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Description of key information

Acute oral toxicity: 

Acute oral toxicity dose (LD50) for target chemical 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) was considered based on experimental study conducted on rats. The LD50 value was considered in between 300 – ≤ 2000 mg/kg bw, for acute oral toxicity. Thus, comparing this value with the criteria of CLP regulation, 1-phenylethan-1-ol (1-phenylethanol) can be classified in “Category 4” for acute oral toxicity.

Acute Inhalation toxicity:

The acute Inhalation toxicity dose (LC50) for 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) was considered based on the data available for the structurally and functionally similar read across chemicals. The study concluded that the LC50 value is >5 mg/L, for acute inhalation toxicity. Thus, comparing this value with the criteria of CLP regulation, 1-phenylethan-1-ol (1-phenylethanol) cannot be classified for acute inhalation toxicity.

Acute Dermal toxicity:

The acute dermal toxicity dose (LD50) for target chemical 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) was considered based on experimental study conducted on rats, the value was considered to be >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 1-phenylethan-1-ol (1-phenylethanol) cannot be classified for acute dermal toxicity.

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Data is from experimental study report.
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Principles of method if other than guideline:
The objective of this acute oral toxicity study was to assess the toxicological profile of the test item when administered to rats by a single oral gavage.
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no
Specific details on test material used for the study:
- IUPAC Name: 1-phenylethan-1-ol
- Common Name: 1-Phenylethanol
- InChI: 1S/C8H10O/c1-7(9)8-5-3-2-4-6-8/h2-7,9H,1H3
- Smiles: c1(ccccc1)C(C)O
- Molecular formula :C8H10O
- Molecular weight :122.166 g/mol
- Substance type:Organic
- Physical state:Clear colourless liquid
- Purity as per Certificate of Analysis:99.8%
- Lot No.:10207187
- Manufactured date:20 June 2017
- Retest date:20 June 2027
- pH:4.44
- Density:1.004 g/cm3 at 30°C
- Storage conditions:Ambient (+18 to +36°C)
- SAFETY PRECAUTIONS: Gloves, cap and face mask were used in addition to protective body garments and shoes, to ensure adequate personal health and safety and to avoid inhalation and skin contact with the test item.
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Geniron Biolabs Pvt. Ltd. Bengaluru
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 9 to 11 Weeks
- Weight at study initiation: 187.72 to 219.59 g
- Identification:By rat accession number. Identification of individual rats was by cage card and turmeric colour body markings. The rat accession number was allotted during the course of the study. The temporary body marking during acclimatization period was done with crystal violet.
- Fasting period before study: rats were fasted for approximately 16 to 18 hours
- Housing:Rats were housed individually in standard polysulfone cages (Size: L 425 x B 266 x H 185 mm), with stainless steel top grill
- Diet (e.g. ad libitum): Hypro Rat & Mice pellet feed, ad libitum
- Water (e.g. ad libitum): Deep bore-well water passed through activated charcoal filter and exposed to UV rays in Aquaguard on-line water filter-cum-purifier, Mumbai, ad libitum
- Acclimation period: The animals were acclimatized six days for G1-FTS, eight days for G1-STS and twelve days for G2-FTS before treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 to 25°C
- Humidity (%): 66 to 68%
- Air changes (per hr): air conditioned with adequate fresh air supply (12.4 air changes/hour).
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark cycle.

IN-LIFE DATES: From: 05 April 2018 To: 27 April 2018
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 300 & 2000 mg/kg body weight.
- Amount of vehicle (if gavage):dose volume was 0.30 & 1.99 mL/kg body weight
Doses:
G1 (FTS) - 300 mg/kg
G1 (STS) - 300 mg/kg
G2 (FTS) - 2000 mg/kg
No. of animals per sex per dose:
G1 (FTS) - 300 mg/kg - 3
G1 (STS) - 300 mg/kg - 3
G2 (FTS) - 2000 mg/kg - 3
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical signs and pre-terminal deaths - At each step, the animals were observed five times on test day 1 (day of administration) i.e. at 30 minutes and four times at hourly intervals and once daily during days 2 to 15 post administration. Observations included changes in skin and fur, eyes and mucous membranes, and also respiratory, circulatory, autonomic and central nervous systems and somatomotor activity and behaviour pattern. Attention was directed to the observations of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma and all observed clinical signs were recorded. Body weights - The body weights were recorded on test day 1 (pre-administration), day 8 (7 days post administration) and day 15 (14 days post administration).
- Necropsy of survivors performed: yes, the rats surviving to the end of the observation period were euthanised by using isoflurane anaesthesia and subjected to detailed necropsy.
- Other examinations performed: Gross pathological findings were recorded and reported. Microscopic examination was not carried out as no gross pathological changes were observed.
Statistics:
not specified
Preliminary study:
not specified
Key result
Sex:
female
Dose descriptor:
LD50 cut-off
Effect level:
500 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no other details available
Mortality:
G1 (FTS) - 300 mg/kg - There were no pre-terminal deaths observed.
G1 (STS) - 300 mg/kg - There were no pre-terminal deaths observed.
G2 (FTS) - 2000 mg/kg - All the rats died at 1 hour post-dose.
Clinical signs:
other: G1 (FTS) - 300 mg/kg - Clinical signs of recumbency and ataxia – slight were observed in one rat at 30 minutes to 3 hours and the rat was normal from 4th hour onwards. G1 (STS) - 300 mg/kg - Clinical sign of ataxia – slight was observed in one rat at 30 m
Gross pathology:
There were no gross pathological changes at necropsy.
Other findings:
not specified

TABLE 1.      Body weight, body weight change and pre-terminal deaths

Group and

Dose

(mg/kg

body weight)

Rat

No.

