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Administrative data

Description of key information

Subchronic oral (diet) study in rats, 90 days: NO(A)EL 20 mg/kg bw (Burdock et al., 1991).

From two other 14 week oral studies with dosing of F344/N rats and B6C3F1 mice with 0, 1250, 2500, 5000, 10000 or 20000 ppm continuously via diet no NO(A)EL values were derived due to effects even at the lowest dose. The LOAEL for rats and mice was given with 75-80 mg/kg bw and 200-270 mg/kg bw, resp. (NTP, 2000).

For the dermal and inhalation route, there are no data available.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Due to the staggered starts of the mid- and high-dose groups vs. the low-dose and control groups, meaningful statistical evaluation of body weights, food consumption and organ weights of the mid- and high-dose groups was not possible.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
The low dose group was treated for 90 days and the mid and high dose groups for 28 days. No ocular and neurobehavioral examinations were included.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Canada (St Constant, Quebec, Canada)
- Age at study initiation: 6 weeks
- Weight at study initiation: ca. 150g
- Fasting period before study: no
- Housing: individually in stainless-steel cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.9 +/- 0.18
- Humidity (%): 61.0 +/- 2.11
- Photoperiod: 12 hrs dark / 12 hrs light
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet: once weekly
- Mixing appropriate amounts with powdered certified rodent chow no. 5002
- Storage at room temperature
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability and homogeneity of benzophenone were determined in samples of the diets for the low- and high-dose groups obtained immediately after preparation, and stability was determined after storage at room temperature for 1 week. No significant differences were seen after the week of storage. The concentration of benzophenone in the low-, mid- and high-dose diets was evaluated at week 1 of the study and the concentration in the low-dose also was determined at week 6 and 13. All batches were within 6.8% of nominal concentration.
Duration of treatment / exposure:
After 28 days of treatment, all mid- and high-dose animals and 50% of the low-dose and control animals were killed. The remaining animals were killed after a further 62 days of treatment.
Frequency of treatment:
continuously via diet
Remarks:
Doses:
Nominal via diet: 0, 20, 100 or 500 mg/kg bw/d
Actual ingested: 0, 18.6, 91.7 or 485 mg/kg bw/d for males and 0, 21.6, 102.8 or 557.5 mg/kg bw/d for females
No. of animals per sex per dose:
10 - 32 rats/sex/group
Control animals:
yes, plain diet
Details on study design:
The low dose of 20 mg/kg bw/d was selected to achieve a NOAEL and higher doses were selected to obtain information about the toxic potential of the test item.
This study was part of a larger study in which three other test articles were evaluated. Due to the large number of groups in the study, the initiation of the treatments was staggered within a 7-day period. Due to the staggered starts of the mid- and high-dose groups vs. the low-dose and control groups, meaningful statistical evaluation of body weights, food consumption and organ weights of the mid- and high-dose groups was not possible. However, the body and organ weights of the low-dose animals and controls were statistically comparable, and did not indicate any dose-related effect.
Positive control:
n.a.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes (two-times daily for mortality)
DETAILED CLINICAL OBSERVATIONS: Yes (daily for behaviour and/or signs of reaction to treatment)
BODY WEIGHT: Yes (once before treatment and weekly during the study)
FOOD CONSUMPTION: Yes (food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day)
COMPOUND INTAKE: Yes (calculated as time-weighted averages from the consumption and body weight gain data)
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: Yes (all groups; time schedule: before the scheduled kill at 28 days and on the remaining animals in the control and low-dose groups just before the 90-day kill; parameters examined: haematocrit, haemoglobin, red-blood-cell count, and total and differential white-blood-cell counts)
CLINICAL CHEMISTRY: Yes (all groups; time schedule: before the scheduled kill at 28 days and on the remaining animals in the control and low-dose groups just before the 90-day kill; parameters examined: blood urea nitrogen (BUN), total protein, alkaline phosphatase, glutamic-pyruvic transaminase (GPT); glutamic oxaloacetic transaminase (GOT), total bilirubin, glucose, albumin, sodium, potassium, calcium and inorganic phosphate)
URINALYSIS: Yes (time schedule: before the scheduled kill at 28 days and on the remaining animals in the control and low-dose groups just before the 90-day kill; parameters examined: gross and microscopic appearance, volume, specific gravity, pH and for the presence of protein, glucose, ketones, urobilinogen, bile pigments and haemoglobin)
NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (gross autopsies were conducted on the only rat that died spontaneously and on all those killed on schedule)
HISTOPATHOLOGY: Yes (following organs were examined: adrenals, thoracic aorta, femoral bone marrow, brain, caecum, colon, duodenum, epididymides, heart, ileum, jejunum, kidneys, liver, lungs, inguinal mammary gland, ovaries, pancreas, pituitary, prostate, seminal vesicles, skeletal muscle, spleen, stomach, testes, thymus, thyroid, urinary bladder, uterus, and any abnormalities)
Statistics:
Statistical analyses of the data on body weights and food consumption were based on analysis of variance (ANOVA), and in some cases followed by one-way ANOVA and Dunnett’s t-test. Because of obvious differences in male and female body weight and food consumption, the two sexes were analysed separately. Attempts were made to identify possible outliers using Dixon's test. In the cases of the presence of outliers and/or missing values, analyses were repeated, initially by excluding them and finally by replacing them with their group mean values at the specific intervals.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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 examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
There was a slight but significant reduction in haemoglobin at 4 weeks in both males and females in the high-dose group. In female rats, this reduction was accompanied by parallel reductions in haematocrit and red-blood-cell count in the mid- and high-dose groups.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
At 4 weeks of treatment, albumin was significantly increased in the low-, mid- and high-dose males and females and total protein was increased in the high-dose males and in the mid- and high-dose females. BUN was significantly increased in the mid- and high-dose males and alkaline phosphatase was significantly decreased in the high-dose males and females. At the end of the study (90 days) no differences were observed in these values between the control and low-dose animals of either sex. GOT values were significantly decreased in comparison with the controls in the low- and mid-dose males and in the low-, mid- and high-dose females. At the end of the study, these values remained significantly lower than those of the controls in the low-dose rats of both sexes. None of the apparent differences were considered to be toxicologically meaningful.
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
At 4 weeks of treatment, mid- and high-dose males and females had significantly increased mean absolute and relative liver weights in comparison with the controls. Low-dose females also had a significantly increased relative liver weight at 4 weeks. Mean absolute or relative liver weights were not significantly affected in the low-dose animals at the end of the study. Mean absolute kidney weights were increased in the mid-dose males at 4 weeks and in the low-dose males at 90 days. The high-dose females had an increased mean absolute right kidney weight at 4 weeks, but no differences were seen between the low-dose and control groups at the end of the treatment. The mean relative kidney weights of the mid- and high-dose males and of the low-, mid- and high-dose females were increased at 4 weeks of treatment (right kidney only in the low-dose group).
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathological evaluation revealed a dose-related effect in the livers of both males and females in the mid- and high-dose groups. This effect was characterized by slight to moderate hepatocyte hypertrophy which was observed in 11 out of 12 males and in 12 out of 12 females in the mid-dose group and in eight out of ten males and 10 out of 10 females in the high-dose group. The changes were characterized by slight to moderate enlargement of the hepatocytes with an associated clumping of the cytoplasmic basophilic material, and the distribution of the change was primarily around the central veins. These changes are associated with reactive structural alterations occurring in hepatocytes. There was focal hepatic necrosis in one out of 10 females in the high-dose group. Histopathological evaluation of the animals killed at 90 days did not reveal a treatment-related effect in either males or females in the low-dose group.
Histopathological findings: neoplastic:
no effects observed
Key result
Dose descriptor:
NOEL
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Conclusions:
The liver was the target organ for benzophenone with concomitant changes in weight, clinical chemistry and histopathological changes in the 100 and 500 mg/kg/day groups. A no-effect level was demonstrated at 20 mg/kg bw/d for 90 days of administration.
Executive summary:

