiation. All animals in the study were subjected to a complete necropsy and the gross pathological changes were recorded. Histological examination was not carried out in the absence of gross pathological changes.

Statistics:

The LD50 and the confidence intervals were calculated using the software program (AOT425StatPgm) available on EPA’s Internet Web site at http:// www.epa.gov/oppfead1/harmonized

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

Dimethyl phenyl ethyl carbinol (DMPEC) did not cause any mortality in the treated female rats at the dose level of 2000 mg/kg body weight.

Clinical signs:

other: Abnormal clinical signs were observed in treated rats at the dose level of 2000 mg/kg body weight. Test Item induced abdominal breathing and hypoactivity in the treated rats. The animals became free of these signs on day 1 after treatment

Gross pathology:

No gross pathological alterations were encountered in any of the female rats in this study at necropsy conducted at termination of the study.

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute oral toxicity study in rats, the LD50 (female) for DMPEC was >2000 mg/kg bw.

Executive summary:

In an acute oral toxicity study (R/16936/AOR/17), Wistar female rats (5/dose) were given DMPEC (99.7%) at doses of 2000 mg/kg bw and observed for 14 days.

LD50 (female): was >2000 mg/kg bw.

DMPEC did not cause any mortality in the treated female rats at the dose level of 2000 mg/kg body weight. Abnormal clinical signs were observed in treated rats at the dose level of 2000 mg/kg body weight. Test Item induced abdominal breathing and hypoactivity in the treated rats. The animals became free of these signs on day 1 after treatment. The body weight gain by rats treated at 2000 mg/kg was not affected during the 14 days observation period post dosing . No gross pathological alterations were encountered in any of the female rats in this study at necropsy conducted at termination of the study.

This acute oral study is classified as acceptable. It does satisfy the guideline requirement for an acute oral study (OECD 425) in the rat.  

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

There is one key study available and it an OECD 425/GLP study. The quality of the database is high.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

Please see the read-across justification.

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LC50

Effect level:

4.63 mg/L air (nominal)

Exp. duration:

4 h

Sex:

male/female

Dose descriptor:

LC50

Effect level:

1.38 mg/L air (analytical)

Exp. duration:

4 h

Conclusions:

In an acute inhalation study in Sprague-Dawley rats, the LC50 fro PEA was >4.63 mg/L (nominal concentration).

Executive summary:

In an acute inhalation toxicity study (5692-07/14), a group of young adult Sprague Dawley strain rats (5/sex) were exposed to a test atmosphere of PEA for 4 hours (whole body) at a target concentration of 4.63 mg/L. Animals were then observed for 14 days.

LC50 male/female = > 4.63 mg/L (nominal concentration)

The mean achieved concentration was 1.38 ±0.19 mg/L (MMAD: 1.08 µm; GSD: 0.05). There were no deaths and no clinical changes of possible toxicological importance. Although small body weight losses occurred on the days following exposure the losses were generally made good by day 7 of the study. Focal grey-green areas observed grossly on the lungs were characterized histologically by aggregates of mononuclear leucocytes mainly about blood vassels· and air passages and occasionally extending to alveolar walls., some interstitial fibrosis and infiltration by foamy macrophages. These lesions were considered to be spontaneous and caused as a result of mild infection with murine respiratory mycoplasmosis. Pulmonary edema and mild congestion revealed in 3 rats could be attributed to euthanasia.

This acute inhalation toxicity test in rats is acceptable and satisfies the guideline requirement for an OECD 403 study.

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

March 10th 1980 to 14th July 1980

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 403 (Acute Inhalation Toxicity)

GLP compliance:

yes

Test type:

traditional method

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source of test material: Research. Institute for Fragrance Materials, Englewood Cliffs, NJ.

