4,4'-dihydroxybenzophenone

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

There is no reproduction toxicity data available for this substance. The substance benzophenone (BP), which is the parent molecule for the di hydroxy species 4,4 -dihydroxybenzophenone, is used widely in personal care products and has been evaluated for both toxicology and ecotoxicology. It has been assessed that in the absence of other spcific data on 4,4 -dihydroxybenzophenone that benzophenone can be used as a suitable surrogate molecule for evaluation of this end point.

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.

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 based on body weight and liver and kidney observation.

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.

Link to relevant study records

Reference

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

Reason / purpose for cross-reference:

reference to other study

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

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

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

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

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.

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: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

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

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

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Exactly the same findings for P1 as for P0

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

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

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

Key result

Reproductive effects observed:

no

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.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Species:

rat