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Toxicological information

Carcinogenicity

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Description of key information

In a 2-year study (NTP, 2006) benzophenone was tested in male and female F344/N rats and B6C3F1 mice. The animals were dosed via diet with 0, 312, 625 and 1250 ppm benzophenone for 105 weeks (male rats: ca. 0, 15, 30 and 60 mg/kg bw; female rats: ca. 0, 15, 30 and 65 mg/kg bw; male mice: ca. 0, 40, 80 and 160 mg/kg bw; female mice: ca. 0, 35, 70 and 150 mg/kg bw). Due to effects even in the low dose groups no NOAEL could be derived. The LOAEL for the rat study was 15 mg/kg bw based on increased incidences of mononuclear cell leukaemia and bile duct hyperplasia in all treated females and nephropathy and renal tubule hyperplasia in all treated males. The LOAEL for mice was ca. 35 mg/kg bw based on multiple hepatocellular adenoma in treated males and nephropathy accompanied by mineralization in treated females and increased severity of nephropathy in treated males. 

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.4200 (Carcinogenicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
no
GLP compliance:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Taconic Laboratory Animals and Services (Germantown, NY)
- Age at study initiation: 6 weeks
- Housing: 2 or 3 (males); 5 females
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 11 (males) or 12 days (females)

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72° ± 3° F
- Humidity (%): 50% ± 15%
- Air changes (per hr): 10/hour
- Photoperiod (12 hrs dark / 12 hrs light):

IN-LIFE DATES:
Date of first exposure: August 16 (males) or August 17 (females), 1999
Date of last exposure: August 13 or 14 (males) or August 14, 15, or 16 (females), 2001
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): at least once a month
- Mixing appropriate amounts with (Type of food): NTP-2000 irradiated open formula meal (Zeigler Brothers, Inc., Gardners, PA), changed twice weekly
- Storage temperature of food: Formulations were stored in five-gallon, white plastic buckets lined with plastic can liners at approximately 5° C for up to 35 days.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The dose formulations were prepared at least once a month by mixing benzophenone with feed. Formulations were stored in five-gallon, white plastic buckets lined with plastic can liners at approximately 5° C for up to 35 days. Homogeneity was confirmed, and stability was confirmed for at least 35 days for dose formulations stored in sealed glass containers protected from light at up to 5° C. Under simulated animal room dosing conditions, there were small losses after 3 days and significant losses after 7 days. To confirm these findings, the study laboratory performed simulated animal room stability studies of the 312 and 1,250 ppm dose formulations using HPLC. Results indicated that feeder changes twice weekly should be acceptable, though there would be a slight decrease in concentration of benzophenone.
During the 2-year studies, the dose formulations were analyzed at least every 11 weeks. Of the dose formulations analyzed and used, all 63 for rats were within 10% of the target concentrations. Animal room samples of these dose formulations were also analyzed; 8 of 48 samples analyzed for mice were within 10% of target concentrations. The decline in benzophenone concentration was not anticipated from animal room simulations with air and light performed during pre-study developmental work. After the decline was observed, additional experiments were performed in which benzophenone feed formulations were spiked with rodent urine and faeces. Declines were approximately 5% with light and air and increased to approximately 15% in the presence of urine and faeces. Contamination occurs when the animals crawl into or onto the feeders. The problem increases in cages where multiple animals are housed and are worst with female mice. Feeders were changed twice per week during the study to minimize the problem, but some contamination was unavoidable.
Duration of treatment / exposure:
105 weeks
Frequency of treatment:
continuously via diet
Post exposure period:
none
Dose / conc.:
0 ppm (nominal)
Dose / conc.:
312 ppm (nominal)
Remarks:
m and f: ca. 15 mg/kg bw
Dose / conc.:
625 ppm (nominal)
Remarks:
m and f: ca. 30 mg/kg bw
Dose / conc.:
1 250 ppm (nominal)
Remarks:
m: ca. 60 mg/kg bw; f: ca. 65 mg/kg bw
No. of animals per sex per dose:
50 males and 50 females
Control animals:
yes, plain diet
Details on study design:
The highest dose of 1250 ppm was based on the minimal toxicity observed at this level in a 14-week study (see section 7.5.1)
Positive control:
not applicable
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes (twice daily)
DETAILED CLINICAL OBSERVATIONS: Clinical findings were recorded on day 36 and at 4-week intervals (rats had one interval each at 3 and 5 weeks)
BODY WEIGHT: Yes (time schedule: initially, on day 8, at 4-week intervals thereafter, and at the end of the study)
FOOD CONSUMPTION: Yes (consumption was recorded for 1 week out of every 4 weeks beginning the first week of the study)
COMPOUND INTAKE: Yes (calculated as time-weighted averages from the consumption and body weight gain data)
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (all rats and all organs)
HISTOPATHOLOGY: Yes (complete histopathology was performed on all rats. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone with marrow, brain, clitoral gland, esophagus, eyes, harderian gland, gallbladder (mice only), heart, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, liver (2 sections including left lateral lobe and median lobe), lung, lymph nodes (mandibular and mesenteric), mammary gland with adjacent skin, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea, urinary bladder, and uterus)
Other examinations:
To perform an extended evaluation of renal tubule proliferative lesions, additional sections of both kidneys in the residual formalin-fixed wet tissues from each male and female rat were embedded in separate paraffin blocks and step sectioned at 1 mm intervals. Up to eight step sections were examined for each animal.
Statistics:
The Poly-k test was used to assess neoplasm and non-neoplastic lesion prevalence. This test is a survival-adjusted quantal-response procedure that modifies the Cochran-Armitage linear trend test to take survival differences into account.
Tests of significance included pairwise comparisons of each exposed group with controls and a test for an overall exposure-related trend. Continuity-corrected Poly-3 tests were used in the analysis of lesion incidence, and reported P values are one sided. The significance of lower incidences or decreasing trends in lesions is represented as 1–P with the letter N added (e.g., P=0.99 is presented as P=0.01N). Average severity values were analysed for significance with the Mann-Whitney U test.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No differences in survival of female rats. Survival was significantly reduced in 1250 ppm males, most likely due to nephropathy.
Mortality:
mortality observed, treatment-related
Description (incidence):
No differences in survival of female rats. Survival was significantly reduced in 1250 ppm males, most likely due to nephropathy.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weights of 1250 ppm males were less than those of the controls after week 62, and those of 625 ppm males were less after week 86. Mean body weights of 625 and 1250 ppm females were generally less than those of the controls after week 10.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Feed consumption in 1250 ppm males was less than that by the controls after week 70 of the study. Feed consumption in 1250 ppm females was generally less than that by the controls throughout the study.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Increased incidences of renal tubule hyperplasia in all exposed groups of males. Incidences of renal tubule hyperplasia in all exposed females were significantly greater than that of the control group when the single and step section evaluations were combined.
The incidences of centrilobular hepatocellular hypertrophy in all exposed groups of males and females were significantly greater than those in the control groups. This hepatocellular hypertrophy is consistent with the induction of P450 enzymes previously observed in the 14-week study.
There was also an increase of cystic liver degeneration in 625 and 1250 ppm males, and bile duct hyperplasia in all exposed groups of females.