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories Ltd., Wilmington, Mass, USA.
- Age at study initiation: approximately 8 weeks old
- Weight at study initiation: 175 to 225 g
- Fasting period before study:
- Housing: Housed individually in stainless steel, wire meshed-bottom cages
- Diet: Certified Purina Laboratory Rat Chow ad libitum
- Water: tap water ad libitum

ENVIRONMENTAL CONDITIONS (in inhalation chamber room)
- Temperature (°C): 22.3±0.29°C
- Humidity (%): 38.5±0.58%

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

1.08 µm

Geometric standard deviation (GSD):

0.05

Details on inhalation exposure:

Inhalation Exposure Equipment
A 27" cube (400 liter volume) stainless steel whole body exposure chamber was utilized. A complete group of rats (5 males and 5 females) was housed in the chamber during treatment in a stainless steel wire mesh compartmentalized cage with each compartment being 7" X 3" X 4". Temperature and relative humidity in the inhalation chamber were. monitored hourly by means of remote sensors (YSI model 705 Temperature Probe and 91HC Dew Point Hygrometer) located inside the chamber. Air flow rate through the chamber was set at 45 L/min and was measured in the exhaust line by means of an orifice plate and Magnehelic differential pressure gauge. ' This arrangement in turn had been calibrated against a conventional balltype flow meter. The negative pressure within the chamber with respect to the room atmosphere was set at less than 0. 5 inches of water. Decontamination of chamber air was accomplished by passing the air through ~ HEPA filter, an activated charcoal filter arid a liquid scrubber prior to eliminating it from the facility.

Generation of Test Atmospheres
An aerosol of the test article was generated using a Thermo Systems Inc. six jet atomizer. The atomizer was used at a pressure of 9 psig with two jets in operation.

Exposure Procedure
After loading into the chamber the test animals were exposed to an aerosol of the test article for a single period of four hours. Nominal chamber concentrations were calculated from the weight loss from the atomizer and total airflow through.the chamber during the exposure period.

Measurement of Chamber Concentration and Particle Size Distribution
Hourly air samples for measurement of chamber concentration were drawn from the chamber, at a rate of 5 L/min for two minutes, through a preweighed Gelman glass fibre filtet paper in a Gelman in-line filter holder. Chamber concentration was calculated from the increase in weight of the filter and volume of air sample. Hourly air samples from the inhalation chamber for particle size analysis were withdrawn and passed through a Casella Cascade Impactor. The distribution and size of particles which deposited on each of the four stages of the Impactor were determined by light microscopy. The method was originally described in Cascade Impactor Casella leaflet 3018/RT and was modified in this laboratory (see Bio Standard Operating Procedures No. I AC 01, 02 and 04) to include the following procedures:

1) Circular cover-slips upon which the aerosol had been impacted were mounted on a slide and examined microscopically.
2) A representative region of eaqh slide was selected for analysis.
3) An observing field of 0.47 mm X 0.47 mm (square grid) under 400 X magnification was superimposed on 'the region selected.
4) All particles falling within this grid were observed with a calibrated filar micrometer eyepiece and the numbers falling into various size ranges were recorded.
5) The numbers of particles in each size range were plotted against particle size on log probability graph paper. The line of best fit was drawn and the geometric mean particle size and its standard deviation calculated.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

Nominal concentration of 4.63 mg/L
Measured chamber concentration of 1.38 mg/L ±0.19

No. of animals per sex per dose:

5 males
5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: All animals were observed closely during and immediately after exposure, and at least twice daily during the 14 day recovery period.
- Frequency of observations and weighing: Each animal was weighed on the_ day of exposure and on days 2, 3, 4, 7 and 14 of the study.
- Necropsy of survivors performed: Yes. All animals were killed 14 days. after exposure by intraperitoneal injection of Hoechst T-61 euthanasia solution and examined macroscopically. Liver and kidneys were preserved in 10% buffered formalin solution. Lungs were preserved by perfusion with the fixative. Bronchial lymph nodes were examined macroscopically but not retained·for histological assessment. All other macroscopically abnormal tissues were preserved.
- Histopathology: Samples of lung, liver, kidney and any macroscopic abnormality, from all animals were fixed in formalin for at least 48 hours, routinely processsed, embedded in paraffin wax stained with haematoxylin and eosin and examined microscopically.

Statistics:

Mean and standard deviatl6n will be determined for chamber temperature and humidity. In addition, animal. body weight will also be tabula.ted.
Clinical findings and gross and histopathological observations will be summarized in incidence tables.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

4.63 mg/L air (nominal)

Exp. duration:

4 h

Sex:

male/female

Dose descriptor:

LC50

Effect level:

1.38 mg/L air (analytical)

Exp. duration:

4 h

Mortality:

There were no deaths.

Clinical signs:

other: There were no clinical changes of possible toxicological importance.

Body weight:

Although small body weight losses occurred on the days following exposure the losses were generally made good by day 7 of the study. Body weight gains during the second week of the observation period were considered to be satisfactory.

