Diphenyl carbonate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

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:

2002

Report date:

2002

Materials and methods

Test guideline

Qualifier:

according 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:

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:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

according to Guideline
body weight on day 0 p.c.: 207 to 249 g
age of females on day 0 p.c.: 12-16 weeks

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

vehicle: carboxymethylcellulose 0.5 % in deionized water
administration volume: 10 ml/kg bw
The dose levels used were selected according to a preceding dose-range  finding study (Study No. T0062796) in rats with dose levels of 0, 20,  125, and 750 mg/kg bw/d.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Investigations on stability and homogeneity of the test compound in samples of 1 mg/ml and 100 mg/ml were performed. Stability and homogeneity were confirmed.

Details on mating procedure:

1 male/2 females per cage; if sperm was detected in the vaginal smear  this day was day 0 of gestation

Duration of treatment / exposure:

days 6 - 19 of gestation

Frequency of treatment:

once daily

Duration of test:

cesarian section and sacrifice at day 20 of gestation

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

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

Doses / concentrations 2

Dose / conc.:

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

Doses / concentrations 3

Dose / conc.:

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

No. of animals per sex per dose:

No. of females/dose: 25 (50 mg/kg and 750 mg/kg group: 28) inseminated females

Control animals:

yes, concurrent vehicle

Details on study design:

Sex: female
Duration of test: sacrifice on day 20 of gestation

Examinations

Maternal examinations:

Body weight gain: on day 0 p.c. and daily from day 6-20
Food consumption: yes
Water consumption: yes (by visual estimation)
Clinical observations: appearance, behaviour, excretory products and  mortality, from day 0 -20 twice daily
Gross pathological examination: at time of cesarian section on day 20  p.c. or after death/premature sacrifice

Ovaries and uterine content:

gravid uterine weight, no. of corpora  lutea, no. of implantations, no. of resorptions, placenta weight

Fetal examinations:

Examination of fetuses: number, weight and sex of live fetuses, external,  visceral and skeletal malformations
Total numer of live fetuses examined: 275/249/269/253

Statistics:

Kruskal-Wallis test, analysis of variance, Dunnett's test, Chi² test were  used

Historical control data:

yes

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

only in 750 mg/kg group: signs of severe toxicity after  administration (convulsions and ventral posture), which disappeared  within 4 hours; in surviving females such clinical signs became less  severe or were not longer evident with increasing duration of treatment;  piloerection;

Mortality:

mortality observed, treatment-related

Description (incidence):

In 750 mg/kg group 5 females died (4 after 1st dose, 1 after 7th dose) 

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight development: stat. sign. reduced at 750 mg/kg throughout the  entire study (mean body weight gain day 0-20 reduced by 24%); in the 200  mg/kg bw/day group stat. sign. reduced only on day 6-7 p.c. and remained  marginally reduced up to sacrifice

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

distinctly reduced in 750 (up to 36%) and slightly reduced  in 200 mg/kg group (up to 12% on days 6-12)

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Description (incidence and severity):

water consumption increased only in high dosed females

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Placenta weight: unaffected

Description (incidence and severity):

In 750 mg/kg group some females showed empty of  gas filled stomach, related to morbidity/mortility and regarded as unspecific finding.
Placenta appearance: at 750 mg/kg engorged placentae/ necrotic placental  borders

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Maternal developmental toxicity

Description (incidence and severity):

Total number of females with implantations (vehicle control, 50, 200, 750  mg/kg bw/d): 23/22/25/21
No. of resorptions: 0/0/1/0
Total number of females with viable fetuses: 23/22/24/21
No. of corpora lutea/female: 14.3/14.3/14.9/14.7
Postimplantation loss/female: no meaningful effects (0.7/0.8/1.1/1.2)  since no. of viable fetuses per litter not affected and inbetween historical control range

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

>= 50 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects: yes

Details on embryotoxic / teratogenic effects:
see Remarks on results
For selected fetuses a peer review of fetal visceral findings was  performed by Tesh Consultants International, UK.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

>= 50 mg/kg bw/day

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

No. of viable fetuses: 275/249/269/253

No. of dead fetuses: 0/0/2/1 (deaths did not affect the mean number of viable fetuses per litter and was comparable to the incidences in historical control, so that toxicological relevance was not assumed)

