4,4'-dihydroxybenzophenone

Endpoint summary

Description of key information

There is no repeat dose 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.

EFSA conducted a study "SCIENTIFIC OPINION Toxicological evaluation of benzophenone" (Scientific Opinion of the Panel on food contact materials, enzymes, flavourings and processing aids (CEF) May 2009.

The purpose was to re-assess the TDI (Tolerable Daily Intake) of benzophenone and hydroxybenzophenone since these materials can be used in food packaging and can migrate through packaging into the food and hence into humans by consumption.

Based on all available toxicity data carried out up to end May 2009 they concluded 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. 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.Thus, EFSA derived a LOAEL of 6 mg benzophenone/kg b.w. per day from this study. The TDI of 0.03 mg/kg b.w. per day for benzophenone consumption in humans has been set based on all relevant data

On the basis that this review has considered all the oral toxicological data studies for benzophenone and considered this level to be safe for daily human consumption.

In addition, the substance 4,4 -dihydroxybenzophenone sole use for this registration is that of a monomer in the manufacture of a PEK polymer. Residual monomr in the plastic is negligable. The only exposure to this substance would be in the manufacturing process and this is carried out under carefully controlled conditions so exposure will be minimal. Further animal testing can not be justifed

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

EFSA conducted a study "SCIENTIFIC OPINION Toxicological evaluation of benzophenone" (Scientific Opinion of the Panel on food contact materials, enzymes, flavourings and processing aids (CEF)
Question N° EFSA-Q-2009-411 Adopted on 14 May 2009. The purpose was to re-assess the TDI (Tolerable Daily Intake) of benzophenone and hydroxybenzophenone since these materials are used in food packaging and can migrate through packaging into the food and hence into humans by consumption.
Based on all available toxicity data carried out up to end May 2009 they concluded 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. 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.Thus, EFSA derived a LOAEL of 6 mg benzophenone/kg b.w. per day from this study. The TDI of 0.03 mg/kg b.w. per day for benzophenone consumption in humans has been set based on all relevant data
On the basis that this review has considered all the oral toxicological data studies for benzophenone and considered this level to be safe for daily himan consumption, further animal testing can not be justifed.

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

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:

Details of the methodology are not given in the review. Test was for 90 days on rats

Deviations:

not specified

Principles of method if other than guideline:

Benzophenone-1, fed to 40 rats at doses of 0, 0.19, 0.6, 1.9 g/kg for 90 days. Exact details are no given in the report.

GLP compliance:

not specified

Remarks:

Data produced prior to GLP requiements being required.

Species:

rat

Strain:

other: Albino

Sex:

not specified

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Duration of treatment / exposure:

90 days

Frequency of treatment:

Daily

Sacrifice and pathology:

Depressed growth, liver and kidney lesions at 0.6 and 1.9 g/kg

Mortality:

no mortality observed

Dose descriptor:

NOEL

Effect level:

0.19 other: g/kg

Based on:

test mat.

Sex:

not specified

Basis for effect level:

body weight and weight gain

clinical signs

Critical effects observed:

yes

Lowest effective dose / conc.:

0.6 other: g/kg

System:

urinary

Organ:

kidney

liver

Treatment related:

not specified

Conclusions:

Benzophenone-1, fed to 40 rats at doses of 0 - l .9 g/kg for 90 days, produced depressed growth and liver and kidney lesions in animals at doses of 0.6 and 1.9 g/kg.

Reference 3

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.