Mono- and/or di- and/or tri(1-phenylethyl)-m-cresol and p-cresol

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Jan-Aug 2012

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

All the deviations that happened were reported to Study director, and records of the deviations are enclosed in the study raw data file. The integrity of the study was not affected.

Principles of method if other than guideline:

Deviations recorded during the study:
- Different body weight values of females at the start of the study (February 2, 2012): the females prepared for the study had higher body weight than that planned in the study plan; during the randomization, the animals were divided into groups for a balanced body weight mean in all groups
- The measurements for clinical chemistry not performed in some animals (June 12, 2012): in the cases of insufficient serum sample volume for clinical chemistry evaluation, sufficient information for statistical evaluation was obtained from other animals
- Temporary oscillations of the temperature and humidity in the experimental room (July 11, 2012): minor deviations in the relative air humidity and temperature were recorded during the study, but they have not influenced the health condition of the animals
- Sending of samples for re-analysis (August 15, 2012): during the study, samples were not sent to the Sponsor for re-analysis in accordance with the study plan.

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Mono- and/or di- and/or tri(1-phenylethyl)-m-cresol and p-cresol

EC Number:

700-427-9

Molecular formula:

CnHn+1O; n=15, 23 and 31

IUPAC Name:

Mono- and/or di- and/or tri(1-phenylethyl)-m-cresol and p-cresol

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

other: Each animal from the dose groups received orally the appropriate dose of the Test item as suspension in the volume of 1 mL/100 g b.w. . Individual doses were adjusted according to the weekly body weight.

Vehicle:

other: 95% Methylcellulose 0.5 % +5% sunflower oil

Duration of treatment / exposure:

90 days

Frequency of treatment:

Dosing: Daily for 90 consecutive days

Doses / concentrations

Remarks:

Doses / Concentrations:
The concentrations of the Test item in the emulsions for dose groups D1, D2 and D3 were 0.5 %, 12.5 % and 30 %, respectively (50, 125, 300 mg/kg).
Basis:
nominal in diet

No. of animals per sex per dose:

group C, D3: 20 males + 20 females
group D1, D2: 10 males + 10 females

Control animals:

other: Yes: The control animals were treated with the vehicle in the same regime and volume.

Results and discussion

Effect levels

Dose descriptor:

NOAEL

Effect level:

> 300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

No clinical signs of intoxication and changes in health condition were observed during acclimation and administration periods in control group C and treated groups D1 (50 mg/kg of body weight), D2 (125 mg/kg of body weight) and D3 (300 mg/kg of body weight).

 

The individual values of body weight increased normally according to the animals’ age.

 

The oscillation of food consumption in all four groups during the study did not affect the growth of animals and the increase of body weight in all the animals. 

 

A decrease in the mean corpuscular volume values of erythrocytes was recorded in Examination 2, but this decrease influenced neither the changes in red blood cell count nor those in the amount of hemoglobin. Thus this finding was biologically insignificant. No treatment related changes were documented in white blood cell parameters, coagulation parameter of bone marrow count after 90-day repeated administration of Test item.

 

No treatment related changes of clinical chemistry parameters were observed after 90-day oral administration of Atlen SK. The relation of the increase in the triglycerides in the recovery D3 animals to Atlen SK administration is not probable.

 

No treatment related changes were found in urine parameters monitored after 90-day oral administration of Atlen SK.

 

None of the animals in this study showed any ophthalmologic findings, both before and at the end of the observation period (before necropsy).

 

Organ weight analysis did not find any treatment-related changes.

 

Athlen SK in doses used did not cause gross or histopathological changes in the liver and kidneys of the animals indicative of a toxic effect.

Atlen SK orally administered to rats did not cause any pathological changes in the gastrointestinal tract.

Other lesions found in the treated animals were either of spontaneous character or they were not in direct relation with the Atlen SK administered.

Applicant's summary and conclusion

Conclusions:

Based on available data Atlen SK is not classified as toxic after repeated exposure via oral route (STOT RE 2 according to CLP or R48/22 according to DSD).