[No public or meaningful name is available]

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

1960

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to valid methods and considered reliable, adequate and relevant. Limited details were available.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Chronic Toxicity Studies on Two Epoxidized Soybean Oils in the Rat and Dog.

Author:

Larson P.S., Finnegan J.K., Haag H.B., Blackwell Smith Jr. R. and Hennggar Gordan R.

Year:

1960

Bibliographic source:

Toxicology and Applied Pharmacology 2, 649-658

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Soybean oil, epoxidized

EC Number:

232-391-0

EC Name:

Soybean oil, epoxidized

Cas Number:

8013-07-8

IUPAC Name:

8013-07-8

Details on test material:

- Name of test material (as cited in study report): Paraplex G-62 and Paraplex G-60 (two epoxidized Soybean Oils)
- Substance type: UVCB
- Physical state: no data
- Analytical purity: no data
- Other: Supplied by the Rohm and Haas Company, Philadelphia, Pennsylvania

Test animals

Species:

rat

Strain:

other: young albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Not provided
- Age at study initiation: young
- Housing: . The rats were individually caged.
- Diet (e.g. ad libitum): Finely ground Purina Dog Chow Kibbled Meal served as the basic diet

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Remarks:

Finely ground Purina Dog Chow Kibbled Meal as basic diet

Details on oral exposure:

- Mixing appropriate amounts with (Type of food): Finely ground Purina Dog Chow Kibbled Meal served as the basic diet, and into this was incorporated amounts of Paraplex G-60 calculated to achieve the dietary concentrations of 0, 0.1, 0.5, 1.0, 2.5, and 5.0%.

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

Estimate of the effective concentration by analysis of regression of the data with 95 % confidence limits

Duration of treatment / exposure:

1 year continuous for the subgroups with 5 M/F per group.
2 years ciontinuous for the subgroups with 10 M/F per group.

Frequency of treatment:

daily in food

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.1, 0.5, 1.0, 2.5, and 5.0%
Basis:
nominal in diet

No. of animals per sex per dose:

15: Each group of 15 was subdivided into subgroups of 10 and 5 animals. At the end of one year, the survivors in the subgroups of 5 were sacrificed for histopathologic studies; organ to body weight measurements were made for liver, kidney, and testes. The subgroups of 10 were continued on diet for a second year.

Control animals:

yes, plain diet

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: The rats were weighed once weekly.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): no

HAEMATOLOGY: Yes
- Time schedule for collection of blood:
Paraplex G-60: Blood studies (hemoglobin, red blood cell, and differential white cell counts) were made during the eleventh and twenty-fourth months.
Paraplex G-62: Hematologic studies were made at 6 as well as at 12 and 24 months
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: subgroups of 10
- Parameters examined: hemoglobin, red blood cell, and differential white cell counts

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY:
No data
HISTOPATHOLOGY: Yes.
-Paraplex G-60: At the end of one year, the survivors in the subgroups of 5 were sacrificed for histopathologic studies; organ to body weight measurements were made for liver, kidney, and testes. Histopathologic studies were made on two-year survivors from the 0, 2.5, and 5.0% diets.
-Paraplex G-62: : At the end of 6 months, the survivors in the subgroups of 5 were sacrificed for histopathologic studies; organ to body weight measurements were made for liver, kidney, and testes. Histopathologic studies were made on two-year survivors from the 0, 2.5, and 5.0% diets.

Statistics:

Estimate of the effective concentration, liver ratio and kidney ratio by analysis of regression of the data with 95 % confidence limits.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

No definite effect on survival is apparent.

Mortality:

no mortality observed

Description (incidence):

No definite effect on survival is apparent.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

see details on results

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

see details on results

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

no lesions attributable to treatment

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
No definite effect on survival is apparent.

BODY WEIGHT AND WEIGHT GAIN
-Paraplex G-60: In both sexes there was early depression of growth at the 5% dietary level (P = < 0.05 at 2 and 4 weeks); this was followed by accelerated growth.
-Paraplex G-62: Among female rats, growth was significantly depressed during the early period on the diet. Analysis of regression of the data (linear at 2 and 8 weeks; curvilinear being required by the data at 4 weeks) with 95% confidence limits indicated the effective concentration to be about 3.75% at 2 weeks and 1.0% at 4 weeks, followed by no significant depression by 8 weeks. Among male rats, growth was also depressed during the early period. Analysis of linear regression of the data with 95 % confidence limits indicated the effective concentration to be about 2.1% at 2 weeks, 1.6% at 4 weeks, and 3.7% at 8 weeks, after which the effect gradually disappeared.

