Pentaerythritol, reaction product with fatty acids, C8 to 18 (even numbered) and/or branched and/or unsaturated

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study has been performed according to OECD guidelines and according to GLP principles

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2008

Report date:

2008

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

yes

Remarks:

One thyroid (an 2) and the colon (an 39) were not available for histopathology. The brain weight of an 6 was inadvertently not determined. Evaluation: sufficient tissues/organs/data were available for evaluation.

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Deviations:

yes

Remarks:

One thyroid (an 2) and the colon (an 39) were not available for histopathology. The brain weight of an 6 was inadvertently not determined. Evaluation: sufficient tissues/organs/data were available for evaluation.

Principles of method if other than guideline:

United States Environmental Protection Agency (EPA). Health Effects Test Guidelines, OPPTS 870.3050, Repeated dose 28- day oral toxicity study in rodents. Office of Prevention, Pesticides and Toxic Substances (7101), EPA 712-C-00-366, July 2000.

GLP compliance:

yes

Limit test:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Details on test material:

- Name of test material Pentaerythritol, reaction product with fatty acids, C8 to 18 (even numbered) and/or branched and/or unsaturated
- Physical state: Pale yellow liquid
- Analytical purity: Not indicated
- Lot/batch No.: OE70406
- Expiration date of the lot/batch: 06 April 2011
- Stability under test conditions: Stable
- Storage condition of test material: In refrigerator (2-8ºC) in the dark

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: The test substance was administered undiluted.

Details on oral exposure:

Method of administration:
Oral gavage, using a plastic feeding tube.

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

No analyses were conducted since the test substance was dosed undiluted.

Duration of treatment / exposure:

28 days

Frequency of treatment:

7 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 150, 450, 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

Based on the results of a 5-day range finding study (NOTOX Project 485757), the dose levels for this 28-day oral gavage study were selected to be 0, 150, 450 and 1000 mg/kg bw/d.

Examinations

Observations and examinations performed and frequency:

The following parameters were evaluated:
Clinical signs daily, functional observation tests in week 4, body weight and food consumption weekly, clinical pathology and macroscopy at termination, organ weights and histopathology on a selection of tissues.

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):

no effects observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

Clinical observations:
No mortality occurred during the study period.
No clinical signs were noted during the observation period.

Functional observations:
Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all animals.
The variation in motor activity did not indicate a relation with treatment.

Body weights:
No toxicologically significant changes in body weights and body weight gain were noted.
The statistically significant higher body weight gain of females at 1000 mg/kg bw/d in week 3 of the study was of a very slight nature, and an opposite effect increasing with time would be expected. Therefore this change was considered to be of no toxicological significance.

Food Consumption:
No toxicologically significant changes in food consumption.

Laboratory findings:
Haematology:
No toxicologically relevant changes occurred in haematological parameters of treated rats.
Any statistically significant changes were considered to be of no toxicological significance as they occurred in the absence of a treatment-related distribution and/or remained within the range considered normal for rats of this age and strain. These changes included lower relative neurtophil counts and higher relative lymphocyte counts in males at 150 mg/kg/day. lower relative eosinophil counts in males at 150 mg/kg/day and higher, and al ower mean corpuscular haemoglobin concentration (MCHC) in males at 1000 mg/kg/day.

Clinical biochemistry:
The following statistically significant changes in clinical biochemistry parameters distinguished treated animals from control animals:
- Increased creatinine levels in males at 1000 mg/kg/day,
- Increased glucose levels in males at 1000 mg/kg/day,
- Increased potassium levels in males at 1000 mg/kg/day,
- Increased chloride levels in females at 1000 mg/kg/day.
Other statistically significant changes occurred in the absence of a treatment-related distribution and remained within the range considered normal for rats of this age and strain. These changes included higher alkaline phosphatase activity (ALP) in males at 450 mg/kg/day. These alterations were considered to be of no toxicological significance.

Pathology:
Macroscopy:
Necropsy did not reveal any toxicologically relevant alterations.
Incidental necropsy findings were found, and are occasionally seen among rats used in these kind of studies, and no treatment related distribution was seen. Therefore considered of no toxicological significance.

Organ weights:
Organ weights and organ to body weight ratios of treated animals were similar to those of control animals.

Microscopy:
There were no microscopic findings recorded which could be attributed to treatment with the test substance. All findings were within the range of background pahtology.

Effect levels

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects at highest dose tested.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Comments:
No toxicologically significant changes in body weights and
body weight gain were noted.

No toxicologically significant changes in food consumption
before or after allowance for body weight were noted.


The few minor changes in clinical biochemistry parameters
observed in animals at 1000 mg/kg/day had no
histopathological correlates. Also considering their minor
nature, these changes were considered not to represent an
adverse effect on functional integrity of organ systems.
Therefore, no toxicological significance was ascribed to
these changes.

Applicant's summary and conclusion

Conclusions:

A NOAEL for Pentaerythritol, reaction product with fatty acids, C8 to 18 (even numbered) and/or branched and/or unsaturated of >=1000 mg/kg/day was established.