Males:
Kidney: renal tubule, hyperplasia (standard evaluation - 1/50, 5/50, 20/50, 23/50; standard and extended evaluations combined - 3/50, 11/50, 30/50, 40/50); pelvis, transitional epithelium, hyperplasia (1/50, 11/50, 29/50, 34/50); severity of nephropathy (1.3, 2.4, 3.3, 3.8).
Liver: hepatocyte, centrilobular, hypertrophy (0/50, 17/50, 31/50, 19/50); degeneration, cystic (8/50, 11/50, 20/50, 15/50)

Females:
Kidney: renal tubule, hyperplasia (standard evaluation - 0/50, 1/50, 1/50, 1/50; standard and extended evaluations combined - 1/50, 8/50, 10/50, 7/50); severity of nephropathy - (1.1, 1.4, 1.7, 2.0)
Liver: hepatocyte, centrilobular, hypertrophy (0/50, 27/50, 30/50, 33/50); bile duct, hyperplasia (10/50, 35/50, 39/50, 40/50)
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
There was some evidence of carcinogenic activity of benzophenone in male rats based on increased incidences of renal tubule adenoma. Mononuclear cell leukaemia in male rats may have been related to benzophenone exposure.
There was equivocal evidence of carcinogenic activity of benzophenone in female rats based on the marginally increased incidences of mononuclear cell leukaemia and histiocytic sarcoma.

Males:
Kidney: renal tubule, adenoma (standard evaluation - 1/50, 1/50, 2/50, 4/50; standard and extended evaluations combined - 2/50, 2/50, 7/50, 8/50)
Equivocal findings: Mononuclear cell leukaemia: (27/50, 41/50, 39/50, 24/50)

Females:
Equivocal findings: Mononuclear cell leukaemia: (19/50, 25/50, 30/50, 29/50); Histiocytic sarcoma: (0/50, 0/50, 1/50, 2/50)
Decreased incidences: Mammary gland: fibroadenoma (27/50, 24/50, 15/50, 7/50)
Key result
Dose descriptor:
NOAEC
Effect level:
<= 312 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: neoplastic
histopathology: non-neoplastic
Remarks on result:
not determinable

For survival and histopathological data, refer below to the tables under "attached background material".