HAEMATOLOGY
-Paraplex G-60: Hematologic values were within normal limits at all dietary level.
-Paraplex G-62: Hematologic values were within normal limits at each examination.

ORGAN WEIGHTS
-Paraplex G-60: Male rats receiving the 5% diet had significantly elevated liver to body weight ratios.
-Paraplex G-62: Analysis of regression of the liver ratio data ( curvilinear for females, linear for males) with 95 % confidence limits indicate that significantly elevated ratios result from the treatment and that the effective concentration should fall at 0.5% for females and 2.3% for males. Similar statistical treatment of the kidney ratio data indicates the occurrence of significantly elevated ratios from the treatment for females only and that the effective concentration should fall at 1.6%.

HISTOPATHOLOGY: NON-NEOPLASTIC
-Paraplex G-60: Histopathologic studies on heart, lung, liver. kidney, spleen, gastroenteric, thyroid, adrenal pancreas, gonad. muscle, and bone marrow tissues of the rats at one and two years on the diet showed no lesions attributable to treatment.
-Paraplex G-62: Histopathologic studies made on the same tissues as listed above for Paraplex G-60 showed no lesions attributable to treatment.

Effect levels

Dose descriptor:

LOAEL

Effect level:

1 other: % nominal in diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: liver & kidney

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

-Paraplex G-60

Fifteen young male and 15 female albino rats were placed on each of the following dietary levels of the test material: 0, 0.1, 0.5, 1.0, 2.5, and 5.0%. Finely ground Purina Dog Chow Kibbled Meal served as the basic diet, and into this was incorporated amounts of Paraplex G-60 calculated to achieve the above dietary concentrations. The rats were individually caged and were weighed once weekly. Each group of 15 was subdivided into subgroups of 10 and 5 animals. At the end of one year, the survivors in the subgroups of 5 were sacrificed for histopathologic studies; organ to body weight measurements were made for liver, kidney, and testes. The subgroups of 10 were continued on diet for a second year. Blood studies (hemoglobin, red blood cell, and differential white cell counts) were made during the eleventh and twenty-fourth months.

Histopathologic studies were made on two-year survivors from the 0, 2.5, and 5.0% diets.

-Paraplex G-62

This study on rats was identical in all respects to that described above for Paraplex G-60 except that the rat subgroups of 5 were sacrificed at the end of 6 months and hematologic studies were made at 6 as well as at 12 and 24 months.

Applicant's summary and conclusion

Conclusions:

Two epoxidized soybean oils, Paraplex G-60 and Paraplex G-62, were added to the diets of rats for a two-year period in concentrations up to 5%. No effects were observed on survival or on the blood picture and histologic examination of tissues revealed no lesions attributable to treatment. Early depression in growth was observed in rats from both materials (Paraplex G-62 being the most potent), but this effect disappeared on continued feeding.
Elevated liver to body weight ratios resulted at the 5% concentration in male rats receiving Paraplex G-60 and at lower concentrations in both male and female rats receiving Paraplex G-62; kidney to body weight ratios were also elevated with the latter material in female rats.

Executive summary:

Two epoxidized soybean oils, Paraplex G-60 and Paraplex G-62, were added to the diets of rats for a two-year period in concentrations up to 5%. Groups of rats (15/sex) were given diets containing 0, 0.1, 0.5, 2.5 or 5% (up to approximately 1250 mg/kg bw) ESBO for up to 2 years. Five rats/sex/group were sacrificed at 6 months. Organ to body weight measurements were made for liver, kidney and testes. Blood studies (hemoglobin, red blood cell and differential white cell counts) were made during the eleventh and twenty-fourth months. Histopathology of heart, lung, kidney, spleen, gastroenteric, thyroid, adrenal, pancreas, gonad, muscle and bone marrow tissues was conducted on survivors from the 0, 2.5% and 5% diet groups. Growth appeared to be essentially normal at 2.5%, but appeared to be permanently low in the 5% group. A limited evaluation of the blood (red blood cell and white blood cell counts) revealed no effects. Liver weight was increased in both sexes at 1% and above. There was some evidence that kidney weight was increased in the females at 1% and above.

Microscopic examination of the major tissues revealed no cellular changes at 2.5% or 5% (only dose groups examined). In conclusion, Lowest Adverse Effect Level (LOAEL) was 1% in the diet (approximately 250 mg/kg bw).