Sex

Body weight (g)

Day of Death

(Time of Death)

No. dead/

No. tested

Pre-terminal deaths

(%)

Initial

(Day 1)

8thday

Weight change

(day 8 – Initial)

15thday

Weight change

(day 15 – Initial)

At Death

G1

(FTS)

300

 

Rm8895

F

209.41

225.63

16.22

238.18

28.77

-

-

0/3

0

Rm8896

F

187.72

197.16

9.44

206.08

18.36

-

-

Rm8897

F

209.99

226.15

16.16

232.04

22.05

-

-

G1

(STS)

300

 

Rm8898

F

209.31

215.81

6.5

227.11

17.80

-

-

0/3

0

Rm8899

F

214.86

220.91

6.05

228.06

13.20

-

-

Rm8900

F

193.13

201.97

8.84

211.97

18.84

-

-

G2

(FTS)

2000

 

Rm8901

F

196.12

-

-

-

-

196.57

1 (10.48 AM)

3/3

100

Rm8902

F

219.59

-

-

-

-

219.97

1 (10.48 AM)

Rm8903

F

214.48

-

-

-

-

214.64

1 (10.48 AM)

F: Female        FTS: First Treatment Step            STS: Second Treatment Step             NA: Not Applicable           

 

APPENDIX 1.      Individual clinical signs, dose administration and necropsy findings

Group and

Dose

(mg/kg

body weight)

Date and

time of administration

Rat

No.

Sex

Body

weight

(Day 1)

(g)

Total volume administered

(mL)

Day of observation

Day 1

30 min

1hour

2 hours

3 hours

4 hours

G1

(FTS)

300

 

11 April 2018 and

10:51 AM

to

10:52 AM

Rm8895

F

209.41

0.06

N

N

N

N

N

Rm8896

F

187.72

0.06

055 (b)

055 (b)

043 (1)

043 (1)

N

Rm8897

F

209.99

0.06

N

N

N

N

N

Group and

Dose

(mg/kg

body weight)

Rat

No.

Sex

Day of observation

Necropsy

Findings

2

3

4

5

6

7

8

9

10

11

12

13

14

15

G1

(FTS)

300

 

Rm8895

F

N

N

N

N

N

N

N

N

N

N

N

N

N

N

NAD

Rm8896

F

N

N

N

N

N

N

N

N

N

N

N

N

N

N

NAD

Rm8897

F

N

N

N

N

N

N

N

N

N

N

N

N

N

N

NAD

F: Female            FTS: First treatment step              N: Normal            min: minutes         mg: milligrams            kg: kilograms       

mL: millilitre         055 (b): Recumbent;            043 (1): Ataxia – slight;              NAD: No Abnormality Detected 

 

APPENDIX 2 contd. Individual clinical signs, dose administration and necropsy findings                 

 

Group and

Dose

(mg/kg

body weight)

Date and

time of administration

Rat

No.

Sex

Body

weight

(Day 1)

(g)

Total volume administered

(mL)

Day of observation

Day 1

30 min

1hour

2 hours

3 hours

4 hours

G1

(STS)

300

 

 

13 April 2018 and

11:30 AM

to

11:33 AM

Rm8898

F

209.31

0.06

N

N

N

N

N

Rm8899

F

214.86

0.06

N

N

N

N

N

Rm8900

F

193.13

0.06

043 (1)

043 (1)

043 (1)

043 (1)

N

Group and

Dose

(mg/kg

body weight)

Rat

No.

Sex

Day of observation

Necropsy

Findings

2

3

4

5

6

7

8

9

10

11

12

13

14

15

G1

(STS)

300

 

Rm8898

F

N

N

N

N

N

N

N

N

N

N

N

N

N

N

NAD

Rm8899

F

N

N

N

N

N

N

N

N

N

N

N

N

N

N

NAD

Rm8900

F

N

N

N

N

N

N

N

N

N

N

N

N

N

N

NAD

F: Female        STS: Second treatment step               N: Normal              min: minutes       mg: milligrams                      kg: kilograms             

mL: millilitre         043 (1): Ataxia – slight;             NAD: No Abnormality Detected           

 

APPENDIX 2 contd. Individual clinical signs, dose administration and necropsy findings                 

 

Group and

Dose

(mg/kg

body weight)

Date and

time of administration

Rat

No.

