L-97-034-PB

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

22nd January - 3rd June 1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Pentaerythritol mixed esters with 2-methyl butyric acid, n-pentanoic acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid, n-decanoic acid

Cas Number:

141686-49-9

IUPAC Name:

Pentaerythritol mixed esters with 2-methyl butyric acid, n-pentanoic acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid, n-decanoic acid

Constituent 2

Reference substance name:

Trimethylol propane mixed esters with 2-methyl butyric acid, n-pentanoic acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid, n-decanoic acid

Cas Number:

141686-50-2

IUPAC Name:

Trimethylol propane mixed esters with 2-methyl butyric acid, n-pentanoic acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid, n-decanoic acid

Test material form:

liquid

Details on test material:

Identification: Hatcol ® 1772
Appearance/physical state: Clear colorless liquid
Purity: 100% (no solvent present)
Composition: 70% pentaerythritol esters described by CAS# 141686-49-9; 30% trimethylolpropane esters described by CAS# 141686-50-2

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

The rat was selected for this study as it is a readily available rodent species historically used in safety evaluation studies and is acceptable to appropriate regulatory authorities.

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

arachis oil

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Slight reduction in food consumption detected for females treated with 1000 mg/kg/day throughout the dosing period when compared with that of controls. No such effects were detected for 1000 mg/kg/day males or for animals of either sex treated with 500 or 150 mg/kg/day.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not specified

Behaviour (functional findings):

no effects observed

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Animals of either sex treated with 1000 mg/kg/day showed an increase in liver weight, both absolute and relative to bodyweight, when compared with controls, the effect extending to 500 mg/kg/day animals. Absolute and relative kidney weights were also elevated at 1000 and 500 mg/kg/day but this was confined to the males only. No adverse effect on organ weights was detected at 150 mg/kg/day.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Macroscopic abnormalities were detected in animals treated with 1000 mg/kg/day. All of the males showed speckled kidneys and two females showed pallor of the liver at terminal kill. One female treated with 500 mg/kg/day also showed a pale liver at necropsy. No treatment-related macroscopic abnormalities were detected in animals treated with 150 mg/kg/day.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histopathological examination revealed treatment-related changes in the kidneys. Globular accumulations of eosinophilic material were observed in the renal proximal tubular epithelium of males treated with 1000, 500 or 150 mg/kg/day. This condition is typical of hydrocarbon nephropathy which is peculiar to the male rat. It does not, therefore, represent a hazard to human health.

Effect levels

1

Key result

Dose descriptor:

NOEL

Based on:

test mat.

Sex:

male

Remarks on result:

not determinable

2

Key result

Dose descriptor:

NOEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

gross pathology

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Oral administration of the test material to rats for twenty-eight consecutive days, at dose levels of up to 1000 mg/kg/day, resulted in treatment-related changes for males at all dose levels and for females at 1000 mg/kg/day. A clear No Observed Effect Level (NOEL) for males was, therefore, not obtained whilst the NOEL for females was considered to be 500 mg/kg/day. Nevertheless, the treatment-related effects were confined to increased liver weight with no concomitant histopathology and the male rat specific condition, hydrocarbon nephropathy. These changes were not considered to represent serious damage to health, as defined by the criteria given in the EC labelling guide of Commission Directive 93/21/EEC.

Executive summary:

Introduction

The study was designed to investigate the systemic toxicity of the test material. Following the Sponsor's revised requirements for notification of the test material the data reported complies with the requirements for notification of a new chemical substance in the EC and follows the testing method described in Commission Directive 96/54/EC (Method B7) and OECD Guidelines for Testing of Chemicals No. 407 "Repeated Dose 28 Day Oral Toxicity Study in Rodents" (Adopted 27 July 1995).

The test material was administered by gavage to three groups, each of five male and five female Sprague-Dawley Crl:CD®BR strain rats, for twenty-eight consecutive days, at dose levels of 1000, 500 and 150 mg/kg/day. A control group of five males and five females was dosed with vehicle alone (Arachis oil BP). Clinical signs, functional observations, bodyweight development and food and water consumption were monitored during the study. Haematology and blood chemistry were evaluated for all animals at the end of the study.

All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed.

Mortality

There were no deaths during the study.

Clinical observations

There were no clinically observable signs of toxicity detected in test or control animals during the study.

Functional observations

No intergroup behavioural differences were detected.

No intergroup functional performance differences were detected.

No intergroup sensory reactivity assessment differences were detected.

Bodyweight

No adverse effect on bodyweight development was detected.

Food consumption

A slight reduction in food consumption was detected for females treated with 1000 mg/kg/day throughout the dosing period when compared with that of controls. No such effect was detected for 1000 mg/kg/day males or for animals of either sex treated with 500 or 150 mg/kg/day.

Water consumption

Visual inspection of water bottles revealed no intergroup differences.

Haematology

No treatment-related effects were detected in the haematological parameters measured.

Blood chemistry

No treatment-related effects were detected in the blood chemical parameters measured.

Organ weights

Animals of either sex treated with 1000 mg/kg/day showed an increase in liver weight, both absolute and relative to bodyweight, when compared with controls, the effect extending to 500 mg/kg/day animals. Absolute and relative kidney weights were also elevated at 1000 and 500 mg/kg/day but this was confined to the males only. No adverse effect on organ weights was detected at 150 mg/kg/day.

Necropsy

Macroscopic abnormalities were detected in animals treated with 1000 mg/kg/day. All of the males showed speckled kidneys and two females showed pallor of the liver at terminal kill.One female treated with 500 mg/kg/day also showed a pale liver at necropsy.No treatment-related macroscopic abnormalities were detected in animals treated with 150 mg/kg/day.

Histopathology

Histopathological examination revealed treatment-related changes in the kidneys. Globular accumulations of eosinophilic material were observed in the renal proximal tubular epithelium of males treated with 1000, 500 or 150 mg/kg/day. This condition is typical of hydrocarbon nephropathy which is peculiar to the male rat. It does not, therefore, represent a hazard to human health.

Conclusion

Oral administration of the test material to rats for twenty-eight consecutive days, at dose levels of up to 1000 mg/kg/day, resulted in treatment­ related changes for males at all dose levels and for females at 1000 mg/kg/day. A clear No Observed Effect Level (NOEL) for males was, therefore, not obtained whilst the NOEL for females was considered to be 500 mg/kg/day. Nevertheless, the treatment-related effects were confined to increased liver weight with no concomitant histopathology and the male rat specific condition, hydrocarbon nephropathy. These changes were not considered to represent serious damage to health, as defined by the criteria given in the EC labelling guide of Commission Directive 93/21/EEC.