Heptanoic acid, mixed esters with pentaerythritol and valeric acid

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

09 Jul - 10 Oct 1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions (no data on test substance purity; only 2 dose groups, open application, limited parameters examined)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)

Deviations:

yes

Remarks:

(no data on test substance purity, only 2 dose groups, open application, limited parameters examined)

GLP compliance:

no

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

IUPAC Name:

67762-53-2

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Lakeview, NJ, USA
- Age at study initiation: approx. 7 weeks
- Housing: individually in hanging, stainless steel cages with wire bottoms and fronts
- Diet: Purina Certified Lab Chow ' 5002 in pellet form; ad libitum
- Water: tap water; ad libitum
- Acclimation period: at least 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:

open

Vehicle:

unchanged (no vehicle)

Details on exposure:

TEST SITE
- Area of exposure: no data
- Type of wrap if used: no wrap used, open
- Time intervals for shavings or clipplings: 24 h before the first treatment; at least weekly afterwards
- Application site: back (shaved)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no washing; wiping off with a gauze pads every saturday (applications on working days)

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): no data
- Concentration (if solution): undiluted
- Constant volume or concentration used: no

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes (collars), removal during the weekend

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

5 days per week (65 exposures), 24 hours/day, removal of substance on saturdays (once a week)

Doses / concentrations

Remarks:

Doses / Concentrations:
800 and 2000 mg/kg bw/day
Basis:
nominal per unit body weight

No. of animals per sex per dose:

10
(5 additional animals of the control and the high dose group were included for dermal bioavailability experiments only.)

Control animals:

yes, concurrent no treatment

Details on study design:

The test substance was dispensed by volume from a syringe and left uncovered on the shaved skin. The rats were fitted with cardboard Elizabethan collars to minimze ingestion of the test material.
The controls were treated in the same manner except that no material was applied to their skin.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: appearance, behaviour, secretory function and discharges

DETAILED CLINICAL OBSERVATIONS: No

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: weekly
- Parameters evaluated: erythema and edema according to Draize, chronic deterioration: flaking, thickening, stiffening, cracking and slouthing

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

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

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at study termination
- Animals fasted: No data
- How many animals: all animals
- Parameters examined: red blood cells, white blood cells, and platelets

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at study termination
- Animals fasted: No data
- How many animals: all animals
- Parameters examined: glucose, urea nitrogen, alanine aminotransferase, albumin, phosphorus; only females: lactate dehydrogenase, aspartate aminotransferase

URINALYSIS: Yes
- Time schedule for collection of urine: weeks 5 and 13
- Metabolism cages used for collection of urine: No
- Parameters examined: pH, bilirubin, specific gravity, urobilinogen, blood, protein, glucose, ketones

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: sperm morphology: at termination
- Parameters: percentage normal sperm, abnormal heads, headless, tailless, and curled tail

Sacrifice and pathology:

GROSS PATHOLOGY: Yes; organ weights: kidneys, liver; only males: brain, spleen; only females: thyroids
HISTOPATHOLOGY: Yes (no further information available)

Statistics:

The level of statistical significance was P < 0.05.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

slight erythemal and flaking; slight epidermal hyperplasia and chronic inflammation (both treatment groups)

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

reduced body weight gain in males (800 mg/kg: 7% and 2000 mg/kg: 10%)

Food consumption and compound intake (if feeding study):

not examined

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:

no effects observed

Behaviour (functional findings):

not examined

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 SIGNS AND MORTALITY
No treatment-related effects were observed.

BODY WEIGHT AND WEIGHT GAIN
Treated males gained slightly less weight than the controls (800 mg/kg bw: 7%, 2000 mg/kg bw: 10%). As the difference is low, the decrease in body weight was not interpreted as a sign for systemic toxicity.

HAEMATOLOGY
No adverse effects on any haematologic parameters measured were observed.

CLINICAL CHEMISTRY
A few of the serum paramters of the high-dose animals were statistically different from the controls, but the differences were small, not consistent between males and females, and did not present any pattern suggestive of effects on any specific organ (no corresponding histological findings). Thus, the effects were considered not to be of toxicological relevance.
- high-dose males (compared to controls): glucose: -14%, albumin: -3%, and phoshorus: +16%
- high-dose females (compared to controls): lactate dehydrogenase: +45% (low-dose: +22%), and aspartate aminotransferase: +22%

URINALYSIS
No additional data given on Urinalysis in study report.

ORGAN WEIGHTS
Increased thyroid weight in the low-dose (+ 25%) females and decreased spleen weight (- 10%) in the low-dose males were not considered to be toxicologically relevant, as these effects were not observed in the high-dose groups.

GROSS PATHOLOGY
No abnormalities were detected.

HISTOPATHOLOGY:
No abnormalities were detected.

OTHER FINDINGS
- Sperm morphology: No effects on sperm morphology were detected.
- Local effects: Slight erythema and flaking of the skin were observed in the treated groups during the dosing phase. Microscopic examination of the skin indicated trace to slight epidermal hyperplasia and chronic inflammation of the superficial dermis.

SKIN PENETRATION
Skin penetration values of 2 - 6% were obtained.
The results of the in vivo skin penetration study indicate that the 13-week treatment with the test substance does not increase the skin penetration of the test substance (only the value for females was statistically different from the penetration in untreated animals). The skin penetration of untreated rats was less than 2% and the mean value for treated rats was approx. 6%. The recovery of radioactivity was measuered in the urine and faeces as well as the remaining radioactivity in tissue samples.

Effect levels

Dose descriptor:

NOAEL

Effect level:

>= 2 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: highest dose tested

Target system / organ toxicity

Critical effects observed:

not specified