Sex

Body

weight

(Day 1)

(g)

Total volume administered

(mL)

Day of observation

Day 1

30 min

1hour

2 hours

3 hours

4 hours

G2

(FTS)

2000

17 April 2018 and

9:47 AM

to

9:49 AM

Rm8901

F

196.12

0.39

055 (b)

016

-

-

-

Rm8902

F

219.59

0.44

055 (b)

016

-

-

-

Rm8903

F

214.48

0.43

055 (b)

016

-

-

-

Group and

Dose

(mg/kg

body weight)

Rat

No.

Sex

Day of observation

Necropsy

Findings

2

3

4

5

6

7

8

9

10

11

12

13

14

15

G2

(FTS)

2000

Rm8901

F

-

-

-

-

-

-

-

-

-

-

-

-

-

-

NAD

Rm8902

F

-

-

-

-

-

-

-

-

-

-

-

-

-

-

NAD

Rm8903

F

-

-

-

-

-

-

-

-

-

-

-

-

-

-

NAD

F: Female         FTS: First treatment step                 min: minutes   mg: milligrams                       kg: kilograms     mL: millilitre      

055 (b): Recumbent;    016: Dead;              NAD: No Abnormality Detected

 


Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Based on the results of the present study, The LD50 of 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) is 500 mg/kg as per the as per LD50 cut-off value. The test item is classified as “Category 4 (300 – ≤ 2000)” criteria of CLP.
Executive summary:

The acute oral toxicity study of 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) in Wistar rats was conducted to assess the toxicological profile of the test item. Undiluted test item (Purity: 99.8%) was administered via oral gavage route. The dose volume was 0.30 mL/kg to attain the dose of 300 mg/kg body weight. A single oral gavage administration was done to overnight fasted (approximately 16 to 18 hours) three female rats (G1-FTS) at the dose of 300 mg/kg body weight. Clinical signs of recumbency and ataxia - slight were observed in one rat at 30 minutes to 3 hours and the rat was normal from 4th hour onwards and no pre-terminal deaths were observed, hence three additional female rats were tested at the same dose of 300 mg/kg body weight (G1-STS). The rats were observed for mortality and clinical signs for 14 days post treatment. Body weights were recorded prior to dosing on day 1 and again on days 8 and 15. Necropsy was performed for all the rats at termination. Clinical signs of ataxia - slight were observed in one rat at 30 minutes to 3 hours and the rat was normal from 4th hour onwards and no pre-terminal deaths were observed. All survived rats gained weight during experimental period. There were no gross pathological changes at necropsy. The treatment was continued with the next higher dose of 2000 mg/kg body weight (1.99 mL/kg body weight) - G2-FTS. The rats were observed for mortality and clinical signs for 14 days post treatment. Body weights were recorded prior to dosing on day 1 and again on days 8 and 15. Necropsy was performed for all the rats at termination. Clinical sign of recumbency was observed in all the three rats and all the rats died at 1 hour post-dose, the dosing was stopped. Thus, the acute oral LD50 (Cut-off value) of 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) was considered to be 500 mg/kg body weight. Thus, it was concluded that the acute toxicity study of 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1), when administered via oral route in Wistar rats falls into the “Category 4 (300 – ≤ 2000)” criteria of CLP.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 000 mg/kg bw
Quality of whole database:
Data is Klimisch 1 and from experimental study report.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Experimental data of read across substances
Justification for type of information:
Data for the target chemical is summarized based on the structurally and functionally similar read across chemicals
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
WoE report is based on two acute inhalation toxicity studies as- WoE 2 and WoE 3.
Acute inhalation toxicity test was carried out to study the effects of the test chemicals on rodents
GLP compliance:
not specified
Test type:
other: not specified
Limit test:
no
Specific details on test material used for the study:
- IUPAC Name: 1-phenylethan-1-ol
- Common Name: 1-Phenylethanol
- InChI: 1S/C8H10O/c1-7(9)8-5-3-2-4-6-8/h2-7,9H,1H3
- Smiles: c1(ccccc1)C(C)O
- Molecular formula (if other than submission substance): C8H10O
- Molecular weight (if other than submission substance): 122.166 g/mol
- Substance type: Organic
- Physical state: liquid
Species:
other: 1. Mouse 2. Rat
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
1. not specified
2. not specified
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
not specified
Remark on MMAD/GSD:
1. not specified
2. not specified
Details on inhalation exposure:
1. not specified
2. not specified
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
7 h
Remarks on duration:
not specified
Concentrations:
1. 10000 mg/m³
2. 38600 mg/m3
No. of animals per sex per dose:
1. not specified
2. not specified
Control animals:
not specified
Details on study design:
1. - Other examinations performed: Animals were observed for mortality and clinical signs.
2. - Other examinations performed: Animals were observed for clinical signs.
Statistics:
1. not specified
2. not specified
Preliminary study:
1. not specified
2. not specified
Sex:
not specified
Dose descriptor:
LC50
Effect level:
10 000 mg/m³ air
Based on:
test mat.
Exp. duration:
7 h
Remarks on result:
other: 50% mortality was observed
Sex:
not specified
Dose descriptor:
LC50
Effect level:
38 600 mg/m³ air
Based on:
test mat.
Remarks on result:
other: 50% mortality was observed
Mortality:
1. 50% mortality was observed
2. 50% mortality was observed
Clinical signs:
other: 1. Observations were noted such as, changes in spleen, multiple effects in liver, kidney, ureter, and bladder, changes observed in both tubules and glomeruli. 2. Rats showed the symptoms like: difficulty in breathing, ataxia, exhaustion, sedation and narc
Body weight:
1. not specified
2. not specified
Gross pathology:
1. not specified
2. No substance-related macroscopic changes to organs were observed.
Other findings:
1. not specified
2. not specified
Interpretation of results:
other: Not classified
Conclusions:
According to CLP regulation, the test chemical 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) cannot be classified for acute inhalation toxicity, as the LC50 value is >5 mg/L.
Executive summary:

