4,4'-dihydroxybenzophenone

Toxicity to reproduction

Administrative data

Endpoint:

two-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

90 days

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Version / remarks:

Method not specified in the review document

Deviations:

not specified

Principles of method if other than guideline:

Benzophenone (FEMA No. 2134; CAS No. 119-61-9) was administered in the diet to rats at target dose levels of 20 mg/kg body weight/day for 90 days and 100 or 500 mg/kg/day for 28 days. Body weights and food consumption were measured weekly; haematology, clinical chemistry and urinalysis values were obtained at 4 wk and at the end of the study. Gross and microscopic pathological examinations were conducted and organ weights were recorded

GLP compliance:

not specified

Remarks:

Study carried out in 1991 by Burdock et al in the USA. GLP compliance is not specified inthe abstract.

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Administration was started at the age of 6 weeks for a period of 90 days

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Duration of treatment / exposure:

90 days

Frequency of treatment:

Daily

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Dose / conc.:

20 mg/kg bw/day (actual dose received)

Observations and examinations performed and frequency:

Body weights and food consumption were measured weekly; haematology, clinical chemistry and urinalysis values were obtained at 4 wk and at the end of the study. Gross and microscopic pathological examinations were conducted and organ weights were recorded

Dose descriptor:

NOEL

Effect level:

> 20 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

Critical effects observed:

no

The study detailed here are the results for the 90 day study.

In the same study, the authors carried out a 28 day study at the same time. They used 100 or 500 mg/kg/day on SD mixed sex rats for 28 days.

Body weights and food consumption were measured weekly; haematology, clinical chemistry and urinalysis values were obtained at 4 wk and at the end of the study. Gross and microscopic pathological examinations were conducted and organ weights were recorded.

Treatment-related changes resulted in decreases in red blood cell count and haematocrit, increases in urea nitrogen, bilirubin, total protein and albumin, increases in liver and kidney weights and hypertrophy of liver cells in the 100 and 500 mg/kg/day groups.

Decreases in haemoglobin and alkaline phosphatase and increase in glucose in 500 mg/kg/day group.

Conclusions:

A no-effect level was demonstrated at 20 mg/kg/day for 90 days of administration. This would be equivalent to an intake of 1200 mg/day for a 60-kg human.
For the 28 day study, some changes in the blood make-up and increased liver and kidney weight were observied in the 100 mgkg/day and 500 mg/kg/day groups.

Data source

Reference

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Version / remarks:

OECD 1983

GLP compliance:

not specified

Remarks:

Testing carried out in Japan in 2005 by Hoshino et al. Details not given in paper

Test material

Test material information

1

Reference substance name:

Benzophenone

EC Number:

204-337-6

EC Name:

Benzophenone

Cas Number:

119-61-9

Molecular formula:

C13H10O

IUPAC Name:

benzophenone

Specific details on test material used for the study:

Details specified in publication by Hoshino et al, published in 2005, the summary of which is contained in the EFSA review paper.
Analytical purity: 99.98% or higher
- Lot/batch No.: 112D2013

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

Male and female Sprague-Dawley (SD) rats, parental (F0) and first generation (F1), were exposed to benzophenone by feeding diet with concentrations of 0 (control), 100, 450 or 2000 ppm (corresponding approximately to doses of 6-9, 29-40 and 130-179 mg/kg body weight/day, respectively) .

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Administration of F0 parental animals started from an age of 5 weeks and continued in males for 10 weeks. For females, administration lasted through 10 weeks or more of the pre-mating, mating, gestational, lactational and during weaning of the F1 offspring (PND 21).
Administration to F1 parental animals was started from the time of weaning (three weeks old); in F1 males it was continued until necropsy trough 10 weeks or more of the pre-mating and mating periods, and in F1 females until necropsy through 10 weeks or more of the pre-mating, mating, gestational, lactational periods, and during weaning of the F2 offspring (PND 21).

