Benzophenone

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1998 - 1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: A NTP (National Toxicology Program) study. Test method equivalent to OECD 414. GLP study.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Benzophenone

EC Number:

204-337-6

EC Name:

Benzophenone

Cas Number:

119-61-9

Molecular formula:

C13H10O

IUPAC Name:

benzophenone

Details on test material:

- Name of test material (as cited in study report): Benzophenone

Test animals

Species:

rat

Strain:

Sprague-Dawley

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: methylcellulose

Details on exposure:

VEHICLE
- Concentration in vehicle: 0.5%
- Amount of vehicle (if gavage): 5 mL/kg

Duration of treatment / exposure:

Gestational days (GD) 6 through 19

Frequency of treatment:

Once daily

Duration of test:

On gd 20, timed-mated females were sacrificed.

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 200, or 300 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

25 to 26 time-mated female rats per group.

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose selection was based on a screening study in which Sprague-Dawley-derived rats were treated by gavage with benzophenone (0, 25, 50, 100, 200, or 300 mg/kg body weight/day) on GD 6 through 19. Maternal toxicity was found at all doses, but evidence of developmental toxicity was limited to a 6-8% decrease for average fetal body weight per litter (not statistically significant) at the high dose.

Examinations

Maternal examinations:

Dams were monitored at regular intervals throughout gestation for clinical signs, feed and water intake, and body weight.
At necropsy on GD 20, the following were recorded: maternal clinical condition; body, liver, paired kidney weights.

Ovaries and uterine content:

At necropsy on GD 20, the following were recorded: gravid uterine weights; pregnancy status; and number of corpora lutea. In the gravid uterus, the numbers of resorbed, dead, or live fetuses were recorded.

Fetal examinations:

All live fetuses were weighed, sexed, and examined for external morphological anomalies. Approximately one-half of the fetuses were examined for visceral anomalies, including internal head structures, and the remaining fetuses were examined for skeletal anomalies.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: (reduced body weights, food and water consumption; and increased liver and kidney weight)

Details on maternal toxic effects:
MORTALITY
No treatment-related maternal deaths occurred in this study.

CLINICAL SIGNS
Clinical signs at all doses of benzophenone included lethargy, pilo-erection, weight loss and rooting in the bedding after dosing.

BODY WEIGHT AND BODY WEIGHT GAIN
Maternal body weight was decreased at the low dose on GD 9, 12, and 15, at the mid dose on GD 9 and 12, and at the high dose on GD 9, 12, 15, 18, 19, and 20 at sacrifice. Decreased maternal weight gain was observed at all doses from gd 6 to 9, and at the high dose from gd 9 to 12. In-creased weight gain was noted at the mid dose (GD 9 to 12 and 19 to 20) and at the high dose (GD 18 to 19 and 19 to 20). Maternal body weight gain during treatment and gestation was decreased only at the high dose, while gestational weight gain corrected for gravid uterine weight was reduced at all doses.

FEED AND WATER INTAKE
Maternal relative feed intake (g/kg/day) was decreased at all doses from gd 6 to 9, and at the mid and high doses from gd 9 to 12. Rebound increases in feed intake were noted at all doses of benzophenone from gd 15 to 18, and 18 to 19. The high dose showed a significant decrease in relative feed intake for the treatment period as a whole. Maternal relative water intake (g/kg/day) was increased at the low dose (gd 15 to 18 and 18 to 19), and the mid and high doses (gd 12 to 15, 15 to 18, 18 to 19, and 19 to 20). Relative water intake for the treatment period as a whole (gd 6 to 20) was not affected.

ORGAN WEIGHTS
Gravid uterine weight was not affected. Maternal liver and kidney weights (absolute and/or relative) were significantly increased at all doses.

Effect levels (maternal animals)

1

Dose descriptor:

LOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes. Remark: (decreased fetal body weight)

Details on embryotoxic / teratogenic effects:
BODY WEIGHT
Average fetal body weight per litter exhibited decreasing dose-response trends (males, females, and both sexes combined). At the high dose, a 6.5% decrease for male fetal body weight was statistically significant; a 5% decrease for female fetal body weight was biologi-cally significant, but did not reach statistical significance.

DEVELOPMENTAL PARAMETERS
Benzophenone had no adverse effect on prenatal viability or the overall incidences of fetal malformations or variations. The incidence of unossified sternebrae was increased at all doses of benzophenone, and the incidence of extra rib (full or rudimentary, combined) on Lumbar I was increased at the mid and high doses. However, neither of these skeletal variations exhibited a significant dose-response relationship.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In a pre-natal developmental study in rats, the maternal toxicity LOAEL was determined to be 100 mg/kg/day based on reduced body weights, food and water consumption; and increased liver and kidney weight at all dose levels. No clearly defined LOAL and NOAEL were achieved for developmental toxicity (lower fetal body weight in 300 mg/kg bw/day, incidence of unossified sternebrae at all doses). Nevertheless, the effects were limited to mild developmental delays with a high probability of recovery during early postnatal development.

Executive summary:

The developmental toxic potential of the test substance to Sprague-Dawley rats was assessed by the National Toxicology Program with a test method similar to OECD 414. Benzophenone (100, 200, or 300 mg/kg bw/day) or its vehicle (0.5% methylcellulose) was administered to female CD rats by gavage on gd 6 through 19. The dose volume was 5 mL/kg. 25 to 26 timed-mated rats were assigned to each group. Dams were monitored at regular intervals throughout gestation for clinical signs, feed and water intake, and body weight. At necropsy on GD 20, the following were recorded: maternal clinical condition; body, liver, paired kidney and gravid uterine weights; pregnancy status; and number of corpora lutea. In the gravid uterus, the numbers of resorbed, dead, or live fetuses were recorded. All live fetuses were weighed, sexed, and examined for external morphological anomalies. Approximately one-half of the fetuses were examined for visceral anomalies, including internal head structures, and the remaining fetuses were examined for skeletal anomalies. Maternal toxicity was noted at greater than or equal to 100 mg/kg bw/day administered on GD 6 through 19. Clinical signs were observed and maternal liver and kidney weights were significantly increased in all dosed groups. Reduced maternal body weight gain and decreased feed consumption were observed in the 300 mg/kg bw/day. Thus, the maternal toxicity LOAEL was 100 mg/kg/day and the NOAEL was not determined. Test item had no adverse effects on prenatal viability or overall incidences of fetal malformations or variations. The average fetal body weight per litter in the 300 mg/kg bw/day group was significantly lower than that in the vehicle controls. The incidences of unossified sternebrae were increased at all doses of benzophenone, and the incidences of extra rib on Lumbar I were increased in the 200 and 300 mg/kg groups. Although, clearly defined NOAEL and LOAEL values for developmental toxicity were not achieved, the effects were limited to mild developmental delays with a high probability of recovery during early postnatal development.