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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

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other: GLP-compliant study, available as unpublished report, well-documented, no restrictions, adequate for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Physical state: clear yellow liquid
- Purity: mixture
- Expiration date of the lot/batch: Not supplied; assume at least one year
- Storage condition of test material: Temperature monitored room (60-85°F); closed container.

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., Wilmington, Massachusetts 01887
- Age at study initiation: 9 weeks (males) and 8 weeks (females)
- Weight at study initiation: 319 gr for males (300-339) and 192 gr for females (175-208)
- Housing: doubly housed during the first week then individually housed
- Diet (e.g. ad libitum): ad libitum (Standard laboratory diet) during acclimation period; None during exposure period
- Water (e.g. ad libitum): ad libitum during acclimation period; None during exposure period
- Acclimation period: 21/22 days (4 to 25/26 September 1984)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-31 °C
- Humidity (%): 24-95% (R.H.)
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle (7am to 7 pm)

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: Batelle cascade impactor:
MMAD (microns): 1.9, 1.8, 1.6 for groups exposed to 10, 100 ang 500 mg/m³ respectively.
GSD: 2.0, 1.8, 1.9 for groups exposed to 10, 100 ang 500 mg/m³ respectively.

TSI model:
MMAD (microns): 3.1, 2.0, 4.7 for groups exposed to 10, 100 ang 500 mg/m³ respectively.
GSD: 1.9, 1.9, 2.8 for groups exposed to 10, 100 ang 500 mg/m³ respectively.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Chamber volume: one cubic meter
- Effective volume: 760 liters
- Air flow rate: average of 200 liters per minute (1 ppm)
- Air change rate: one complete air change every 5 minutes (average)
- Method of particle size determination: Using a Batelle cascade impactor and a TSI model 3300/3302 Aerodynamic Particle Sizer.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Exposure levels were determined by gas chromatographic assay (GC) of samples collected on filters. Concentration was also monitored gravimetrically as a secondary assay. In addition, distribution samples were taken at least three times during the study from four locations in the chamber for each group and assayed by GC.
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 hours/day, 5 days/week (67 number of exposures per group/sex)
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/m³ air
Dose / conc.:
10 mg/m³ air
Remarks:
corresponding to 11.4 mg/m³ (males) and 11.3 mg/m³ (females)
Dose / conc.:
100 mg/m³ air
Remarks:
corresponding to 98.7 mg/m³ (males) and 98.4 mg/m³ (females)
Dose / conc.:
500 mg/m³ air
Remarks:
corresponding to 480 mg/m³ (males) and 479 mg/m³ (females)
No. of animals per sex per dose:
15 animals per sex per group
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
MORTALITY AND GROSS SIGNS OF TOXICOLOGIC OR PHARMACOLOGIC EFFECT:
- Time schedule: twice daily

DETAILED PHYSICAL OBSERVATIONS: Yes
- Time schedule: once a week

BODY WEIGHT: Yes
- Time schedule for examinations: Recorded pretest, weekly during the study and at termination.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretest and at termination

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at midterm and after the sixty-fifth exposure (males) and sixty-fourth exposure (females)
- Anaesthetic used for blood collection: Yes (identity): light ether anesthesia.
- Animals fasted: Yes
- How many animals: 40 animals (10/sex/group)
- Parameters checked in Table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at midterm and after the sixty-fifth exposure (males) and sixty-fourth exposure (females)
- Animals fasted: Yes
- How many animals: 40 animals (10/sex/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:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
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:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
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:
One Group I (control) female and one Group II (10 mg/m³) female died spontaneously during the study. Two Group II females and one Group IV (500 mg/m³) female died accidentally during blood collection. The one Group II female's spontaneous death did not appear to be treatment related.

Increased incidences of chromodacryorrhea, excess lacrimation and rough coat were exhibited by all groups of treated males compared to control males. The increased incidence of rough coat noted in the treated males did not appear to correlate with the presence of test material on the fur. Increased incidences of dried brown material around the facial area were exhibited by all treated groups of females compared to control females. These findings were considered to be treatment related.

BODY WEIGHT AND WEIGHT GAIN:
The mean body weights were decreased approximately 8% for the Group IV males during the study compared to the control males. The differences between Group IV and control males were considered suggestive of a treatment related effect. Comparisons between body weights for Group II and III (100 mg/m³) males and all groups of treated females, and the respective control animals were considered unremarkable.

OPHTHALMOSCOPIC EXAMINATION:
The following findings were noted at the terminal ophthalmology examination: proptosis and corneal necrosis (unilateral, 1 Group II male), conjunctivitis secondary to infectious disease or dental abnormality (unilateral, 1 Group IV male), retinal degeneration (bilateral, 1 Group I female) and phthisis bulbi which was secondary trauma or endophthalmitis (unilateral, 1 Group I female and 1 Group III female). These findings were not considered treatment related.

HAEMATOLOGY:
Haematology results were considered unremarkable.

