Esterification product of castor oil fatty acids and pentaerythritol

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:

Nov. 1992 - Dec. 1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1993

Report date:

1993

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

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Fatty acids, C5-9, tetraesters with pentaerythritol

EC Number:

267-022-2

EC Name:

Fatty acids, C5-9, tetraesters with pentaerythritol

Cas Number:

67762-53-2

Molecular formula:

C25H44O8 to C41H76O8

IUPAC Name:

Reaction Products of fatty acids C5-C9 linear saturated and pentaerythritol

Details on test material:

- Substance type: pentaerythritol ester, tetrasubstituted
- Physical state: Not stated
- Analytical purity: 98%
- Composition of test material, percentage of components: pentaerythritol tetrasubstituted with fatty acids (C7: 52%; C8 branched: 25%; C9: 10%; C10: 13%)
- Stability under test conditions: 5 weeks

Test animals

Species:

rat

Strain:

other: Alpk:APfSD

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Zeneca Pharmaceuticals, Alderly Park, Macclesfield, Cheshire, UK
- Age at study initiation: 28 d
- Housing: sexes separately, five per cage, Cages had measurements of 26.5x50.0x20.0 cm and were constructed of stainless steel mesh with one solid side.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: approx. 1 week

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: ethyl acetate

Details on oral exposure:

DIET PREPARATION
- Storage temperature of food: - 20°C, stored at RT for usage up to 14 days

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Chemical stability was determined for diets over a period of 5 weeks following storage at RT or at -20°C.
Samples were extracted by chemical shaking with ethyl acetate. The supernatant was diluted with ethyl acetate to give solutions containing appropriate concentrations of the test substance. Extracts were analysed by gas chromatography using flame ionisation detection. The extract concentration was calculated by reference to data from a standard containing a known concentration.

Duration of treatment / exposure:

daily

Frequency of treatment:

28 d

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0 ppm, 1000 ppm, 5000 ppm, 12500 ppm
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
112 mg/kg/d, 562 mg/kg/d, 1450 mg/kg/d
Basis:
other: actual ingested for males

Doses / concentrations 3

Remarks:

Doses / Concentrations:
119 mg/kg/d, 586 mg/kg/d, 1613 mg/kg/d
Basis:
other: actual ingested for females

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Dose selection rationale: Based on results of preliminary feeding studies
- Rationale for animal assignment (if not random): sexes separately

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked: changes in clinical condition and behaviour and significant changes were recorded.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: on days 8, 15, 22, 29
- assessment of autonomic function, description, incidence and severity of convulsions, tremors, abnormal motor function, alteration in respiration, Reactivity to stimuli, changes in the level of arousal, sensorimotor responses,


BODY WEIGHT: Yes, intervals not reported.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as mg food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes, Platelet count, White Blood Cell Count, Neutrophil count, Lymphocyte count, Monocyte count, Eosinophil count, Prothrombin time and Kaolin-cephalin Time

CLINICAL CHEMISTRY: Yes, Plasma gamma-glutamyl transferase, plasma alanine aminotransferase, plasma aspartate aminotransferase, plasma creatine kinase, plasma sodium, plasma potassium, plasma chloride, plasma calcium and plasma phosphorus

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: on days 8, 15, 22, 29
- Dose groups that were examined: All
- Battery of functions tested: sensory activity / grip strength

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (Adrenals, Aorta, Bladder, Bone and Bone marrow (femur), Brain, Caecum, Colon, Cervical lymph node, Cervix, Colon, Duodenum, Epididymis, Eye and harderian gland, Heart, Ileum, Jejunum, Kidney, Liver, Lungs, Mammary gland, Mesenteric lymph node, Nasal passages, Oesophagus, Oral cavity, Ovaries, Pancreas, Parathyroid glad, Pituary gland, Prostate gland, Rectum, Salivary glands, Sciatic nerve, Seminal vesicles, Skin, Spinal chord, Spleen, Sternum, Stomach, Testes, Thymus, Thyroid gland, Trachea, Uterus, Voluntary muscle)

Statistics:

Bodyweights were considered by analysis of covariance on initial body weight, separately for males and females.

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

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:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
No mortality, 3 isolated cases of slightly reduced splay reflex were considered to be incidental to treatment

BODY WEIGHT AND WEIGHT GAIN
No effects on body weight gain

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
The dose received for each group was highest at the start of the study and declined rapidly during the period of rapid growth to week 4.

NEUROBEHAVIOUR
There were no differences in time taken to tail flick in either sex

ORGAN WEIGHTS
Kidney weight was statistically increased in males at 5000 and 12500 ppm and all females in the treatment groups had slightly increased kidney weights compared to the control. There was no evidence of a coherent dose response relationship.
Liver weight was statistically increased in males at 5000 and 12500 ppm and in females at 12500 ppm. Treatment related changes are considered not relevant for human and therefore not employed for NOEL determination.

GROSS PATHOLOGY
There were no treatment related macroscopic pathological findings at the end of the study.

HISTOPATHOLOGY: NON-NEOPLASTIC
Treatment related findings in the liver of male rats occurred at all doses. At 5000 and 12500 ppm increased tubular hyaline droplet formation and tubular basophilia and granular cast formation was found. In the 1000 ppm group analogous effects except for granular cast formation were seen. This is considered specific to the male rat and as such appears to have no relevance to man.
Four out of five male rats had hepatocyte hypertrophy in the 12500 ppm group, this is considered to be evidence of an adaptive response.


HAEMATOLOGY: No adverse effects on haematological parameters

CLINICAL CHEMISTRY: No adverse effects on tested parameters

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

12 500 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No effects observed in female rats

2

Key result

Dose descriptor:

NOAEL

Effect level:

1 613 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No effects observed in female rats

3

Key result

Dose descriptor:

NOAEL

Effect level:

12 500 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Treatment related histopathological changes and changes in kidney and liver weight in male rats at 5000 ppm and above are considered not relevant for human and therefore not employed for NOEL determination.

4

Key result

Dose descriptor:

NOAEL

Effect level:

1 450 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Treatment related histopathological changes and changes in kidney and liver weight in male rats at 5000 ppm and above are considered not relevant for human and therefore not employed for NOEL determination.

Target system / organ toxicity

Key result

Critical effects observed:

not specified