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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
Not reported
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study was classified as reliable without restrictions because it was GLP compliant and was conducted according to OECD 453 guidelines.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2004

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: Oily liquid
Details on test material:
- Name of test material (as cited in study report): P70H and P100H
- Substance type: Hydrocarbon
- Physical state: Clear colourless Liquid
- Analytical purity: Not reported
- Lot/batch No.: MRD-97-059
- Expiration date of the lot/batch: August 2002
- Stability under test conditions: Not reported
- Storage condition of test material: Room temperature under a nitrogen blanket
- See attachment for further characteristics of test substance, i.e. density, refractive index, kinematic viscosity, viscosity index, refractive intercept (RI), viscocity-gravity constant (VGC), Carbon distribution (C/A, C/N, C/P), simulated distillation (ASTM D 2887 ext.), IBP, FBP, Carbon number at 5% boiling point ((ASTM D 2887 ext.), molecular weight, UV Absorption (260-240 nm) for white oils

Test animals

Species:
rat
Strain:
other: CDF(F-344)/CrlBR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina
- Age at study initiation: Approximately 6 weeks old
- Weight at study initiation: Not reported
- Housing: Individually housed in suspended stainless steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 15 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 24
- Humidity (%): 40% to 70%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light


IN-LIFE DATES: Not reported

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): Weekly
- Mixing appropriate amounts with (Type of food): Certified rodent diet #5002 (meal)
- Storage temperature of food: Not reported
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
24 months
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 60, 120, 240, or 1200 mg/kg/day
Basis:
nominal in diet
No. of animals per sex per dose:
Fifty animals per sex per dose were used in the main study, twenty animals per sex per dose were used in the recovery groups, and twenty-five to forty-seven females per dose group were used for mineral hydrocarbon analysis and sacrificed at different times
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Not reported
- Rationale for animal assignment (if not random): Not reported
- Rationale for selecting satellite groups: Not reported
- Post-exposure recovery period in satellite groups: 12 months
- Section schedule rationale (if not random): Not reported

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once or twice a day
- Cage side observations checked for viability, mortality, and overt signs of toxicity.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly


BODY WEIGHT: Yes
- Time schedule for examinations: Study initiation, weekly for the first 13 weeks, then monthly throughout the study duration


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data


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: Yes


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Pretest and at 3 month intervals
- Dose groups that were examined: All groups


HAEMATOLOGY: Yes
- Time schedule for collection of blood: 3 month intervals
- Anaesthetic used for blood collection: Yes (methoxyflurane or halothane)
- Animals fasted: Yes
- How many animals: Twenty per sex per dose
- Parameters checked in table 1 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 3 month intervals
- Animals fasted: Yes
- How many animals: Ten animals per sex per dose
- Parameters checked in table 2 were examined.


URINALYSIS: Yes
- Time schedule for collection of urine: 3, 6, 12, and 18 months
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table 3 were examined.


NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see table 4)
Other examinations:
Organs marked in table 4 were weighed. Mineral hydrocarbon analysis was conducted in the liver, kidneys, mesenteric lymph nodes and the spleen from designated animals.
Statistics:
Statistical treatment of the results was conducted where appropriate. Statistical evaluation of equality of means was done by an appropriate one-way analysis of variance and a test for ordered response in the dose groups. First, Bartlett’s Test was performed to determine if the dose groups had equal variance. If the variances were equal, the testing was done using parametric methods
(a standard one-way ANOVA using the F distribution followed by Dunnett’s Test). In addition to the ANOVA, a standard regression analysis for linear response in the dose groups was performed. The regression analysis was also tested for linear lack-of-fit in the model. For the nonparametric procedures, the test of equality of means was performed using the
Kruskal-Wallis Test followed by Dunn’s Summed Rank Test. In addition to the Kruskal-Wallis Test, Jonckheere’s Test for monotonic trend in the dose-response was performed. The statistical t-test was used to compare the mineral hydrocarbon data from the 6-month interval. The tumour data were analyzed statistically by the method of Peto. The analysis of the severity of non-neoplastic lesions was based on a cumulative logit model.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
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:
effects observed, treatment-related
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: There were no treatment-related effects on clinical signs or mortality.

BODY WEIGHT AND WEIGHT GAIN: Body weight was higher in the high-dose group compared to the controls, but this was a result of increased food consumption.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): There were no toxicologically significant effects on food consumption, but the high-dose group consumed more food than the controls. Compound intake was not reported.