Gross pathology:

Focal grey-green areas observed grossly on the lungs were characterized histologically by aggregates of mononuclear leucocytes mainly about blood vassels· and air passages and occasionally extending to alveolar walls., some interstitial fibrosis and infiltration by foamy macrophages. These lesions were considered to be spontaneous and caused as a result of mild infection with murine respiratory mycoplasmosis. Pulmonary edema and mild congestion revealed in 3 rats could be attributed to euthanasia.

Other findings:

- Histopathology: There were no treatment related changes.

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute inhalation study in Sprague-Dawley rats, the LC50 fro PEA was >4.63 mg/L (nominal concentration).

Executive summary:

In an acute inhalation toxicity study (5692-07/14), a group of young adult Sprague Dawley strain rats (5/sex) were exposed to a test atmosphere of PEA for 4 hours (whole body) at a target concentration of 4.63 mg/L. Animals were then observed for 14 days.

LC50 male/female = > 4.63 mg/L (nominal concentration)

The mean achieved concentration was 1.38 ±0.19 mg/L (MMAD: 1.08 µm; GSD: 0.05). There were no deaths and no clinical changes of possible toxicological importance. Although small body weight losses occurred on the days following exposure the losses were generally made good by day 7 of the study. Focal grey-green areas observed grossly on the lungs were characterized histologically by aggregates of mononuclear leucocytes mainly about blood vessels and air passages and occasionally extending to alveolar walls., some interstitial fibrosis and infiltration by foamy macrophages. These lesions were considered to be spontaneous and caused as a result of mild infection with murine respiratory mycoplasmosis. Pulmonary edema and mild congestion revealed in 3 rats could be attributed to euthanasia.

This acute inhalation toxicity test in rats is acceptable and satisfies the guideline requirement for an OECD 403 study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

4.63 mg/m³ air

Quality of whole database:

There is one key study available and it a read-across study (equivalent or similar to OECD 403/GLP) from PEA (CAS No. 60-12-8). The quality of the database is medium.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity

There is one acute oral toxicity study available in rats.

In an acute oral toxicity study (OECD 425/GLP), Wistar female rats (5/dose) were given DMPEC (99.7%) at doses of 2000 mg/kg bw and observed for 14 days. DMPEC did not cause any mortality in the treated female rats at the dose level of 2000 mg/kg body weight. Abnormal clinical signs were observed in treated rats at the dose level of 2000 mg/kg body weight. Test item induced abdominal breathing and hypoactivity in the treated rats. The animals became free of these signs on day 1 after treatment. The body weight gain by rats treated at 2000 mg/kg was not affected during the 14 days observation period post dosing. No gross pathological alterations were encountered in any of the female rats in this study at necropsy conducted at termination of the study. The LD50 (female) is >2000 mg/kg bw.

Acute inhalation toxicity

There is no acute inhalation toxicity study for DMPEC available. Read-across was performed to an acute inhalation toxicity study in rats from PEA (CAS No. 60 -12 -8).

In an acute inhalation toxicity study (equivalent or similar to OECD 403/GLP), a group of young adult Sprague Dawley strain rats (5/sex) were exposed to a test atmosphere of PEA for 4 hours (whole body) at a target concentration of 4.63 mg/L. Animals were then observed for 14 days. The mean achieved concentration was 1.38 ±0.19 mg/L (MMAD: 1.08 µm; GSD: 0.05). There were no deaths and no clinical changes of possible toxicological importance. Although small body weight losses occurred on the days following exposure the losses were generally made good by day 7 of the study. Focal grey-green areas observed grossly on the lungs were characterized histologically by aggregates of mononuclear leucocytes mainly about blood vessels and air passages and occasionally extending to alveolar walls, some interstitial fibrosis and infiltration by foamy macrophages. These lesions were considered to be spontaneous and caused as a result of mild infection with murine respiratory mycoplasmosis. Pulmonary edema and mild congestion revealed in 3 rats could be attributed to euthanasia. The LC50 male/female was > 4.63 mg/L (nominal concentration).

The results from these studies are acceptable to use in the human health risk assessment.

Justification for classification or non-classification

Based on the available information in the dossier, the substance DMPEC (CAS No. 103-05-9) does not need to be classified for acute toxicity or specific target organ toxicity - single exposure when the criteria outlined in Annex I of 1272/2008/EC are applied.