Diphenyl carbonate

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)

GLP compliance:

yes

Type of assay:

micronucleus assay

Test material

Test material information

Constituent 1

Reference substance name:

102-09-9

IUPAC Name:

102-09-9

Constituent 2

Reference substance name:

Diphenyl carbonate

EC Number:

203-005-8

EC Name:

Diphenyl carbonate

Cas Number:

102-09-0

Molecular formula:

C13H10O3

IUPAC Name:

diphenyl carbonate

Details on test material:

purity: 99.98 %

Test animals

Species:

mouse

Strain:

other: Hsd/Win: NMRI

Sex:

male

Details on test animals or test system and environmental conditions:

according to Guideline

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

TS was suspended in 0.5% aqueous Cremophor emulsion, using a microdismembrator for 5 minutes. The suspensions were stirred with a magnetic mixer during administration. CP was dissolved in  deionized water.
administered volume: 10 mg/kg bw

Details on exposure:

animals were treated intraperitoneally

Duration of treatment / exposure:

animals were treated twice, separated by 24 hours

Frequency of treatment:

diphenyl carbonate was administered twice, whereas the positive control cyclophosphamide was administered only once.

Post exposure period:

24 hours after the last dose the animals were sacrificed.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

75 mg/kg bw/day

Remarks:

2 applications separated by 24 hours

Doses / concentrations 2

Dose / conc.:

150 mg/kg bw/day

Remarks:

2 applications separated by 24 hours

Doses / concentrations 3

Dose / conc.:

300 mg/kg bw/day

Remarks:

2 applications separated by 24 hours

No. of animals per sex per dose:

5 males per dose

Control animals:

yes, concurrent vehicle

Positive control(s):

Cyclophosphamide, dissolved in deionized water, single i.p. injection with 20 mg/kg bw

Examinations

Tissues and cell types examined:

bone marrow smears
No. of cells scored for micronuclei: 2000 polychromatic erythrocytes (PCEs)/animal
PCE/normochromatic erythrocytes (NCE)-ratio determined for 2000 PCEs/animal

Details of tissue and slide preparation:

according to Guideline

Evaluation criteria:

A test was considered positive if there was a relevant and significant increase in the number of micronucleated polychromatic erythrocytes showing micronuclei in comparison to the negative control.

Statistics:

Wilcoxon's non-parametric rank sum test; p<0.001 for significance

Results and discussion

Test results

Sex:

male

Genotoxicity:

negative

Toxicity:

yes

Remarks:

Symptoms of toxicity (e.g. apathy, loss of weight) after administration of >= 2x75 mg/kg bw; no substance-induced mortalities; PCE/NCE ratio reduced in highest dose group

Vehicle controls validity:

valid

Positive controls validity:

valid

Additional information on results:

Symptoms of toxicity (apathy, roughened fur, loss of weight, spasm,  twitching, difficulty in breathing, slitted eyes and closed eyes) after  administration of >= 2x75 mg/kg; no substance-induced mortalities; 
the  ratio between polychromatic and normochromatic erythrocytes was reduced in the highest  dose group by > 30%, indicating cytotoxic effects in the bone marrow; 
No indication of a test substance dependent  clastogenic effect at any diphenyl carbonate dose.
Micronucleated PCEs/2000 PCEs (MNPCE in %)  (mean values of 5 animals in each group):
vehicle control: 3.6 (0.18%)
2 x 75 mg/kg: 2.6 (0.13%)
2 x 150 mg/kg: 2.8 (0.14%)
2 x 300 mg/kg: 5.6 (0.28%)
No statistically significant increase. The highest dose group with the mean of 0.28% MNPCE includes one animal  with an exceptional high number of 16 MNPCE. Since this value is clearly  different from the other findings in this group (1-5 MNPCE), it is  interpreted as outlier. Without this outlier the MNPCE-value for this  group would be 3.0 (0.15%).

Any other information on results incl. tables

The appropriate reference mutagen (cyclophosphamide, single i.p. application of 20 mg/kg bw) was used as positive control and showed the expected results (23.4 MNPCE/ 2000 PCEs). Also vehicle controls showed the expected results.

Applicant's summary and conclusion

Conclusions:

In the mouse bone marrow micronucleus test (MNT) with two intraperitoneal injection of diphenyl carbonate in concentrations of 75, 150, and 300 mg/kg bw no indications of a clastogenic effect were found. Relevant systemic exposure was demonstrated by symptoms of toxicity starting at 75 mg/kg bw and an altered PCE/NCE ratio.

Executive summary:

An in vivo micronucleus test was conducted in accordance with OECD 474 and under GLP conditions.

During the study male Hsd/Win: NMRI mice were dosed twice in an intraperitoneal fashion with the test material at 75, 150 and 300 mg/kg bw suspended in 0.5 % aqueous Cremophor emulsion. The doses were administered 24 hours apart. Test material was administered at a dose volume of 10 mg/kg bw. Twenty four hours after the last dose the animals were sacrificed.

Symptoms of toxicity were observed after administration of all dose levels, though no test material-induced mortalities occurred. The ratio between polychromatic and normochromatic erythrocytes was reduced in the highest dose group by > 30 %, indicating cytotoxic effects in the bone marrow. These symptoms demonstrate relevant systemic exposure. No indication of a test material-dependent clastogenic effect was observed at any dose.

Under the conditions of this study, the test material was non-mutagenic in the mouse bone marrow micronucleus test.