CLINICAL CHEMISTRY:
The mean serum glutamic oxaloacetic transaminase and glucose levels were decreased for the Group IV females compared to the control females, and the mean total protein, albumin and calcium levels were increased for Group III and IV females compared to control females. Because the findings followed a pattern related to exposure concentration for Group III and IV females, these differences appeared to be treatment related. However, the majority of values were within historical control ranges and the nature of changes is not suggestive of an adverse effect. The absence of supporting microscopic lesions or organ weight findings in the liver, heart or other tissues suggests these clinical chemistry differences were insufficient to be considered toxicologically significant.
The mean blood urea nitrogen level was increased for Group IV males at Test Week 14 compared to control males. However, values were within historical ranges and no renal pathology was seen. Therefore, this difference is not considered to be toxicologically significant.

ORGAN WEIGHTS:
The mean absolute and relative liver weights were increased for all groups of treated males compared to control males. The differences between treated and control males were statistically significant for all comparisons except for the absolute liver weights of Group II and III males. These findings were considered treatment related. Mean absolute and relative liver weights were unremarkable in the treated females. There were no other findings in the organ weight data of the males or females which were attributed to the test material.

GROSS PATHOLOGY & HISTOPATHOLOGY (NON-NEOPLASTIC)
Postmortem findings, observed grossly and microscopically, either occurred in the treated and control animals with comparable incidence and severity or they occurred sporadically. These findings did not appear to be related to the test article.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
0.1 mg/L air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
ophthalmological examination
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
Dose descriptor:
LOAEL
Effect level:
0.5 mg/L air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
ophthalmological examination
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

1) 0.01 mg/L
liver, weight, incr, M;
lacrimation, M;
chromodacryorrhea, M;

Dried brown material around the facial area, F.

2) 0.1 mg/L
Liver, weight, incr, M;
Lacrimation, M;
Chromodacryorrhea, M;

Dried brown material around the facial area, F;

NOAEL.

3) 0.5 mg/L
Liver, weight, incr, M;
Body weight, decr, M;
Lacrimation, M;
Chromodacryorrhea, M;

Dried brown material around the facial area, F;

LOAEL.

Applicant's summary and conclusion

Conclusions:
NOAEL = 100 mg/m³ or 0.1 mg/L air.
Executive summary:

Terphenyl, hydrogenated when administered by whole-body inhalation exposure as an aerosol to 90 CD (Sprague-Dawley derived) rats (15/sex/group) for six hours per day, five days per week for thirteen weeks at target concentrations of 0, 10, 100 and 500 mg /m³ (groups I, II, III,IV). Exposure levels for Groups I-IV were determined by gas chromatographic assay (GC) of samples collected on filters. Concentration was also monitored gravimetrically for Groups II, III and IV as a secondary assay. In addition, distribution samples were taken at least three times during the study from four locations in the chamber for each group (Groups II-IV) and assayed by GC. Particle size distribution measurements were made using a Batelle cascade impactor and a TSI Model 3300/3302 Aerodynamic Particle Sizer. Detailed physical examinations were conducted once a week on all animals; in addition, once per exposure the animals were observed as a group in-chamber. Body weights were recorded pretest, weekly during the study and at termination. Blood specimens for hematology and clinical chemistry evaluations were collected from 40 animals (10/sex/group) at midterm and from the same 10 animals/sex/group after the sixty-fifth exposure(males) and sixty-fourth exposure (females). All animals (Groups I-IV) were weighed prior to sacrifice. Complete gross postmortem examinations were conducted on all animals ; selected organs were weighed and organ/body weight ratios were calculated. Histopathological evaluations were performed on selected tissues from all animals of the control and high-dose groups ( Groups I and IV). The tissues and organs with visible lesions, and masses from all animals were examined microscopically. The treated animals were exposed to cumulative mean analytical concentrations of 11, 99/98 (Male/Female) and 480 mg/m³ Terphenyl, hydrogenated, respectively. Particle size distribution measurements revealed the test atmospheres contained particles of respirable size. One Group I female and one Group II female died spontaneously during the study. The Group II female’s death was not considered treatment related. Increased incidences of chromodacryorrhea, excess lacrimation and rough coat were exhibited by all groups of treated males compared to control males. Increased incidences of dried brown material around the facial area were exhibited by all treated groups of females compared to control females. These findings were considered to be treatment related. The mean body weights were decreased approximately 8% for the Group IV males during the study compared to the control males. The differences between Group IV and control males were considered suggestive of a treatment related effect. Although some statistically significant differences were seen at study termination between clinical chemistry values for control and treated groups, values were generally within control ranges and the absence of supporting microscopic lesions or organ weight findings suggests these clinical chemistry results were insufficient to be considered toxicologically significant. The mean absolute and relative liver weights were increased for all groups of treated males compared to control males. The differences between treated and control males were statistically significant for all comparisons except for the absolute liver weights of Group II and III males. Postmortem findings, observed grossly and microscopically, either occurred in the treated and control animals with comparable incidence and severity or they occurred sporadically. These findings did not appear to be related to the test article. The NOAEL was considered to be 100 mg/m³ or 0.1 mg/L air.