Frequency of treatment:

Daily through diet

No. of animals per sex per dose:

24 of each sex

Control animals:

yes, concurrent no treatment

Details on study design:

Dosing was based on the results of a preliminary dose-range finding study over 4 weeks with dietary concentrations of 0, 600, 2000, 6000 or 20000 ppm. The highest dose for the definite study was set at 2000 ppm

Positive control:

No

Examinations

Parental animals: Observations and examinations:

In F0 and F1 parental animals, inhibition of body weight gain and food consumption, significantly elevated renal weights, dilatation of the renal proximal tubules, and regeneration of the proximal tubular epithelium were recognized at doses of 450 ppm and 2000 ppm, along with an increase in hepatic weight and centrilobular
hepatocytic hypertrophy.
Obvious effects on the endocrine system and reproductive toxicological effects were not observed up to the highest dose of 2000 ppm in the F0 or F1 parent animals (no test substance related changes in the estrous cycle, reproductive capability, delivery and lactation, sperm parameters, serum hormone levels, or necropsy findings).

Litter observations:

Inhibition of body weight gain was observed in both the F1 and F2 males and females of the 2000 ppm group, but no other treatment-related effects were observed (in the number of male and female F1 or F2 pups delivered, viability, anogenital distance, physical development, the results of reflex and response tests, or on the observation results of external abnormalities)., where there was an increase in liver weight and centrilobular hypertrophy, and in kidney.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

100 ppm: hypertrophy of centrilobular hepatocytes in males and females
>= 450 ppm: dilation of renal proximal tubules in both males and females.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Effect levels (P0)

1

Dose descriptor:

NOEL

Remarks:

general clinical observations

Effect level:

< 100 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

organ weights and organ / body weight ratios

histopathology: non-neoplastic

2

Dose descriptor:

NOEL

Remarks:

reproduction and endocrine system

Effect level:

> 2 000 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive function (oestrous cycle)

reproductive function (sperm measures)

reproductive performance

Results: P1 (second parental generation)

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Details on results (P1)

Exactly the same findings for P1 as for P0

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

inhibition of body weight gain was observed in both the F1 and F2 males and females of the 2000 ppm group

Effect levels (F1)

Dose descriptor:

NOEL

Generation:

F1

Effect level:

450 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Results: F2 generation

Effect levels (F2)

Dose descriptor:

NOEL

Generation:

F2

Effect level:

450 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

Applicant's summary and conclusion

Conclusions:

Regarding effects of BZP on the FO and F I parental animals in the present study, changes such as inhibition of body weight gain and food consumption, increase in renal weights and dilatation and regeneration of renal proximal tubules were recognized in the groups receiving 450 ppm or 2000 ppm, and increase in the hepatic weights and centrilobular hepatocytic hypertrophy were observed in the 100 ppm or higher groups.
These changes were generally in line with the report of Burdock et al. (1991 When BZP was administered to rats at the dose of 20 mg/kg/day for 90 days or at the doses of 100 or 500 mg/kg/day for 28 days, inhibition of the body weight gain, increased relative liver and kidney weights and centrilobular hepatocyte hypertrophy were thus evident (Burdock et al., 1991) - see Repeat dose oral toxicity end point - woe2
Although there have been previous reports of potential effects of BZP on the endocrine system, only weak estrogenic, as well as weak antiestrogenic action was observed in uterotrophic assays (METI, 2002).
No adverse effects seemingly related to these actions were observed in this two-generation reproductive toxicity study. With regard to reproductive toxicity in FO and Fl parental animals, there were no obvious effects even at the highest dose of 2000 ppm.
As for effects on Fl and F2 offspring, inhibition of the body weight gain was observed at the dose of 2000 ppm.
Therefore, from the present study of BZP administered to rats over two-generations, the no observed effect level (NOEL) on the parental animals is concluded to be less than 100 ppm. Concerning effects on the endocrine system and reproductive toxicity in parental animals, the NOEL is 2000 ppm. In terms of the effects on the offspring, the NOEL is considered to be 450 ppm.
Reproductive toxicity was not observed in this study, effects on the offspring were observed at the highest dose only.