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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
15 March 2004 to 11 April 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
yes
Principles of method if other than guideline:
Deviations: The dosage, postdosage and scheduled sacrifice periods were each extended for an additional 3 days. 30 rats were received at the testing facility rather than the 20 rats stated in the protocol. Rat 5389 in the 550 mg/kg/day dosage group was given 3 h and 4 h observations at 4 h 39 minsand 4 h 46 mins, respectively. These deviations are not considered to adversely affect the study integrity.
GLP compliance:
yes
Remarks:
Quality assurance statement only.
Test type:
up-and-down procedure
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Ethyl phenols
- Substance type: Phenol
- Physical state: Liquid
- Analytical purity: 98.81%
- Impurities (identity and concentrations): Not stated
- Composition of test material, percentage of components: Not stated
- Isomers composition: Not applicable
- Purity test date: Not stated
- Lot/batch No.: 13JAN2004
- Expiration date of the lot/batch: Not stated
- Stability under test conditions: Not stated
- Storage condition of test material: Closed container at room temperature and protected from light

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)IGS BR VAF/Plus
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Portage, Michigan, USA
- Age at study initiation: 63 days (at arrival)
- Weight at study initiation: 197 - 223 g (the day after arrival)
- Fasting period before study: Fasted on the night before the dosage administration, with feed returned to the animals following the 4 h clinical observation.
- Housing: Individually housed in stainless-steel wire-bottomed cages.
- Diet (e.g. ad libitum): Certified Rodent Diet #5002 (PMI Nutrition International, Inc., St. Louis, Missouri, USA).
- Water (e.g. ad libitum): Local water, passed through a reverse osmosis membrane, available ad libitum, via individual water bottles. Chlorine was added to the processed water as a bacteriostat.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 64 - 79°F (18 - 26°C)
- Humidity (%): 30 - 70%
- Air changes (per hr): Positive airflow, minimum of 10 changes per hour of HEPA filtered air.
- Photoperiod (hrs dark / hrs light): 12 h dark / 12 h light

IN-LIFE DATES: From: 15 March 2004 To: 11 April 2004

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 35 mg/mL vehicle, 110 mg/mL vehicle and 350 mg/mL vehicle
- Amount of vehicle (if gavage): 5 mL/kg
- Justification for choice of vehicle: Not stated, guideline vehicle substance.
- Lot/batch no. (if required): 062K0006
- Purity: Not stated
Doses:
175, 550 and 1750 mg/kg/day
No. of animals per sex per dose:
All females, 1 rat for 175 mg/kg/day, 4 rats for 550 mg/kg/day, 4 rats for 1750 mg/kg/day,
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Pre-dose, at least once in the 30 mins after dosage, approx. hourly intervals for the first 4 h and then daily thereafter for observations. Body weights were recorded weekly during acclimation, daily during the dosing and observation period and at sacrifice.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, feed consumption

Results and discussion

Effect levelsopen allclose all
Sex:
female
Dose descriptor:
LD50
Effect level:
980.62 other: mg/kg
Remarks on result:
other: Calculated from log10 values.
Sex:
male/female
Dose descriptor:
other: NOEL
Effect level:
ca. 175 mg/kg bw
Based on:
other: Adverse clinical signs at 550 mg/kg bw
Mortality:
3 rats died in the 1750 mg/kg dose group from treatment related effects.
Clinical signs:
Clinical observations which were determined to be dose related included: lacrimation, excess salivation and urine stained fur in both the 550 and 1750 mg/kg dose groups. Decreased motor activity, twitches, prostrate, ptosis, limited use of hindlimbs, lost proprioceptive positioning, no use of both hind and forelimbs, ataxia, lost righting reflex, tachypnea, impaired righting reflex and scant faeces were observed in the 1750 mg/kg dose group.
Body weight:
Body weight changes were reduced in the 550 and 1750 mg/kg dose groups compared to the rat in the 175 mg/kg dose group. However, all surviving rats gained weight after dose administration.
Gross pathology:
Necropsy confirmed the clinical observations. No gross lesions were found.
Other findings:
Feed consumption values, both absolute (g/day) and relative (g/kg/day) showed a dose dependent reduction in the day after dosing in the 550 and 1750 mg/kg dose groups. This trend continued until day 5 post dosing, after which the values remaind comparative to the 175 mg/kg dosed animal.

Any other information on results incl. tables

Three rats in the 1750 mg/kg/day dose group were found dead during the study. Eight of the nine test animals showed dose related effects. There were no deaths in the 175 and 550 mg/kg/day dose groups. Clinical observations which were determined to be dose related included: lacrimation, excess salivation and urine stained fur in both the 550 and 1750 mg/kg dose groups. Decreased motor activity, twitches, prostrate, ptosis, limited use of hindlimbs, lost proprioceptive positioning, no use of both hind and forelimbs, ataxia, lost righting reflex, tachypnea, impaired righting reflex and scant faeces were observed in the 1750 mg/kg dose group. Necropsy confirmed the clinical observations. No gross lesions were found.

Body weight changes were reduced in the 550 and 1750 mg/kg dose groups compared to the rat in the 175 mg/kg dose group. However, all surviving rats gained weight after dose administration. Feed consumption values, both absolute (g/day) and relative (g/kg/day) showed a dose dependent reduction in the day after dosing in the 550 and 1750 mg/kg dose groups. This trend continued until day 5 post dosing, after which the values remaind comparative to the 175 mg/kg dosed animal.

