Diphenyl carbonate

Endpoint summary

Description of key information

ORAL

- The NOAEL in males was 1500 ppm (about 132 mg/kg bw/day), the LOAEL in females was 1500 ppm (about 219 mg/kg bw/day), OECD 415/416, Eiben (2003a).

- The NOAEL in females was 50 mg/kg/day, no guideline followed, Eiben (2003b).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Only females were used

Reason / purpose for cross-reference:

reference to other study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Lower diphenyl carbonate doses were given to females over the same time as in the one-generation study to establish a NOAEL for this gender. Because of instability of diphenyl carbonate below 1500 ppm in food, the substance was administered by gavage. This study was not conducted in accordance with a specific guideline.

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

ANIMALS  
- Age: about 5-6 w
- Weight at study initiation: 140-180 g

Route of administration:

oral: gavage

Vehicle:

other: Tween 20

Details on oral exposure:

- Vehicle for 0, 10, and 200 mg/kg dose: 0.5% Tween 20 in demin. water
- Vehicle for 2 and 50 mg/kg dose: < 0.5% Tween 20 in demin. water  depending on dilution factor
- Adimistration volume: 5 ml/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical investigations on homogeneity, stability and content checks were done by gas chromatography. Generally the content check assured that during the study appropriate and equal mixure prodedures were followed.

Duration of treatment / exposure:

18 weeks

Frequency of treatment:

once daily

Dose / conc.:

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

Dose / conc.:

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

Dose / conc.:

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

Dose / conc.:

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

No. of animals per sex per dose:

10 females per group

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: none
Study was performed to clarify results of a previous study  (one-generation reproduction feeding study, Bayer Report No. AT00196, Jan  13, 2003), where morphological changes were found in adrenals and ovaries of females of all dose groups, and to establish a NOAEL.

Positive control:

none

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS AND FREQUENCY: 
- Clinical signs: at least weekly
- Mortality: twice daily (once on weekends and public holidays)
- Body weight: weekly
- Food consumption: weekly
- Water consumption: not determined
- clinical chemical investigations: blood parameters at sacrifice  (cholesterol, glucose, urea, creatinine, total protein, albumin, alanine  aminotransferase, aspartate aminotransferase, alkaline phosphatase, and  the electrolytes Na, K, Ca, Cl)
- Haematology: not determined
- Urinalysis: not determined

Sacrifice and pathology:

ORGANS EXAMINED AT NECROPSY:
- gross pathology: adrenals, liver, spleen, pituitary, vagina, uterus/cervix, ovaries, oviducts, brain, heart, thymus, tattooed  auricles, kidneys, lungs, and gross lesions
- organ weights: brain, liver, kidneys, adrenals, spleen, ovaries with  oviducts, and uterus
- Histopathology: liver, adrenals, ovaries, oviducts, uterus, and vagina 

Statistics:

Dunnett-Test with variance analysis for body and organ weights; adjusted  welch test

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

No treatment related effects were observed.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

There were no compound-related deaths (due to misapplication throughout  all groups animals died: 1 in vehicle control, 1 in 10 mg/kg bw/day  group, 2 in 50 mg/kg bw/day group, 2 in 200 mg/kg bw/day group. One rat  in the 200 mg/kg bw/day group had to be killed in moribund condition.)

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No treatment-related effects were observed

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No treatment-related effects were observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

No treatment-related effects were observed

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):

No treatment-related effects were observed

Gross pathological findings:

no effects observed

Description (incidence and severity):

There were no significant findings at gross necropsy

Neuropathological findings:

not examined

Description (incidence and severity):

At 200 mg/kg bw/day ovaries of 4 animals exhibited  interstitial glands (control and lower doses 0) characterised by slight  hypertrophy and pale cytoplasm (grade 2); no test material-related effects on number of corpora lutea (both ovaries; 287, 200, 276, 234, 247); in 3 high dosed females adrenal glands showed hypertrophy of Zona fasciculata cells with  microvesicular vacuolation.

Histopathological findings: neoplastic:

no effects observed

Dose descriptor:

NOAEL

Effect level:

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

Sex:

female

Basis for effect level:

histopathology: non-neoplastic

Dose descriptor:

LOAEL

Effect level:

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

Sex:

female

Basis for effect level:

histopathology: non-neoplastic

Critical effects observed:

not specified

Conclusions:

Under the conditions of this study, the NOAEL for female rats was determined to be 50 mg/kg/day.

Executive summary:

The repeated dose toxicity of the test material to female rats was examined in a GLP study.

During the study ten rats per dose were administered 2, 10, 50 and 200 mg/kg bw/day via gavage with Tween 20 as the vehicle for 18 weeks.

No test material related mortalities occurred and no clinical signs were recorded. There were no changes in body weight relating to the test material. However, there were some histopathological observations noted at 200 mg/kg bw/day: the ovaries of four animals exhibited interstitial glands characterised by slight hypertrophy and pale cytoplasm (grade 2). There were no test material related effects on the number of corpora lutea. In 3 high dose females, the adrenal glands showed hypertrophy of Zona fasciculata cells with microvesicular vacuolation.

Under the conditions of this study, the NOAEL for female rats was determined to be 50 mg/kg/day.

