Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
11/01/1991-27/02/1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study (OECD 401)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): phenol 2-(1-methylpropyl)
- Substance type: mono alkylphenol
- Physical state: colourless liquid
- Analytical purity: 99.35 (GC)
- Impurities (identity and concentrations):
- Purity test date: 12/10/1990
- Lot/batch No.: 2-sek-AP/321
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Manston, Kent, U.K.
- Age at study initiation: approximately five to eight weeks old
- Weight at study initiation: At the start of the main study the males weighed 200 - 214 g, and females 156 - 181 g
- Fasting period before study: overnight fast immediately before dosing and for approximately two hours after dosing
- Housing: the animals were housed in groups of up to five by sex in solid-floor polypropylene cages with sawdust bedding
- Diet (e.g. ad libitum): with the excepction of an overnight fast immediately before dosing and for approximately two hours after dosing, food ad libitum (Rat and Mouse Expanded Diet No. 1, Special Diet Services Limited, Witham, Essex, UK)
- Water (e.g. ad libitum): with the excepction of an overnight fast immediately before dosing and for approximately two hours after dosing, drinking water ad libitum
- Acclimation period: after minimum acclimatisation period of at least five days the animals selected at random and given a unique number within the study by indelible ink marking on the tail and a number written on a cage card


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23°C
- Humidity (%): 42-52%
- Air changes (per hr): approximately 15 changes per hr
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
A range-finding study was performed with undiluted test material using pre-selected dose levels to determine the highest of these dose levels that caused no deaths: dose levels 5000 and 2000 mg/kg

VEHICLE
- Concentration in vehicle: range-finding study: 500, 200, 20 mg/ml. main study: 200 mg/ml
- Dose volume 10 ml/kg. The volume administered to each animal was calculated according to its fasted bodyweight at time of dosing.

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: A range-finding study was performed using pre-selected dose levels to determine the highest of these dose levels that caused no deaths
Doses:
Range-finding Study: undiluted 2000 and 5000 mg/kg. In arachis oil B.P. 200, 2000 and 5000 mg/kg
Main Study: In arachis oil B.P. 2000 mg/kg
No. of animals per sex per dose:
Range-finding Study: undiluted 2 male, 2 female. In arachis oil 3 male, 3 female
Main Study: 5 male, 5 female
Control animals:
not specified
Details on study design:
- Duration of observation period following administration:
Range finding study: 5 days
Main study: 14 days

- Frequency of observations and weighing:
Range finding study: deaths and overt signs of toxicity were recorded 1/2, 1, 2 and 4 hours after dosing and then daily for five days. Individual bodyweights were recorded on the day of dosing to allow calculation of individual treatment volumes.
Main study: deaths and overt signs of toxicity were recorded 1/2, 1, 2 and 4 hours after dosing and then daily for 14 days. Individual bodyweights were recorded on the day of treatment (day 0) and on days 7 and 14

- Necropsy of survivors performed:
Range finding study: No necropsies were performed
Main study: Yes, macroscopic observation. At the end of the study the animals were killed by cervical dislocation and subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 200 - < 2 000 mg/kg bw
Mortality:
Range finding study:
- Animals treated with undiluted material at dose levels of 2000 and 5000 mg/kg died within one hour of treatment
- Animals treated with test material in arachis oil B.P. at dose levels of 5000 or 2000 mg/kg were found dead during the day of dosing or one day after treatment.

Main study: there were no deaths
Clinical signs:
Range finding study:
- Animals treated with undiluted material at dose levels of 2000 and 5000 mg/kg: increased salivation, ptosis and coma.
- Animals treated with test material in arachis oil B.P. at dose levels of 5000 or 2000 mg/kg: signs of systemic toxicity noted in these animals were lethargy, loss of righting reflex, decreased respiratory rate, ptosis, ataxia and hunched posture. Animals treated with 200 mg/kg appared normal throughout the study.

Main study: lethargy was noted in all animals up to one hour after dosing. All animals appeared normal two hours after treatment and for the rest of the study.
Body weight:
Main study: all animals showed expected gain in bodyweight during the study
Gross pathology:
Main study: No abnormalities were noted at necropsy (killed day 14)

Any other information on results incl. tables

Individual Clinical Observations and mortality data in the range-finding study

Dose level

Mg/kg

Animal number & sex

Effects noted after dosing (hours)

Effects noted during period after dosing (days)

1/2

1

2

4

1

2

3

4

5

5000

1-0 male

CoPtS

X

2-0 female

CoPtS

X

2000

1-1 male

CoPtS

X

2-1 female

X

200

3-0 male

0

0

0

0

0

0

0

0

0

4-0 female

0

0

0

0

0

0

0

0

0

2000

5-1 male

LRrRd

HLRd PtA

HLRd

PtA

HPtA

X

6-1 female

RrPt

X

5000

5-0 male

X

6-0 female

RrPtRd

X

Key for clinical observations:

Co = coma

S = increased salivation

H = hunched posture

L = lethargy

Rd = decreased respiratory rate

Pt = ptosis

A = Ataxia

Rr = loss of righting reflex

0 = no signs of systemic toxicity

X = animal dead

Individual bodyweights and weekly bodyweight increases in the main study

 Dose Level

 Animal Number

   Bodyweight (g) at Day        Increment (g) During Week
 mg/kg & Sex 0 7 14   1 2  
 200  7 -0 Male 214  263 305 49  42   
   7 -1 Male 200 253  297 53  44  
   7 -2 Male 203 277  314 74  37   
   7 -3 Male 202  274 327  72  53  
 7 -4 Male 204  255  304  51  49  
   8 -0 Female 165  206  237 41  31  
   8 -1 Female  181 201 220 20 19  
   8 -2 Female 161  193  218  32 25  
   8 -3 Female 164 206 234  42 28  
  8 - 4 female  156   192  210  36 18  

Applicant's summary and conclusion

Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral median lethal dose (LD50) of the test material, phenol 2-(1-methylpropyl), in the Sprague-Dawley strain rat was found to be greater than 200 mg/kg bodyweight but less than 2000 mg/kg bodyweight. The test material is classified as harmful and the symbol "Xn" and risk phrase R 22 "harmful if swallowed" are therefore required according to EEC labelling regulations.
Executive summary:

A study was performed to asses the acute oral toxicity of the test material in the Sprague-Dawley strain rat. The method used followed that described in the OECD Guidelines for Testing of chemicals (1981) No. 401 "Acute Oral Toxicity" referenced as Method B1 in Commission Directive 84/449/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

Following a range-finding study, a group of ten fasted animals (five males and five females) was given a single oral dose of test material, as a solution in arachis oil B.P. at a dose level of 200 mg/kg bodyweight. The animals were observed for fourteen days after the day of dosing and were then killed for gross pathological examination.

There were no deaths. Lethargy was noted in all animals during the day of dosing. All animals showed expected gain in bodyweight during the study. No abnormalities were noted at necropsy.

The acute oral median lethal dose (LD50) of the test material, phenol 2-(1-methylpropyl), in the Sprague-Dawley strain rat was found to be greater than 200 mg/kg bodyweight but less than 2000 mg/kg bodyweight.