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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-compliant EPA guideline study, available as unpublishedd report, no restrictions, adequate for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1984
Report Date:
1984

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.8700 (Subchronic Oral Toxicity Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Physical state: clear yellow liquid
- Purity: mixture
- Composition of mixture: mixture hydrogenated terphenyls
- Concentration: Assume 100% active ingredient
- Storage condition of test material: in tightly sealed bottle at ambiant temperature in a locked cabinet

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Kingston, New York 12484
- Age at study initiation: 43 days old
- Weight at study initiation: 197 grams for males (173-213) and 157 grams for females (131-175)
- Housing: doubly housed
- Diet (e.g. ad libitum): ad libitum; standard laboratory diet (Purina certified rodent chow #5002)
- Water (e.g. ad libitum): ad libitum; (Elizabethtown water company)
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 61-75°F
- Humidity (%): 15-65%
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle (7 am to 7 pm)

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): standard laboratory diet (Purina certified rodent chow #5002)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Four ouce samples were taken for the control group and each dose level weekly and were stored frozen at Bio/dynamics, Inc. Duplicate samples were taken for weeks 1, 2, 3, 4, 6, 8, 10 and 12 and analyses for concentration were performed by the Department of Metabolism and Analytical Chemistry of Bio/dynamics, Inc.
Duration of treatment / exposure:
14 weeks
Frequency of treatment:
7 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Remarks:
nominal in diet, corresponding to 0 mg/kg bw/d
Dose / conc.:
50 ppm
Remarks:
nominal in diet, corresponding to 3 mg/kg bw/d (nominal) and 3.6 mg/kg/d (Males; actual ingested) and 4.2 mg/kg/d (Females; actual ingested)
Dose / conc.:
200 ppm
Remarks:
nominal in diet, corresponding to 12 mg/kg bw/d (nominal) and 14.8 mg/kg/d (Males; actual ingested) and 17.0 mg/kg/d (Females; actual ingested)
Dose / conc.:
2 000 ppm
Remarks:
nominal in diet, corresponding to 120 mg/kg bw/d (nominal) and 143.7 mg/kg/d (Males; actual ingested) and 169.2 mg/kg/d (Females; actual ingested)
No. of animals per sex per dose:
12 animals per sex per dose
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
OBSERVATIONS FOR MORTALITY AND GROSS SIGNS OF TOXICOLOGIC OR PHARMACOLOGIC EFFECTS: Yes
- Time schedule: Twice daily, once in the morning and once in the afternoon

DETAILED PHYSICAL EXAMINATION FOR SIGNS OF LOCAL OR SYSTEMIC TOXICITY? PHARMACOLOGIC EFFECTS AND PALPATION FOR TOSSUE MASSES: Yes
- Time schedule: Twice pretest and weekly thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: twice pretest, weekly during treatment and terminally (after fasting)

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption determined : Yes; weekly, beginning one week prior to treatment
- Compound intake calculated : Yes; calculated from food consumption data and based on nominal concentrations

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: once pretest and at study termination
- Dose groups that were examined: all animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at approximately 1 month and at study termination
- Anaesthetic used for blood collection: Yes (light ether anesthesia)
- Animals fasted: Yes
- How many animals: 10 animals per sex per group
- Parameters checked in Table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at approximately 1 month and at study termination
- Animals fasted: Yes
- How many animals: 10 animals per sex per group
- Parameters checked in Table 2 were examined.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see Table 3)
HISTOPATHOLOGY: Yes (see Table 4)

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):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
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:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY:
Physical observations noted in control and treated animals included alopecia, chromodacryorrhea and excessive lacrimation. These observations occured sporadically in control and treated animals. These incidences did not exhibit a dose-response and were not considered related to the administration of the test material. These findings are not uncommon in laboratory rats and may suggest the presence of a sialodacryoadenitis infection in these animals.
All control and treated animals survived the duration of the study.