Benzophenone was administered in the diet to rats at target dose levels of 20 mg/kg bw/d for 90 days and 100 or 500 mg/kg bw/d for 28 days. Treatment-related changes occurred in erythrocyte count, haemoglobin, haematocrit, bilirubin, total protein and albumin at the mid- and high-dose levels, although all changes did not occur in both groups in both sexes. There were indications of increased absolute and relative liver and kidney weights in the mid- and high-dose groups, but this was not statistically consistent for absolute kidney weights. Histopathology of the liver in the mid- and high-dose groups showed hepatocellular enlargement with an associated clumping of cytoplasmic basophilic material around the central vein.

A NOEL was demonstrated at 20 mg/kg bw/d for 90 days of administration.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
20 mg/kg bw/day
Study duration:
subchronic
Species:
rat

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

Benzophenone was administered in the diet to rats at target dose levels of 20 mg/kg bw for 90 days and 100 or 500 mg/kg bw for 28 days. Body weights and food consumption were measured weekly; haematology, clinical chemistry and urinalysis values were obtained at 4 weeks and at the end of the study. Gross and microscopic pathological examinations were conducted and organ weights were recorded. Treatment-related changes occurred in erythrocyte count, haemoglobin, haematocrit, bilirubin, total protein and albumin at the mid- and high-dose levels, although all changes did not occur in both groups in both sexes. There were indications of increased absolute and relative liver and kidney weights in the mid- and high-dose groups, but this was not statistically consistent for absolute kidney weights. Histopathology of the liver in the mid- and high-dose groups showed hepatocellular enlargement with an associated clumping of cytoplasmic basophilic material around the central vein. A no-effect level was demonstrated at 20 mg/kg bw for 90 days of administration.

From two other 14 w oral studies with dosing of F344/N rats and B6C3F1 mice with 0, 1250, 2500, 5000, 10000 or 20000 ppm continuosly via diet no NO(A)EL values were derived due to effects even at the lowest dose. The LOAEL for rats and mice was given with 75-80 mg/kg bw and 200-270 mg/kg bw, resp. (NTP, 2000).

For the dermal and inhalation route there are no data available.

Concerning possible thyroidal effects of benzophenone, the test item has been tested in different oral studies with rats and mice with dosing for up to 2 years. In nearly all of these studies, both thyroid and parathyroid have been examined histologically and the results are not indicating any dose-dependent and significant adverse effects on the thyroid and parathyroid.


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

Justification for classification or non-classification