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Endpoint summary

Description of key information

Weight-of-Evidence for repeated dose oral toxicity was obtained from subacute and chronic toxicity studies with read-across substances Epoxidized tall-oil 2 -EH (ETP:  subacute oral combined repeated dose toxicity and reproductive screening study in rats) and  Epoxidized soybean oil (ESBO: chronic oral toxicity in rats and dogs). Read-across data from ESBO indicate that increased liver and kidney effects in rats (1 and  5% in the diet) and fatty infiltration in the liver of dogs (5% in the diet at 12 months) were identified after 12 and 24 months, respectively. A LOAEL of 250 mg/kg/d was identified in rats after 24 months dosing, whereas in dogs a NOAEL of 250 mg/kg/d was identified after 12 months dosing. For ETP, subacute dosing in rats did not result in any parental or reproductive changes up to 1000 mg/kg/d, therefore this dose was considered as subacute NOAEL. For PSLG-5, a chronic LOAEL of 250 mg/kg/d in rats was retained as most relevant descriptor.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

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.

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

GLP compliance:

not specified

Limit test:

no

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

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

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

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.

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.

Dose descriptor:

LOAEL

Effect level:

1 other: % nominal in diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: liver & kidney

Critical effects observed:

not specified

-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.

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).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

250 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Reliable

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Weight-of-Evidence for repeated dose oral toxicity was obtained from subacute and chronic toxicity studies with read-across substances. A read-across justification based on molecular, physicochemical and toxicological properties was written as a separate document provided under Section 13 (Assessment reports). The following data were used:

-Epoxidized tall-oil 2 -EH (ETP) was administered once daily orally (by gavage) to male Wistar rats at least for 28 days (including 14 days prepairing) and to female Wistar rats throughout the 14 day prepairing period and throughout pairing and gestation up to lactation day 4 (RCC, 2005a). The dose levels were 0 (vehicle control), 100, 300 and 1000 mg/kg bw/d. A standard dose volume of 2 mL/kg body weight with a daily adjustment to the actual body weight was used. Control animals were dosed with vehicle alone (corn oil).

The fertility rate was high resulting in at least 9 litters per group for evaluation of reproduction data. There were no treatment-related effects on precoital time, fertility indices, mean duration of gestation, number of implantations, post-implantation loss, pup survival or litter size from birth through to scheduled pup sacrifice on day four post-partum at any dose level. No test article related histopathological findings were noted in the reproductive organs of either sex. In particular, the assessment of the integrity of the spermatogenetic cycle did not reveal any evidence of impaired spermatogenesis. In the absence of any adverse effects on parental systemic and reproductive parameters, the parental and reproductive NOAEL and NOEL were considered to be 1000 mg/kg bw/d.

- Two epoxidized soybean oils (ESBO), Paraplex G-60 and Paraplex G-62, were added to the diets of rats for a two-year period in concentrations up to 5% (Larson et al., 1960a). 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).

- Two epoxidized soybean oils (ESBO), Paraplex G-60 and Paraplex G-62, were added to the diets of dogs for one year in concentrations up to 5% (Larson et al., 1960b). Groups of three dogs were fed at 0.1, 1 or 5% (approximately 1250 mg/kg bw/day) Paraplex G-60 or G-62 once per day for one year. The dogs were weighed weekly and food intake was monitored. Hematologic studies were made at study initiation, at 6 months and at 12 months. Major tissues were examined microscopically. The dogs were sacrificed at 12 months. Dogs fed 5% Paraplex G-60 or G-62 lost weight. Survival and blood parameters (hemoglobin, red and white blood cell counts) were normal in all treated groups. The major tissues were microscopically normal except for fatty liver changes (fatty infiltration) in one dog given 5% Paraplex G-62. Food intake and body weight were decreased at 5% of either grade. Lowest Adverse Effect Level (LOAEL) was 5% in the diet (1250 mg/kg bw/day). For both batches tested, the 1% concentration (approximately 250 mg/kg bw/day) can be considered to be a NOAEL.

 

Read-across data from ESBO indicate that increased liver and kidney effects in rats (1 and 5% in the diet) and fatty infiltration in the liver of dogs (5% in the diet at 12 months) were identified after 12 and 24 months, respectively. A LOAEL of 250 mg/kg/d was identified in rats after 24 months dosing, whereas in dogs a NOAEL of 250 mg/kg/d was identified after 12 months dosing. For ETP, subacute dosing in rats did not result in any parental or reproductive changes up to 1000 mg/kg/d, therefore this dose was considered as subacute NOAEL. For PSLG-5, a chronic LOAEL of 250 mg/kg/d in rats was retained as most relevant descriptor.

 

The oral route was considered most appropriate for the hazard characterization of PLSG-5. Inhalation of the substance is unlikely as the vapour pressure is very low. Skin contact may be likely, however skin absorption is considered to be very low (see Toxicokinetics).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Weight-of-Evidence from read-across substances; this endpoint has two target organs and LOAEL was identified.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; urogenital: kidneys

Justification for classification or non-classification

Based on the results and according to the EC criteria for classification and labelling according to CLP regulation (EC No. 1272/2008 of 16 December 2008), 'fatty acids, C16 -18 and C18-unsaturated isopentyl esters, epoxidized' does not have to be classified and has no obligatory labelling requirement for repeated dose toxicity.