Table 1: Mortality results of the up and down procedure with ethyl phenols

Step

Dose (mg/kg)

Response

Include

Log10 dose

1

175

O

No

-

2

550

O

Yes

2.740

3

1750

X

Yes

3.243

4

550

O

Yes

2.740

5

1750

X

Yes

3.243

6

550

O

Yes

2.740

7

1750

X

Yes

3.243

8

550

O

No

-

9

1750

O

No

-

Total

17.949

O = alive, X = dead
Sum of log10 doses/# of eligible rats: 17.949/6 = 2.9915, antilog of 2.9915 = 980.62 mg/kg = LD50

Table 2: Summary of observations of adverse effects during study

Observation

175 mg/kg

550 mg/kg

1750 mg/kg

Death

0

0

3

Lacrimation

0/0

1/1

4/4

Decreased motor activity

0/0

0/0

4/4

Twitches

0/0

0/0

3/3

Prostrate

0/0

0/0

3/3

Excess salivation

0/0

1/1

2/2

Ptosis

0/0

0/0

2/2

Limited use of hindlimbs

0/0

0/0

2/2

Lost proprioceptive positioning

0/0

0/0

2/2

No use of both hind and forelimbs

0/0

0/0

2/2

Ataxia

0/0

0/0

2/2

Lost righting reflex

0/0

0/0

2/2

Tachypnea

0/0

0/0

2/2

Urine stained abdominal fur

0/0

4/2

5/1

Impaired righting reflex

0/0

0/0

1/1

Scant faeces

0/0

0/0

1/1

Clear perinasal substance

0/0

1/1

0/0

Chromorhinorrhea

0/0

1/1

0/0

Maximum possible incidence

14/1

56/4

17/4

Maximum possible incidence = (days x rats)/number of rats examined per group
N/N = total number of observations/number of rats with observation

   

Table 3: Summary of body weight data

Rat body weight (g)

175 mg/kg

550 mg/kg

1750 mg/kga

Day 1

203 ± 0.0

216.0 ± 14.4

225.8 ± 14.9

Day 2

219.0 ± 0.0

223.5 ± 22.7

229.0 ± 0.0

Day 3

216.0 ± 0.0

234.2 ± 19.5

220.0 ± 0.0

Day 4

227.0 ± 0.0

235.0 ± 19.1

234.0 ± 0.0

Day 5

228.0 ± 0.0

240.0 ± 22.4

246.0 ± 0.0

Day 6

233.0 ± 0.0

236.2 ± 19.0

254.0 ± 0.0

Day 7

241.0 ± 0.0

239.8 ± 21.4

258.0 ± 0.0

Day 8

239.0 ± 0.0

243.0 ± 25.1

255.0 ± 0.0

Day 9

241.0 ± 0.0

247.5 ± 24.6

262.0 ± 0.0

Day 10

246.0 ± 0.0

248.0 ± 22.2

262.0 ± 0.0

Day 11

261.0 ± 0.0

250.0 ± 18.8

268.0 ± 0.0

Day 12

254.0 ± 0.0

251.0 ± 17.6

272.0 ± 0.0

Day 13

263.0 ± 0.0

249.8 ± 24.0

279.0 ± 0.0

Day 14

263.0 ± 0.0

252.5 ± 24.0

276.0 ± 0.0

Mean ± SD
a= Excludes values for rats found dead.

 

Table 4: Summary of feed consumption data

Feed consumption (g/day)

175 mg/kg

550 mg/kg

1750 mg/kga

Day 1-2

17.0 ± 0.0

11.8 ± 3.9

1.0 ± 0.0

Day 2-3

17.0 ± 0.0

19.8 ± 3.5

1.0 ± 0.0

Day 3-4

17.0 ± 0.0

18.5 ± 5.4

12.0 ± 0.0

Day 4-5

18.0 ± 0.0

17.7 ± 1.2

17.0 ± 0.0

Day 5-6

17.0 ± 0.0

18.0 ± 5.0

20.0 ± 0.0

Day 6-7

20.0 ± 0.0

20.5 ± 1.7

24.0 ± 0.0

Day 7-8

19.0 ± 0.0

19.2 ± 5.1

22.0 ± 0.0

Day 8-9

22.0 ± 0.0

19.2 ± 4.4

22.0 ± 0.0

Day 9-10

17.0 ± 0.0

21.5 ± 1.3

26.0 ± 0.0

Day 10-11

24.0 ± 0.0

19.0 ± 1.6

24.0 ± 0.0

Day 11-12

16.0 ± 0.0

20.5 ± 3.3

24.0 ± 0.0

Day 12-13

17.0 ± 0.0

18.5 ± 3.1

25.0 ± 0.0

Day 13-14

20.0 ± 0.0

18.2 ± 3.3

21.0 ± 0.0

Day 1-14

18.5 ± 0.0

18.7 ± 2.2

18.4 ± 0.0

Mean ± SD
a= Excludes values for rats found dead.

Applicant's summary and conclusion

Executive summary:

Based on this study, the LD50 for ethyl phenols was determined to be 980.62 mg/kg. Mortality occurred in three of the four rats given the highest dose of 1750 mg/kg. Adverse clinical signs were observed at doses of 550 and 1750 mg/kg. A single dose of 175 mg/kg had no observable effect during the study.