 Data available for the structurally and functionally similar read across chemicals has been reviewed to determine the acute inhalation toxicity of the test chemical 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1). The studies are as mentioned below:

1. The acute inhalation toxicity study was conducted by using Cumene (CAS No. 98-82-8) in mice at the concentration of 10000 mg/m³. Animals were observed for mortality and clinical signs. 50% mortality was observed. Observations were noted such as, changes in spleen, multiple effects in liver, kidney, ureter, and bladder, changes observed in both tubules and glomeruli. Hence, LC50 value was considered to be 10000 mg/m³, when mice were exposed to Cumene (CAS No. 98-82-8) via inhalation route for 7 hour exposure.

2. The acute inhalation toxicity study was conducted by using Benzonitrile (CAS No. 100-47-0) in rat at the concentration of 38600 mg/m3. 50% mortality was observed at 38600 mg/m3. Rats showed the symptoms like: difficulty in breathing, ataxia, exhaustion, sedation and narcosis. No substance-related macroscopic changes to organs were observed. Therefore, LC50 was considered to be 38600 mg/m3, when rat was treated with Benzonitrile (CAS No. 100-47-0) by inhalation.

Thus, based on the above summarised studies, 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) and it’s structurally and functionally similar read across substances, it can be concluded that LC50 value is >5 mg/L. Thus, comparing this value with the criteria of CLP regulation, 1-phenylethan-1-ol (1-phenylethanol) cannot be classified for acute inhalation toxicity.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
5 000 mg/m³ air
Quality of whole database:
Data is Klimisch 2 and from authoritative database.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Data is from study report.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Principles of method if other than guideline:
The objective of this acute dermal toxicity study was to assess the toxicological profile of the test item on application as a single semi-occlusive dermal application to rats.
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
no
Specific details on test material used for the study:
- IUPAC Name: 1-phenylethan-1-ol
- Common Name: 1-Phenylethanol
- InChI: 1S/C8H10O/c1-7(9)8-5-3-2-4-6-8/h2-7,9H,1H3
- Smiles: c1(ccccc1)C(C)O
- Molecular formula :C8H10O
- Molecular weight :122.166 g/mol
- Substance type:Organic
- Physical state:Clear colourless liquid
- Purity as per Certificate of Analysis:99.8%
- Lot No.:10207187
- Manufactured date:20 June 2017
- Retest date:20 June 2027
- pH:4.44
- Density:1.004 g/cm3 at 30°C
- Storage conditions:Ambient (+18 to +36°C)
- SAFETY PRECAUTIONS: Gloves, cap and face mask were used in addition to protective body garments and shoes, to ensure adequate personal health and safety and to avoid inhalation and skin contact with the test item.
- Preparation: The undiluted test item at the doses of 200 (0.20 mL/kg body weight), 1000 (1 mL/kg body weight) and 2000 (1.99 mL/kg body weight) - based on the density of the test item 1.004 g/cm3 (as per TIDS provided by the sponsor) was applied directly to the clipped skin of the animal (semi-occlusive)
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Geniron Biolabs Pvt. Ltd. Bengaluru
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 9 to 11 weeks
- Weight at study initiation: Females: 213.88 to 223.58 g
- Identification:By rat accession number. Identification of individual rats is by cage card and crystal violet colour body markings. The temporary body marking during acclimatization period was done with crystal violet. The rat accession numbers were allotted during the course of the study and was included in raw data and reported.
- Housing: Animals were housed individually in standard polysulfone cages (Size: L 425 x B 266 x H 185 mm), with stainless steel top grill. Additionally, polycarbonate rat huts were placed inside the cage as enrichment objects and were changed along with the cage once a week. Bedding: Steam sterilized corn cob was used and changed once a week along with the cage.
- Diet (e.g. ad libitum): Hypro Rat & Mice pellet feed, ad libitum
- Water (e.g. ad libitum): Deep bore-well water passed through activated charcoal filter and exposed to UV rays in Aquaguard on-line water filter-cum-purifier, ad libitum
- Acclimation period: The rats were acclimatized for six, eight, twelve and fourteen days before treatment for dose range finding and main study respectively under standard laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 to 25°C
- Humidity (%): 66 to 68%
- Air changes (per hr): air conditioned with adequate fresh air supply (12.4 air changes/hour)
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark cycle