Conclusions:
Groups of 50 male and 50 female rats were fed diets containing 0, 312, 625 or 1250 ppm benzophenone (ca. 0, 15, 30 or 60 mg/kg bw/d for males and 0, 15, 30 or 65 mg/kg bw/d for females). Survival of 1250 ppm males was significantly less than that of controls. Mean body weights of 1250 ppm males were markedly less than those of the controls during year 2 of the study and weights of exposed females were consistently less than controls throughout the study. Feed consumption by 1250 ppm males was less than that by the controls after week 70; feed consumption by 1250 ppm females was generally less than that by the controls throughout the study.
There was a positive trend in the incidences of renal tubule adenoma in males, and the incidences in 625 and 1250 ppm males exceeded the historical control range; these neoplasms were accompanied by significantly increased incidences of renal tubule hyperplasia. The incidences of pelvic transitional epithelium hyperplasia and the severity of nephropathy were significantly increased in all exposed groups of male rats.
Increased incidences of mononuclear cell leukaemia in all exposed groups of females exceeded the historical control range and the incidence in 625 ppm females was significantly greater than that in the controls. Male rats exposed to 312 or 625 ppm had significantly increased incidences of mononuclear cell leukaemia. One 625 ppm female and two 1250 ppm females had histiocytic sarcomas, and the incidence in the 1250 ppm group exceeded the range in the historical controls.
Liver lesions included significantly increased incidences of hepatocytic centrilobular hypertrophy in all exposed groups of males and females, cystic degeneration in 625 and 1250 ppm males, and bile duct hyperplasia in all exposed groups of females.
Incidences of mammary gland fibroadenoma in females exposed to 625 or 1250 ppm were lower than expected after adjusting for body weight.
Executive summary:

A two-year carcinogenicity study was performed in F344/N rats with benzophenone according to EPA OPPTS 870.4200 and OECD Guideline 451.

Under the conditions of this study, there was some evidence of carcinogenic activity in male rats based on increased incidences of renal tubule adenoma; these neoplasms were accompanied by significantly increased incidences of renal tubule hyperplasia. Mononuclear cell leukaemia in male F344/N rats may have been related to benzophenone exposure.

There was equivocal evidence of carcinogenic activity in female rats based on the marginally increased incidences of mononuclear cell leukaemia and histiocytic sarcoma. Liver lesions included significantly increased incidences of hepatocytic centrilobular hypertrophy in all exposed groups of males and females, cystic degeneration in 625 and 1250 ppm males, and bile duct hyperplasia in all exposed groups of females. Incidences of mammary gland fibroadenoma in females exposed to 625 or 1250 ppm were lower than expected after adjusting for body weight.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
15 mg/kg bw/day
Study duration:
chronic
Species:
rat

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available
Organ:
kidney
other: hematological, urogenital

Mode of Action Analysis / Human Relevance Framework

At present there is no convincing explanation how benzophenone may induce tumours in experimental animals. There is no indication that benzophenone has a genotoxic potential.

In an EFSA report (2009) it was stated that “…Based on the negative in vitro and in vivo results from tests with definite protocols the Panel concluded that benzophenone has no genotoxic potential. Liver and kidney were identified as the primary target organs of benzophenone toxicity in rats and mice. The Panel considered neoplastic and non-neoplastic end-points in rats and in mice, obtained from chronic carcinogenicity and reproductive toxicity studies. Benzophenone caused liver hypertrophy in the rat at the lowest dose level (~6 mg/kg/day) in a two-generation study, described as hypertrophy of centrilobular hepatocytes without any increase in liver weight. However, in a chronic carcinogenicity study in rats benzophenone did not cause liver tumours, even at exposure levels yielding severe liver damage. Therefore the Panel considers that the liver hypertrophy seen in rat is an adaptive response and not an adverse response. In the B6C3F1 mouse, benzophenone causes liver adenomas at a dose of 40 mg/kg b.w. per day. The Panel considers the liver adenomas to be an adverse effect. However, this effect is a less sensitive endpoint than the kidney effects…”

This is also reflected by the statement from IARC, i.e. sufficient (but no clear) evidence for the carcinogenicity in experimental animals and possibly carcinogenic to humans. As stated the mechanistic evidence for the tumour induction by BP is weak.

Justification for classification or non-classification

Based on the data currently available (discussed above) and based on the evaluations presented by competent institutions (e.g. EFSA, IARC), a classification of benzophenone for the endpoint carcinogenicity according to EU-CLP seems unjustified unless more reliable experimental information has been generated.

Additional information