Sex ratio (% males): not affected (48.4/50.1/50.5/48.6)

Fetal weight (mean in g): 3.77/3.74/3.64/3.40 (high dose group p<0.01)

Fetal malformations: at 750 mg/kg bw (severe maternally toxic dose) incidence of common malformations increased on a fetal and litter basis as

- dysplastic forelimb bones: fetal incidence 5.5%, litter incidence 33.3% compared to 0% in control (in historical control groups indicences of up to 4.3/20% were seen)

- 2 cases of multiple malformations

- 3 cases of atrial septal defect of the heart within 3 litters

- 2 cases of flat and stretched kidneys

- 1 case of situs inversus

- 1 case of shortened tail with missing sacral and caudal vertebrae

Fetal external and visceral deviations: no TS-related effects

Fetal skeletal deviations including cartilaginous deviations: slightly retarded ossification in comparison to control could not be completely excluded in the 200 mg/kg group (retarded ossification of distal phalanges of toes, cervical vertebral bodies, sacral vertebral arches and wavy ribs: only stat. sign. when calculated on a fetal basis) and was evident to a more pronounced degree in the 750 mg/kg group.

Fetal cartilage was not affected. The overall number and type of malformations were not increased at a dose level up to and including 200 mg/kg bw/day.

Applicant's summary and conclusion

Conclusions:

Under the conditions of this study, the NOAEL for maternal toxicity and developmental toxicity in rats was 50 mg/kg bw/day. At 200 mg/kg bw/day slight maternal toxicity occurred and a retarding effect on foetal skeletal ossification of toes and cervical vertebral bodies could not be completely excluded.

Executive summary:

The developmental toxicity of the substance was investigated in a study which was conducted in accordance with the standardised guideline OECD 414 under GLP conditions.

During the study test material was administered to rats once daily via oral gavage at dose levels of 50, 200 and 750 mg/kg bw to 25 females per dose. The vehicle was 0.5 % carboxymethylcellulose in deionised water and the dose volume was 10 mL/kg bw. Maternal animals were dosed on days 6 - 19 of gestation and underwent caesarean section and sacrifice on day 20 of gestation.

Administration of 750 mg/kg bw/day led to severe maternal toxicity (mortality, convulsions, piloerection, body weight loss). Foetuses of this dose group showed reduced body weights and increased incidences of unspecific malformations (mainly dysplastic forelimb bones).

No effects were observed on the number of females with implantations, number of resorptions, total number of females with viable foetuses, the number of corpora lutea per female, post implantation loss or placenta weight. At 750 mg/kg bw/day, placentae appeared to be engorged with necrotic placental borders.

The number of dead foetuses did not affect the mean number of viable foetuses per litter and was comparable to the incidences in historical control, so that toxicological relevance was not assumed.

The sex ratio of offspring was not affected by treatment. The foetal weight in the high dose group was statistically significantly reduced.

Foetal malformations were observed at 750 mg/kg bw (severe maternally toxic dose); the incidence of common malformations increased on a foetal and litter basis: dysplastic forelimb bones (foetal incidence 5.5 %, litter incidence 33.3 % compared to 0 % in control, though in historical control groups incidences of up to 4.3/20 % were seen); 2 cases of multiple malformations; 3 cases of atrial septal defect of the heart within 3 litters; 2 cases of flat and stretched kidneys; 1 case of situs inversus; and 1 case of shortened tail with missing sacral and caudal vertebrae.

There were no test material-related effects on foetal external and visceral deviations. The following foetal skeletal deviations (including cartilaginous deviations) were seen: slightly retarded ossification in comparison to control could not be completely excluded in the 200 mg/kg group (retarded ossification of distal phalanges of toes, cervical vertebral bodies, sacral vertebral arches and wavy ribs; this was only statistically significant when calculated on a foetal basis) and was evident to a more pronounced degree in the 750 mg/kg group. Foetal cartilage was not affected. The overall number and type of malformations were not increased at a dose level up to and including 200 mg/kg bw/day.

Under the conditions of this study, the NOAEL for maternal toxicity and developmental toxicity in rats was 50 mg/kg bw/day. At 200 mg/kg bw/day slight maternal toxicity occurred and a retarding effect on foetal skeletal ossification of toes and cervical vertebral bodies could not be completely excluded.