FOOD EFFICIENCY: There were no treatment-related effects on food efficiency.


OPHTHALMOSCOPIC EXAMINATION: There were no treatment-related effects on ophthalmology.


HAEMATOLOGY: Although there were sporadic differences that were statistically significant, they were not consistent over time, or dose-dependent.


CLINICAL CHEMISTRY: Although there were sporadic differences that were statistically significant, they were not consistent over time, or dose-dependent.


URINALYSIS: Although there were sporadic differences that were statistically significant, they were not consistent over time, or dose-dependent.


ORGAN WEIGHTS:Males in the 1200 mg/kg/day group had increased mesenteric lymph node weights (absolute, relative to body weight and relative to brain weight). This effect was observed at 12 and at 24 months but did not occur in the recovery group animals. In females absolute mesenteric lymph node weights were increased in all dose groups (13, 15, 20 & 20% for the 60, 120, 240 & 1200 mg/kg/day groups, respectively). Increases in mesenteric lymph node/body weight and mesenteric lymph node/brain weight ratios were also slightly increased in all female dose groups at 24 months. There was also a significant increase in absolute mesenteric lymph node weights for 240 (55%) and 1200 mg/kg/day females (36%) in the recovery study.


GROSS PATHOLOGY: There were no treatment-related effects on gross pathology.


HISTOPATHOLOGY: NON-NEOPLASTIC: After 12 months of treatment there were no treatment-related histopathological findings in the liver at any dose level. At 24 months, however, there was an increased incidence of angiectasis and cystic degeneration in the males at all dose levels. Similar findings were also observed in control groups and treated females, but at a very low incidence. Although the incidence of these liver lesions was increased in the males, it was not in a dose-related manner. It was also noted by the authors of the report that this lesion is a common finding in F-344 rats, particularly in males. The authors therefore considered these findings to be of questionable relevance, especially in view of the minimal severity and lack of dose response. This lesion was not observed in the recovery group animals. Histiocytosis was observed in the mesenteric lymph nodes at all dose levels and also in the controls at 24 months, but the severity was slightly greater in the treated animals than the controls. It appeared that the increase in severity above controls was dose-related in the males, but not in the females. For the males, on a scale of 1 to 4 for increasing severity, the responses were 1.2, 1.6, 1.8, 2.3 and 2.1 for the 0. 60, 120, 240 and 1200 mg/kg/day groups, respectively. In the females the control value was 1.6 and all other dose groups ranged from 2.4 to 2.6 but not in a dose-related fashion.


HISTOPATHOLOGY: NEOPLASTIC: There was no increase in neoplastic findings.


OTHER FINDINGS: The level of mineral hydrocarbons in the liver was significantly increased at all doses, but there was no dose-response and levels were not significantly increased after the 12-month recovery period.

Effect levels

Dose descriptor:
NOAEL
Effect level:
>= 1 200 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEL was greater than or equal to 1200 mg/kg bw/day. There was no carcinogenic potential or chronic toxicity of highly refined base oil administered via the diet for twenty-four months.
Executive summary:

A 2-year dietary combined chronic toxicity/carcinogenicity studies has been conducted on highly refined base oil P70H and P100H at doses of 0, 60, 120, 240, or 1200 mg/kg/day via the diet. The study was GLP compliant and was conducted to OECD guidelines. Results were similar for both compounds. Survival was unaffected at any dose level and no treatment related clinical effects were observed. Food conversion efficiency, ophthalmology, serum chemistry, haematology, urinalysis, mortality, and neoplastic lesions were unaffected by treatment. In the 1200 mg/kg/day group, food consumption was increased, which was associated with an increase in body weight. The high-dose group had increased mesenteric lymph nodes and increased severity of infiltrating histocytes, which occurred to a greater extend in the P70H treated animals. This was considered not to be toxicologically significant. Mineral hydrocarbons were detected in the liver, but was reversible. Although maximal mineral hydrocarbon levels in the liver were the same regardless of the highly refined base oil, the maximal level occurred more rapidly in the rats treated with P70H. The NOAEL was >=1200 mg/kg bw/day. There was no carcinogenic potential or chronic toxicity of highly refined base oil adminisitered via the diet for twenty-four months.