BODY WEIGHT AND WEIGHT GAIN
The mean body weights of the treated males from all groups were unremarkable throughout the study when compared to the controls.
The mean body weights of the high-dose females (Group IV - 2000 ppm) were slightly (3-7%) lower than control throughout the treatment period. While the differences from control were small, they were consistent over time and were therefore attributed to the administration of the test material.
The mean body weights of the low- and mid-dose females were comparable to the controls throughout the study.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
The mean food consumption values of the high-dose males and females were slightly lower than control during the first week of the study. In addition, feed spillage was noted more frequently in the mid- and high-dose males than in the control males. These findings (decreased food consumption and spillage) may suggest a palatability problem with this material.
Food consumption data was unremarkable for the males and females for the remainder of the treatment-period.

OPHTHALMOSCOPIC EXAMINATION:
There were no ophthalmoscopic findings noted in the treated animals at study termination which were considered related to the administration of the test material.

HAEMATOLOGY:
The high-dose males, at the 1 month bleeding interval, exhibited slight decreases in mean hemoglobin concentration, hematocrit and erythrocyte counts and a slight increase in mean platelet count, these findings were statistically significant. At termination the high-dose males continued to exhibit slight (not statistically significant) decreases in mean hemoglobin concentration, hematocrit and erythrocyte count and a statistically significant increase in mean platelet count. While differences from control were slight the consistency of these findings at month 1 and study termination suggests a relationship to the administration of the test material.
Hematology data was unremarkable in the low- and mid-dose males and in all treated females at 1 month and at study termination.

CLINICAL CHEMISTRY:
The high-dose males exhibited slight, statistically significant elevations in mean cholesterol levels at month 1 and termination. In addition, the mean albumin level of the high-dose males was significantly elevated at study termination. The high-dose females exhibited a slight (statistically significant) reduction in mean glucose levels at month 1 and at study termination (not statistically significant).
The mid- and high-dose females exhibited slight (statistically significant) increases in mean calcium levels at 1 month. Slight (not statistically significant) increases were also noted in the mean calcium level of the mid- and high-dose females at study termination.

ORGAN WEIGHTS:
The high-dose males and females exhibited statistically significant increases in kidney to body weight ratios and slight (not statistically significant) increases in mean kidney weights and kidney to brain weight ratios. These increases were possibly related to slight decreases in mean terminal body weights in the high-dose males (2.5%) and females (6.4%). The high-dose males and females also exhibit significant increases in mean liver weights (47% and 21%), liver to body weight ratios (51% and 29%), and liver to brain weight ratios (49 and 22%). The high-dose females exhibited slight increases in mean adrenal weights, adrenal to body weight ratios and adrenal to brain weight ratios. Similar adrenal weight findings were not noted in the treated males.

GROSS PATHOLOGY:
There was no indication that the gross tissue changes noted during necropsy were treatment associated. Often the gross observations were related to normal color or architectural tissue pattern variations which had no microscopic correlation. Other tissue lesions were sporadic in occurrence or were of the type commonly encountered in laboratory rats of this age group. The were judged to have had no treatment relationship.

HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopic assessment of the tissues revealed no histomorphological evidence of a direct treatment associated toxicopathological effect. There was noted, however, an increased incidence of a spontaneously occuring renal lesions when kidneys from high-dose male rats were compared to those of the male controls.

The minimal lesion was one which has been noted frequently in control male animals and was characterized by single or multiple small foci of proximal tubule epithelial cell hypertrophy and basophillia. These foci were interpreted as representing young regenerative cells. The exact cause of the lesion is obscure. In this study the regenerative foci were noted in 10 of 12 high-dose males and 4 of 12 control males. Similar foci were noted in 5 of 12 mid- and 5 of 12 low-dose rats. The renal lesion was not present in females except for 2 of 12 mid-dose animals.

Although the incidence was increased in high-dose males, the severity of the lesion was comparable to that noted in control males.

An increased of this spontaneous renal lesion in male rats treated with various other non-related compounds has been observed on previous occasions. The pathogenesis and biological significance of the lesion remains unclear.

Various other tissue alterations were noted in rats of both the control and treated groups. They occurred sporadically or with approximately equal frequency and degree in control rats as in treated animals and were judged to have no treatment relationship.