IN-LIFE DATES: From: 05 April 2018 To: 03 May 2018
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: clipped skin of dorsolateral thoracic surface
- % coverage: 10% of the body surface
- Type of wrap if used: The applied area was covered with cotton gauze (size: Females: 8 x 5 cm of 6 ply) and it was secured in position by adhesive tape wound around the torso.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The dressing was removed and the applied area was washed with deionized water and wiped dry using clean towel.
- Time after start of exposure:24 hours
Duration of exposure:
24 hours
Doses:
DRF G1 - 200 mg/kg
DRF G2 - 1000 mg/kg
DRF G3 - 2000 mg/kg
Main G3 - 2000 mg/kg
No. of animals per sex per dose:
DRF G1 - 200 mg/kg - 1
DRF G2 - 1000 mg/kg - 1
DRF G3 - 2000 mg/kg - 1
Main G3 - 2000 mg/kg - 2
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical examination and pre-terminal deaths - The animals were observed for clinical signs and pre-terminal deaths (mortality) once during first 30 minutes after application, and at hourly intervals for 6 hours after application on the day of treatment (day 1) and once daily during Days 2 to 15. In addition, the treatment site was observed for skin reactions at 24, 48 and 72 hours after removal of test chemical using the Draize criteria (Refer Annexure 4 of this report). All rats were observed for changes in skin and fur, eyes and mucous membranes, and also respiratory, circulatory, autonomic and central nervous systems and somatomotor activity and behaviour pattern. Attention was directed to observations of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
Body weights - Individual body weights of animals were recorded on test days 1(Pre-application), 8 (7 days post application), and 15 (14 days post application).
- Necropsy of survivors performed: yes, at the end of the observation period, all rats were euthanised and exsanguinated under isoflurane anesthesia and subjected to detailed necropsy by an experienced prosector and the findings were recorded.
- Other examinations performed: Microscopic examination was not carried out as no gross pathological changes were observed.
Statistics:
not specified
Preliminary study:
not specified
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no pre-terminal deaths (mortality) observed during the study.
Clinical signs:
other: There were no clinical signs observed during the study.
Gross pathology:
No abnormality was detected at necropsy.
Other findings:
not specified

TABLE 1.            Individual body weight, body weight changes and pre-terminal deaths

Group and

Dose

(mg/kg body weight)

Rat

No.

S

e

x

Body weight (g)

Pre-terminal deaths

Initial

(Day 1 - at treatment)

8th

day

Weight change

(day 8 – Initial)

15th

day

Weight change

(day 15 – Initial)

G1 and

200

DRF

Rm8907

F

223.58

228.46

4.88

234.42

10.84

0

G2 and

1000

DRF

Rm8908

F

217.14

222.02

4.88

230.19

13.05

0

G3 and

2000

DRF

Rm8909

F

220.12

224.34

4.22

229.66

9.54

0

G3 and

2000

Main study

Rm8910

F

215.19

220.23

5.04

226.79

11.6

0

Rm8911

F

213.88

219.78

5.9

221.24

7.36

0

 DRF: Dose Range Finding   F: Female

APPENDIX 1.      Individual test item application, clinical signs, skin reactionand necropsy findings

Dose range finding study

 

Group & Dose

(mg/kg

body weight)

Date and time of application

Rat

Number

S

e

x

Initial

Bwt

(g)

Quantity

(mL)

applied

Observations and skin reaction

Days

1

2

3

4

5

30

min

1 h #

2 h #

3 h #

4 h

#

5 h #

6 h

#

*

Er

@

Ed

@

*

Er

@

Ed

@

*

Er

@

Ed

@

G1 and

200

DRF

11 April 2018

and

10.55 AM

Rm8907

F

223.58

0.04

N

N

N

N

N

N

N

N

N

0

0

N

0

0

N

0

0

 

Group & Dose

(mg/kg

body weight)

Rat

Number

S

e

x

Observation

Necropsy

findings

Days

6

7

8

9

10

11

12

13

14

15

G1 and

200

DRF

Rm8907

F

N

N

N

N

N

N

N

N

N

N

NAD

F: Female             N: Normal          h: hour    min: minutes                      NAD: No abnormality detected      Er: Erythema                      Ed: Edema  

Score 0: No Erythema / Edema       

    

*: Clinical signs; @: Skin scoring as per Draize method (approximately 24, 48 and 72 hours) after test patch removal

 

 

APPENDIX 2 contd. Individual test item application, clinical signs, skin reaction and necropsy findings

 

Dose range finding study

 

Group & Dose

(mg/kg

body weight)

Date and time of application

Rat

Number

S

e

x

Initial

Bwt

(g)

Quantity

(mg)

applied

Observations and skin reaction

Days

1

2

3

4

5

30

 min

1 h #

2 h #

3 h #

4 h

#

5 h #

6 h

#

*

Er

@

Ed

@

*

Er

@

Ed

@

*

Er

@

Ed

@

G2 and

1000

DRF

 

13 April 2018

and

11.35 to 11.36 AM

Rm8908

F

217.14

0.21

N

N

N

N

N

N

N

N

N

0

0

N

0

0

N

0

0

 

Group & Dose

(mg/kg

body weight)

Animal

Number

S

e

x

Observation

Necropsy

findings

Days

6

7

8

9

10

11

12

13

14

15

G2 and

1000

DRF

 