 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

There are four studies to address this endpoint, two key studies and two supporting studies. One of the key studies was awarded a reliability score of 1 in accordance with the criteria for assessing data quality as set forth by Klimisch et al. (1997). The remaining key study and the supporting studies were all awarded a reliability score of 2. The quality of the database is therefore considered to be high.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral Toxicity  

The first key study (Eiben, 2003a) is a one-generation study performed following the standardised guideline OECD 416 without treatment of F1 weanlings after developmental milestones had occurred. The conduct of this study includes also recommendations of the standardised guidelines OECD 415 and OECD 407 (open field observation and Functional Observation Battery). The study was performed in accordance with GLP and has been awarded a reliability score of 1 in accordance with the criteria for assessing data quality as set forth by Klimisch et al. (1997).

Male and female Wistar rats were dosed with the test material at 1500, 5000, and 1 5000 ppm, administrated in feed containing 1 % peanut oil. Animals were exposed during the premating period (about 11 weeks) and during the mating period (up to 3 weeks). Males were sacrificed after the mating period. Females were further exposed during pregnancy and lactation, and were sacrificed when F1 offspring was weaned (after 4 weeks).

Repeated oral dosing led to changes in weight and histopathology of the liver and adrenals in males at a dietary concentration of 5000 ppm (about 427 mg/kg bw/day), and in females of 1500 ppm (about 219 mg/kg bw/day). At 1500 ppm, females also exhibited morphological changes in the ovaries.

Under the conditions of this study, the NOAEL in males was 1500 ppm (about 132 mg/kg bw/day). In females a NOAEL could not be determined; the LOAEL was 1500 ppm (about 219 mg/kg bw/day), based on increased relative and absolute adrenal weights with histopathological changes in the zona fasciculata, and morphological changes in the ovaries.

 

The second key study (Eiben, 2003b) was conducted in female rats over the same time as in the one-generation study using lower dose levels in order to establish a NOAEL for this gender. This study was not conducted in accordance with a specific guideline, though GLP conditions were adhered to. The study was awarded a reliability score of 2 in accordance with the criteria for assessing data quality as set forth by Klimisch et al. (1997).

This study used only female Wistar rats. Ten rats per dose were administered 2, 10, 50 and 200 mg/kg bw/day via gavage with Tween 20 as the vehicle for 18 weeks.

No test material related mortalities occurred and no clinical signs were recorded. There were no changes in body weight relating to the test material. However, there were some histopathological observations noted at 200 mg/kg bw/day: the ovaries of four animals exhibited interstitial glands characterised by slight hypertrophy and pale cytoplasm (grade 2). There were no test material related effects on the number of corpora lutea. In 3 high dose females, the adrenal glands showed hypertrophy of Zona fasciculata cells with microvesicular vacuolation.

Under the conditions of this study, the NOAEL for female rats was determined to be 50 mg/kg/day.

 

The first supporting study (Eiben, 2002) was a pilot for the one-generation study, with a limited number of evaluated endpoints and limited documentation. The study was conducted under GLP conditions and was awarded a reliability score of 2 in accordance with the criteria for assessing data quality as set forth by Klimisch et al. (1997).

Male and female Wistar rats were dosed with the test material at 5000, 10000, and 15 000 ppm in the diet (5 animals/sex/dose) for 13 weeks. There was no determination of haematology, biochemistry, urinalysis, and histopathology, as the defined limits of analytics could not be met.

At termination, high dose males and females exhibited slightly lower body weight when compared to the controls (-8 and -5 %, respectively). Significantly increased relative liver weights in 15 000 ppm males (+22 %) and females at 5000, 10000, and 15 000 ppm (+11, +7 and +16 %, respectively) were observed. The relative kidney weights were significantly enhanced in 15 000 ppm males (+27 %). Uterus weights were dose-independently lower in treated females than in the wide spreading control means.

 

The second supporting study (Kimmerle, 1967) was conducted prior to the inception of GLP with only limited observation parameters. It was awarded a reliability score of 2 in accordance with the criteria for assessing data quality as set forth by Klimisch et al. (1997).

The study was conducted using male Wistar rats (15/dose) for 10 weeks. The test material was administrated via gavage at dose levels of 85, 165, 415, 550, 660, 830 and 1000 mg/kg bw/day, as an aqueous emulsion in Cremophor E. The rats were dosed once daily, and received a total of five doses per week.

At the dose levels of 85 to 830 mg/kg bw/day, no clinical signs or weight gain were observed. The haematology and gross necropsy appeared normal. At the dose level of 1000 mg/kg bw, elevated absolute (18 %) and relative (15 %) liver weights were observed, though other parameters were recorded to be normal.

Under the conditions of this study, the NOAEL was determined to be ≥830 mg/kg.

 

Chronic data

Concerning chronic toxicity testing, the substance is not considered to fulfil any of the criteria under Section 8.6.3 of Column 2 of Annex X. Therefore no further testing is proposed.

 

Inhalation and Dermal

In accordance with sections 8.6.1 and 8.6.2 of Column 1 of REACH Annexes VIII and IX, respectively, repeated dose toxicity testing should be carried out using the most appropriate route of administration, having regard to the likely route of human exposure. For this substance, the oral route was deemed to be the most appropriate.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Two key studies were provided to address this endpoint. Both were good quality studies conducted in accordance with sound scientific principles under GLP conditions. The lower value obtained in either study was selected to be used for risk assessment purposes as a precautionary measure.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to repeated dose toxicity.

In accordance with section 3.9.2.9.7. of Regulation (EC) No 1272/2008, classification in Category 2 is applicable when significant toxic effects are observed between the dose levels of 10 and 100 mg/kg/day in a sub-chronic study. No significant toxicological signs were noted in any of the studies at dose levels below the cut off value of 100 mg/kg/day, and as such, no classification is considered to be warranted.