Under the conditions of this test, the following conclusions were made based on the gross and microscopic evaluation:
1. Terphenyl, hydrogenated when fed in the diet caused no specific toxicoppathological alteration in the tissues of male or female rats.
2. Terphenyl, hydrogenated high-dose treated male rats had an increased incidence but no increased severity of a spontaneously occuring regenerative renal lesion which was also present in the control males. The change was not present in high-dose females. The toxicopathological significance of the increased incidence in high-dose males when compared to control males was unclear.

A gross and microscopic correlation of lesions noted at necropsy revealed no evidence of a treatment associated response. No gross or microscopic pathology was noted which would correlate with the increased kidney and liver weights seen in the high-dose and/or females.

Microscopic evaluation of the tissues revealed no histomorphological evidence of a direct toxicopathological effect. Tissues from control rats were comparable to those from the treated animals.

There was, however, an increased incidence of a spontaneously occurring renal tubular lesion in high-dose males when compared to control males. the lesion incidence in low- and mid-dose males was similar to that observed in controls. Females were essentially free of the lesion. The ethiology and toxicopathological significance of the increased incidence rate in high-dose males was unclear.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
12 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
ophthalmological examination
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
Dose descriptor:
LOAEL
Effect level:
120 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
ophthalmological examination
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL = 200 ppm i(12 mg/kg body weight/day)
Executive summary:

Terphenyl, hydrogenated heat transfer fluid was administered orally, via dietary mixture to 72 Sprague-Dawley CD rats (12/sex/group) at dose levels of 50, 200 and 2000 ppm in the diet for a period of approximately 14 weeks, corresponding with nominal doses of 3, 12 and 120 mg/kg body weight/day. Control animals (12/sex/group) received a standard laboratory diet. Physical observations, ophtalmoscopic examinations, body weight and food consumption measurements were performed on all animals at selected intervals during the treatment period. Hematology and clinical chemistry evaluations were performed on 10 animals/sex/group at approximately 1 month and at study termination. After approximately 14 weeks of treatment, all survivors were sacrificed, selected organs were weighed and organ/body and organ/brain weight ratios calculated. Complete gross postmortem examinations were conducted on all animals. Histopathological evaluations were conducted on specified tissues for all animals in Group I (0 ppm) and IV ( 2000 ppm). Lungs, liver and kidneys were evaluated from all animals in Groups II (50 ppm) and III (200 ppm). All rats survived the 3-month test. The mean body weights of the high-dose females (Group IV – 2000 ppm) were slightly (3-7%) lower than control throughout the treatment-period. The mean food consumption values of high-dose males and females were slightly lower than control during the first week of the study and were unremarkable for the remainder of the treatment-period. The high-dose males, at the 1 month and terminal bleeding intervals exhibited slight decrease in mean hemoglobin concentration, hematocrit and erythrocyte counts and a slight increase in mean platelet count. While differences from control were slight the consistency of these findings at Month 1 and study termination suggests a relationship to administration of the test material. The high-dose males exhibited slight, statistically significant elevations in mean cholesterol levels at month 1 and termination. In addition, the mean albumin level of the high-dose males was significantly elevated at study termination. The high-dose females exhibited a slight (statistically significant) reduction in mean glucose levels at month 1 and at study termination (not statistically significant). The mid- and high-dose females exhibited slight (statistically significant) increases in mean calcium levels at 1 month. Slight (not statistically significant) increases were also noted in the mean calcium level of the mid- and high-dose females at study termination. A gross and microscopic correlation of lesions noted at necropsy revealed no evidence of a treatment associated response. Microscopic evaluation of the tissues revealed no histomorphical evidence of a direct toxicopathological effect. Tissues from control rats were comparable to those from the treated animals. There was, however, an increased incidence of a spontaneously occurring renal tubular lesions in high dose males when compared to control males. The lesion incidence in low and mild dose males was similar to that observed in controls. Females were essentially free of the lesion. The etiology and toxicopathological significance of the increased incidence rate in high dose males was unclear. Various other tissue alterations were encountered; however, they occurred sporadically or with approximately equal frequency and degree in control rats as in treated animals. They were judged to have had no treatment relationship. NOAEL was therefore set at 200 ppm in the diet, corresponding with 12 mg/kg body weight/day.