Rm8908

F

N

N

N

N

N

N

N

N

N

N

NAD

F: Female             N: Normal          h: hour    min: minutes                       NAD: No abnormality detected      Er: Erythema                       Ed: Edema  

Score 0: No Erythema / Edema       

    

*: Clinical signs; @: Skin scoring as per Draize method (approximately 24, 48 and 72 hours) after test patch removal

APPENDIX 2 contd. Individual test item application, clinical signs, skin reaction and necropsy findings

 

Dose range finding study

 

Group & Dose

(mg/kg

body weight)

Date and time of application

Rat

Number

S

e

x

Initial

Bwt

(g)

Quantity

(mg)

applied

Observations and skin reaction

Days

1

2

3

4

5

30

min

1 h #

2 h #

3 h #

4 h

#

5 h #

6 h

#

*

Er

@

Ed

@

*

Er

@

Ed

@

*

Er

@

Ed

@

G3 and

2000

DRF

17 April 2018

and

9.53 AM

Rm8909

F

220.12

0.44

N

N

N

N

N

N

N

N

N

0

0

N

0

0

N

0

0

 

Group & Dose

(mg/kg

body weight)

Animal

Number

S

e

x

Observation

Necropsy

findings

Days

6

7

8

9

10

11

12

13

14

15

G3 and

2000

DRF

Rm8909

F

N

N

N

N

N

N

N

N

N

N

NAD

F: Female             N: Normal          h: hour    min: minutes                       NAD: No abnormality detected      Er: Erythema                       Ed: Edema  

Score 0: No Erythema / Edema       

    

*: Clinical signs; @: Skin scoring as per Draize method (approximately 24, 48 and 72 hours) after test patch removal

 

 

APPENDIX 2 contd. Individual test item application, clinical signs, skin reaction and necropsy findings

 

Main study

 

Group & Dose

(mg/kg

body weight)

Date and time of application

Rat

Number

S

e

x

Initial

Bwt

(g)

Quantity

(mg)

applied

Observations and skin reaction

Days

1

2

3

4

5

30

min

1 h

2 h

3 h

4 h

5 h

6 h

*

Er @

Ed @

*

Er @

Ed @

*

Er @

Ed @

G3 and

2000

Main study

 

19 April 2018

and

10.38 to 10.39 AM

Rm8910

F

215.19

0.43

N

N

N

N

N

N

N

N

N

0

0

N

0

0

N

0

0

Rm8911

F

213.88

0.43

N

N

N

N

N

N

N

N

N

0

0

N

0

0

N

0

0

 

Group & Dose

(mg/kg

body weight)

Animal

Number

S

e

x

Observations

Necropsy

findings

Days

6

7

8

9

10

11

12

13

14

15

G3 and

2000

Main study

 

Rm8910

F

N

N

N

N

N

N

N

N

N

N

NAD

Rm8911

F

N

N

N

N

N

N

N

N

N

N

NAD

F: Female             N: Normal          h: hour    min: minutes                       NAD: No abnormality detected      Er: Erythema                       Ed: Edema  

Score 0: No Erythema / Edema          

*: Clinical signs; @: Skin scoring as per Draize method (approximately 24, 48 and 72 hours) after test patch removal

 


Interpretation of results:
other: Not classified
Conclusions:
Based on the present study results, the acute dermal LD50 of 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) is >2000 mg/kg body weight in female Wistar rats. The test item is classified as "Not classified”.
Executive summary:

The acute dermal toxicity of 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) was tested in 5 females (3 females for dose range finding study followed by 2 females for main study) Wistar rats at the doses of 200, 1000 and 2000 mg/kg body weight. Based on the individual body weight, the undiluted test item at the doses of 200 (0.20 mL/kg body weight), 1000 (1 mL/kg body weight) and 2000 (1.99 mL/kg body weight) was applied directly to the clipped skin of the animal to cover about 10% of the body surface of the animal (semi-occlusive). The area of application was covered with cotton gauze (size: Females: 8 x 5 cm of 6 ply) and it was secured in position by adhesive tape wound around the torso. The test item contact period with the skin was for 24 hours. After the 24 hours contact period, the dressing was removed and the applied area was washed with deionized water and wiped dry using clean towels. All the rats were observed for clinical signs of toxicity and mortality for 14 days post application. There were no clinical signs of toxicity and mortality. There was no skin reaction observed at test item applied area. Body weight was measured on days 1, 8 and 15 and all rats gained weight during experimental period. At the end of observation period, all surviving animals were euthanized and subjected to necropsy. There were no abnormalities detected at the necropsy. Thus, it was concluded that the acute dermal median lethal dose (LD50) of 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1), when administered to female Wistar rats was considered to be >2000 mg/kg body weight. Thus, according to CLP criteria for acute toxicity rating for the chemicals, it infers that the given test chemical 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) does not classify as an acute dermal toxicant. CLP Classification: “Not classified”.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Data is Klimisch 1 and from experimental study report.

