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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
April 1977 to May 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: NTP study carried out to national standards that applied at the time
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982
Report Date:
1982

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: EPA OPPTS 870.4300 (Combined Chronic Toxicity / Carcinogenicity)
Deviations:
yes
Remarks:
current guidelines require three treatment groups plus a control group
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:

- Name of test material (as cited in study report): butyl benzyl phthalate
- Substance type: no data
- Physical state: no data
- Analytical purity: about 98%
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: no data
- Purity test date: February 1978
- Lot/batch No.: Lot No. M2676 was used for the first 34 weeks, and Lot No. M81977 was used for the final 70 weeks of the study.
- Expiration date of the lot/batch: no data
- Stability under test conditions: stable in feed for two weeks at temperatures as high as 45°C
- Storage condition of test material: stored in dark

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
- Source: NCI Frederick Cancer Research Center, Frederick, Maryland, USA
- Age at study initiation: 4-5 weeks
- Weight at study initiation: females: about 15 g; males: about 27 g
- Fasting period before study: no data
- Housing: suspended polycarbonate cages on hardwood chips as bedding
- Diet (e.g. ad libitum): conventional, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18°-30°C (20°-26°C for 77% of study period)
- Humidity (%): 10-88
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
- Rate of preparation of diet (frequency): every two weeks
- Mixing appropriate amounts with (Type of food): mixed with an aliquot of powdered feed which was then combined with the rest of the feed and
mixed for 15 min
- Storage temperature of food: 4°C
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The butyl benzyl phthalate concentration was determined by the net ultraviolet absorbances at 275 nm of 50-ml methanol extracts of 2-g samples of feed.
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 6000 or 12000 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0, 5200-6350 or 10200-12900 ppm
Basis:
other: analytical conc.
Remarks:
Doses / Concentrations:
0, 780 or 1560 mg/kg bw/day
Basis:
other: nominal ingested
No. of animals per sex per dose:
50/sex/dose
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: based on the outcome of a 90-day repeated dose study
- Rationale for animal assignment (if not random): assigned at random until the average cage weights were approximately equal for the same sex
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: animals inspected twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: animals inspected twice daily


BODY WEIGHT: Yes
- Time schedule for examinations: every 4 weeks


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- 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: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No


CLINICAL CHEMISTRY: No


URINALYSIS: No



OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Gross examination of all major tissues, major organs, and all gross lesions from killed animals and from animals found dead (unless it was not possible due to autolysis or cannibalization) .

HISTOPATHOLOGY: Yes. The following tissues were examined microscopically: abnormal lymph nodes, skin, mandibular lymph nodes, mammary gland, salivary gland, bone marrow, costochondral junction, thymus, larynx, trachea, lungs and bronchi, heart, thyroids, parathyroids, esophagus, stomach, duodenum, jejunum, ileum, colon, mesenteric lymph nodes, liver, gallbladder, pancreas, spleen, kidneys, adrenals, urinary bladder, seminal vesicles/prostate/testes, ovaries/uterus, brain, and pituitary.
Statistics:
Statistical analyses for a possible dose-related effect on survival used the method of Cox for testing two groups for equality and Tarone's extensions of Cox's methods for testing for a dose-related trend. The approximate 95% confidence interval for the relative risk of each dosed group compared
with its control was calculated from the exact interval on the odds ratio.

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):
not specified
Food efficiency:
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not specified
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: survival for both dose groups was comparable to that of the control groups; no clinical effects were attributable to the test substance

BODY WEIGHT AND WEIGHT GAIN: a dose-related decrease in body weight gain was seen throughout the study for both sexes. Statistical significance is not reported, and the data are only available in graphical form - but the reduction in body weight gain was around 5% and 5-10% in low-dose males and females respectively, and 15% and 10-25% in high-dose males and females respectively. The effect at the top dose can be considered biologically significant.

GROSS PATHOLOGY: no data

HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment-related effects were observed

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
No treatment-related effects were observed

Effect levels

Dose descriptor:
NOAEL
Effect level:
ca. 780 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Males and females given 1560 mg/kg bw/day showed a 10-25% reduction in body-weight gain.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
When male and female B6C3F1 mice were given butyl benzyl phthalate in the diet at 0, 6000 or 12000 ppm for 103 weeks (equivalent to nominal doses of around 0, 780 or 1560 mg/kg bw/day), growth inhibition occurred in the BBP-treated groups (particularly at the top dose) but there was no other evidence of compound-related toxicity. The NOAEL was 780 mg/kg bw/day.
Executive summary:

Butyl benzyl phthalate was assessed for repeated-dose toxicity in B6C3F1 mice.

 

Groups of 50 mice of each sex were given the test substance in the diet for 103 weeks at concentrations of 0, 6000 or 12000 ppm (providing around 0, 780 or 1560 mg/kg bw/day). The mice were observed daily for clinical signs of toxicity, body weight changes were recorded every 4 weeks, and the animals were sacrificed at 106 weeks. A comprehensive range of organs and tissues was examined for gross and microscopic changes.

 

A dose-related decrease in mean body weights of both male and female mice was observed throughout the study. Statistical significance was not reported, but the reduction in body-weight gain appeared to be around 5% and 5-10% in low-dose males and females respectively, and 15% and 10-25% in high-dose males and females respectively. No other compound-related clinical signs were observed and survival was comparable in the control and treated groups. No toxic lesions were evident and all histological changes observed were similar in both treated and control groups and within the normal historical incidence limits in B6C3F1 mice. Similarly the neoplastic effects observed were deemed to be unrelated to administration of the test substance and also fell within the range of historical controls.

When male and female B6C3F1 mice were given butyl benzyl phthalate in the diet at 0, 6000 or 12000 ppm for 103 weeks (equivalent to a nominal dose of around 0, 780 or 1560 mg/kg bw/day), growth inhibition occurred in the BBP-treated groups (particularly at the top dose) but there was no other evidence of compound-related toxicity. The NOAEL was 6000 ppm (780 mg/kg bw/day).