Additional information

Acute oral toxicity:

In different experimental studies, 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents, i.e. most commonly in rats and mice for 1-phenylethan-1-ol (1-phenylethanol). The studies are summarized as below –

The acute oral toxicity study with 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) in Wistar rats was conducted to assess the toxicological profile of the test item. Undiluted test item (Purity: 99.8%) was administered via oral gavage route. The dose volume was 0.30 mL/kg to attain the dose of 300 mg/kg body weight. A single oral gavage administration was done to overnight fasted (approximately 16 to 18 hours) three female rats (G1-FTS) at the dose of 300 mg/kg body weight. Clinical signs of recumbency and ataxia - slight were observed in one rat at 30 minutes to 3 hours and the rat was normal from 4th hour onwards and no pre-terminal deaths were observed, hence three additional female rats were tested at the same dose of 300 mg/kg body weight (G1-STS). The rats were observed for mortality and clinical signs for 14 days post treatment. Body weights were recorded prior to dosing on day 1 and again on days 8 and 15. Necropsy was performed for all the rats at termination. Clinical signs of ataxia - slight were observed in one rat at 30 minutes to 3 hours and the rat was normal from 4th hour onwards and no pre-terminal deaths were observed. All survived rats gained weight during experimental period. There were no gross pathological changes at necropsy. The treatment was continued with the next higher dose of 2000 mg/kg body weight (1.99 mL/kg body weight) - G2-FTS. The rats were observed for mortality and clinical signs for 14 days post treatment. Body weights were recorded prior to dosing on day 1 and again on days 8 and 15. Necropsy was performed for all the rats at termination. Clinical sign of recumbency was observed in all the three rats and all the rats died at 1 hour post-dose, the dosing was stopped. Thus, the acute oral LD50 (Cut-off value) of 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) was considered to be 500 mg/kg body weight. Thus, it was concluded that the acute toxicity study of 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1), when administered via oral route in Wistar rats falls into the “Category 4 (300 – ≤ 2000)” criteria of CLP.

The above experimental study is supported with the study conducted on rats and mentioned in peer-reviewed journals, handbooks, authoritative databases and secondary source for the target chemical 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1). The acute oral toxicity study was conducted in 6 male albino rats at the dose concentration of 400 mg/kg bw. The given test chemical was dissolved in water and administered via oral route. Animals were observed for mortality during 14 days. 50% mortality was observed at 400 mg/kg bw. Therefore, LD50 value was considered to be 400 mg/kg bw, when 6 male albino rats were treated with 1-phenylethan-1-ol (1-phenylethanol) via oral route.

These studies are supported with the study mentioned in authoritative database and conducted in mice for the target chemical 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1). Acute oral toxicity study was conducted in mice at the dose concentration of 558 mg/kg bw via oral route. Animals were observed for clinical signs. 50% mortality was observed at 558 mg/kg bw. Behavioural changes such as: somnolence (general depressed activity) and respiratory depression was observed in lungs and thorax. Therefore, LD50 value was considered to be 558 mg/kg bw, when mice were treated with 1-phenylethan-1-ol (1-phenylethanol) via oral route.

Above studies are supported with the study mentioned in secondary source for the target chemical 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1). The acute oral toxicity study was conducted in groups of 5 males and 5 females F344/N rats at the dose concentrations of 0, 313, 625, 1250, 2500, or 5000 mg/kg bw. The given test chemical (Purity: 99%) was dissolved in corn oil and administered as 10mL/Kg via oral gavage route. Animals were observed two times per day for 14 days. Animals were weighed at the start and end of the studies. Necropsy performed on all animals. All rats that received 2500 or 5000 mg/kg and 1/5 male rats that received 1250 mg/kg died within 4 days after dosing. On the day of dosing, rats that received 625 mg/kg or more were ataxic or lethargic. All survivors were normal from day 4 to the end of the studies. Final mean body weights were not related to the dose administered. Therefore, LD50 value was considered in between >1250-<2500 mg/kg bw, when groups of 5 males and 5 females F344/N rats were treated with 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) via oral gavage route.

All these studies are further supported with the data available for the target chemical 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) and mentioned in secondary source. Acute oral toxicity study was conducted in groups of 5 males and 5 females B6C3F1 mice at the dose concentrations of 0, 313, 625, 1250, 2500, or 5000 mg/kg bw. The given test chemical (Purity: 99%) was dissolved in corn oil and administered as 10mL/Kg via oral gavage route. Animals were observed two times per day for 14 days. Animals were weighed at the start and end of the studies. Necropsy performed on all animals. All mice that received 2500 or 5000 mg/kg and 1/5 males that received 1250 mg/kg died within 3 days after dosing. Mice that received 1250, 2500, or 5000 mg/kg exhibited ataxia or lethargy after they were dosed; mice that survived were normal after day 1. Final mean body weights of dosed and vehicle control mice were similar. Therefore, LD50 value was considered in between >1250-<2500 mg/kg bw, when groups of 5 males and 5 females B6C3F1 mice were treated with 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) via oral gavage route.

Thus, based on the above summarised key study on target chemical 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1), all rats were died at 2000 mg/kg bw, hence the LD100 was considered to be 2000 mg/kg bw. Considering this value, the LD50 value can be assumed to be 1000 mg/kg bw. Therefore, comparing this value with the criteria of CLP regulation, 1-phenylethan-1-ol (1-phenylethanol) can be classified in “Category 4 (300 – ≤ 2000)” for acute oral toxicity.

Acute Inhalation Toxicity:

Data available for the structurally and functionally similar read across chemicals has been reviewed to determine the acute inhalation toxicity of the test chemical 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1). The studies are as mentioned below:

1. The acute inhalation toxicity study was conducted by using Cumene (CAS No. 98-82-8) in mice at the concentration of 10000 mg/m³. Animals were observed for mortality and clinical signs. 50% mortality was observed. Observations were noted such as, changes in spleen, multiple effects in liver, kidney, ureter, and bladder, changes observed in both tubules and glomeruli. Hence, LC50 value was considered to be 10000 mg/m³, when mice were exposed to Cumene (CAS No. 98-82-8) via inhalation route for 7 hour exposure.

2. The acute inhalation toxicity study was conducted by using Benzonitrile (CAS No. 100-47-0) in rat at the concentration of 38600 mg/m3. 50% mortality was observed at 38600 mg/m3. Rats showed the symptoms like: difficulty in breathing, ataxia, exhaustion, sedation and narcosis. No substance-related macroscopic changes to organs were observed. Therefore, LC50 was considered to be 38600 mg/m3, when rat was treated with Benzonitrile (CAS No. 100-47-0) by inhalation.

Thus, based on the above summarised studies, 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) and it’s structurally and functionally similar read across substances, it can be concluded that LC50 value is >5 mg/L. Thus, comparing this value with the criteria of CLP regulation, 1-phenylethan-1-ol (1-phenylethanol) cannot be classified for acute inhalation toxicity.

Acute Dermal Toxicity:

In different experimental studies 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) has been investigated for acute dermal toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents, i.e. most commonly in rabbits, rats and guinea pigs for 1-phenylethan-1-ol (1-phenylethanol). The studies are summarized as below –

The acute dermal toxicity of 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) was tested in 5 females (3 females for dose range finding study followed by 2 females for main study) Wistar rats at the doses of 200, 1000 and 2000 mg/kg body weight. Based on the individual body weight, the undiluted test item at the doses of 200 (0.20 mL/kg body weight), 1000 (1 mL/kg body weight) and 2000 (1.99 mL/kg body weight) was applied directly to the clipped skin of the animal to cover about 10% of the body surface of the animal (semi-occlusive). The area of application was covered with cotton gauze (size: Females: 8 x 5 cm of 6 ply) and it was secured in position by adhesive tape wound around the torso. The test item contact period with the skin was for 24 hours. After the 24 hours contact period, the dressing was removed and the applied area was washed with deionized water and wiped dry using clean towels. All the rats were observed for clinical signs of toxicity and mortality for 14 days post application. There were no clinical signs of toxicity and mortality. There was no skin reaction observed at test item applied area. Body weight was measured on days 1, 8 and 15 and all rats gained weight during experimental period. At the end of observation period, all surviving animals were euthanized and subjected to necropsy. There were no abnormalities detected at the necropsy. Thus, it was concluded that the acute dermal median lethal dose (LD50) of 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1), when administered to female Wistar rats was considered to be >2000 mg/kg body weight. Thus, according to CLP criteria for acute toxicity rating for the chemicals, it infers that the given test chemical 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) does not classify as an acute dermal toxicant. CLP Classification: “Not classified”.

This study is supported with the another experimental study conducted on rabbits and mentioned in peer-reviewed journal, handbooks, authoritative databases and secondary source for the target chemical 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1). Acute dermal toxicity study was conducted in rabbits at the dose concentration of 2500 mg/kg bw. No mortality was observed at 2500 mg/kg bw. Therefore, LD50 value was considered to be >2500 mg/kg bw, when rabbits were treated with 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) by dermal application.

Both the studies are further supported with the study conducted on guinea pigs and mentioned in handbook and authoritative database for the target chemical 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1). The acute dermal toxicity study was conducted in guinea pigs at the dose concentration of 15000 mg/kg bw. No mortality was observed at 15000 mg/kg bw. Therefore, LD50 value was considered to be >15000 mg/kg bw, when guinea pigs were treated with 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) by dermal application.

Thus, based on the above summarised studies on 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1), it can be concluded that LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 1-phenylethan-1-ol (1-phenylethanol) cannot be classified for acute dermal toxicity.

Justification for classification or non-classification

Based on the above experimental studies on 1-phenylethan-1-ol (1-phenylethanol) (CAS No. 98-85-1) and it’s structurally and functionally similar read across substances, it can be concluded that LD50 value is between 300 – ≤ 2000 mg/kg bw, for acute oral toxicity; LD50 value is >2000 mg/kg bw, acute dermal toxicity; and LC50 value is >5 mg/L, for acute inhalation toxicity. Thus, comparing these values with the criteria of CLP regulation, 1-phenylethan-1-ol (1-phenylethanol) can be classified in “Category 4” for acute oral toxicity and cannot be classified for acute dermal and acute inhalation toxicity.