Diphenyl sulphide

Endpoint summary

Description of key information

In a Subacute oral toxicity study,Kunmingfemale mice were treated withDiphenyl sulfides (DSP) in the concentreation of 0, 1, 10 and 100 mg/kg/day orally by gavage.Superoxide dismutase (SOD) activity was significantly decreased andHepatic malondialdehyde (MDA) level in liver wassignificantly increased in 1, 10 and 100 mg/kg/day treated mice as compared to control. No significant effects were observed at the mortality, morbidity, clinical science, Food consumption, Hematology, gross and histopathology. Therefore, NOAEL was considered to be100 mg/kg/day whenKunming female mice were treated withDiphenyl sulfides (DSP) orally for 28 days.

 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Data is from peer-reviewed journal

Qualifier:

no guideline available

Principles of method if other than guideline:

The objective of this study was to evaluate the subacute oral toxicity study of Diphenyl sulphide (CAS No.139-66-2) orally in female mice.

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): Diphenyl sulfides (DSP)
- Molecular formula: C12-H10-S
- Molecular weight: 186.277 g/mole
- Substance type: Organic
- Physical state: No data available
- Impurities (identity and concentrations): < 1%

Species:

mouse

Strain:

other: Kunming

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Qinglongshan Animal Breeding Center
- Age at study initiation: 5 weeks old
- Weight at study initiation: 18–20 g body wt
- Fasting period before study: Not reported
- Housing: Animals were caged in groups of 10 using dust-free poplar chips for bedding.
- Diet (e.g. ad libitum): Rodent chow, ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.0 ± 1.0 degC
- Humidity (%):50–60%
- Air changes (per hr): 10 times/hr
- Photoperiod (hrs dark / hrs light): 12 h: 12 h light: dark cycle (8:00 AM–8:00 PM).

IN-LIFE DATES: From: To: No data available

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: No data available

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): Considering the lower water solubility of Diphenyl sulfides, corn oil was selected as vehicle.
- Concentration in vehicle: 0, 1, 10 and 100 mg/kg/day
- Amount of vehicle (if gavage): 0.1–0.2 ml/100 g
- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

28 days (4 weeks)

Frequency of treatment:

Daily

Dose / conc.:

0 other: mg/kg/day

Dose / conc.:

1 other: mg/kg/day

Dose / conc.:

10 other: mg/kg/day

Dose / conc.:

100 other: mg/kg/day

No. of animals per sex per dose:

Total: 40
0 mg/kg/day: 10 female
1 mg/kg/day: 10 female
10 mg/kg/day: 10 female
100 mg/kg/day: 10 female

Control animals:

yes, concurrent vehicle

Details on study design:

Details on study design
- Dose selection rationale: No data available
- Rationale for animal assignment (if not random): Randomly
- Rationale for selecting satellite groups: No data available
- Post-exposure recovery period in satellite groups: No data available
- Section schedule rationale (if not random): No data available

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data available
- Time schedule: No data available
- Cage side observations checked in table [No.?] were included. No data available

DETAILED CLINICAL OBSERVATIONS: No data available
- Time schedule: No data available

BODY WEIGHT: No data available
- Time schedule for examinations: No data available

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data available
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data available
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data available

FOOD EFFICIENCY: No data available
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available
- Time schedule for examinations: No data available

OPHTHALMOSCOPIC EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available

HAEMATOLOGY: No data available
- Time schedule for collection of blood: No data available
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the termination of study
- Animals fasted: No data available
- How many animals: All 40 animals were examined.
- Parameters checked in table [No.?] were examined. Superoxide dismutase (SOD) and malondialdehyde (MDA) were examined.

URINALYSIS: No data available
- Time schedule for collection of urine: No data available
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined. No data available

NEUROBEHAVIOURAL EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data available

OTHER: No data available

Sacrifice and pathology:

The mice were killed at the end of the experiment (28 d), and the livers were sampled and washed with normal saline.
HISTOPATHOLOGY: Yes

Other examinations:

No data available

Statistics:

Statistical analysis was performed by using SPSS Version 12.0 for Windows. The differences between the control and experimental groups were analyzed using one-way analysis of variance, and Tukey’s test. Values of p<0.05 were considered significant, and values of p<0.01 were accepted as having high statistical significance.

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

Superoxide dismutase (SOD) activity was significantly decreased in 1, 10 and 100 mg/kg/day treated mice as compared to control.

Hepatic malondialdehyde (MDA) level in liver was significantly increased in 1, 10 and 100 mg/kg/day treated mice as compared to control.

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No significant effect were observed at this dose.

Critical effects observed:

not specified

Conclusions:

NOAEL was considered to be 100 mg/kg/day when Kunming female mice were treated with Diphenyl sulfides (DSP).

Executive summary:

In a Subacute oral toxicity study,Kunmingfemale mice were treated withDiphenyl sulfides (DSP) in the concentreation of 0, 1, 10 and 100 mg/kg/day orally by gavage.Superoxide dismutase (SOD) activity was significantly decreased andHepatic malondialdehyde (MDA) level in liver wassignificantly increased in 1, 10 and 100 mg/kg/day treated mice as compared to control. No significant effects were observed at the mortality, morbidity, clinical science, Food consumption, Hematology, gross and histopathology. Therefore, NOAEL was considered to be100 mg/kg/day whenKunmingfemale mice were treated withDiphenyl sulfides (DSP) orally for 28 days.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subacute

Species:

mouse

Quality of whole database:

The data is Klimicsh 2 and from peer-reviewed journal.

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

Repeated dose toxicity: oral

Various repeated dose toxicity studies has been investigated to observe the adverse general toxicological effects occurring as a result of repeated daily dosing with, or exposure, to a substance for a specified period up to the expected lifespan of the test species. Often are the studies based on experimental data in rodents for Diphenyl sulphide (CAS No. 139-66-2). The studies are summarized as below: 

 

In a Subacute oral toxicity study,Kunmingfemale mice were treated withDiphenyl sulfides (DSP) in the concentreation of 0, 1, 10 and 100 mg/kg/day orally by gavage.Superoxide dismutase (SOD) activity was significantly decreased andHepatic malondialdehyde (MDA) level in liver wassignificantly increased in 1, 10 and 100 mg/kg/day treated mice as compared to control. No significant effects were observed at the mortality, morbidity, clinical science, Food consumption, Hematology, gross and histopathology. Therefore, NOAEL was considered to be100 mg/kg/day whenKunmingfemale mice were treated withDiphenyl sulfides (DSP) orally for 28 days.

 

Moreover, the study was conducted to evaluate the chronic toxicity of Diphenyl sulphide (CAS No. 139-66-2) in Charles River CD rats published in a NTRL study report (Union Carbide Corporation, OTS0543748, 1992). Diphenyl sulphide was incorporated in the diets of Charles River CD rats for three months. Some indication of depression of appetite was found at the two highest dosage levels; at 0.20 and. 0.05% diphenyl sulfide in the diet. Body Weight gain was depressed at the 0.20% level and liver and kidney weights significantly increased at both levels. An increase in the incidence of gross diffuse cortical degeneration of the kidney was also found with these dosages in the rats killed at the end of the study. No mortality resulted at any dosage level. The only gross effect at 0.0125% was an increase in liver weight of the female rats. None of the criteria of effect measured were grossly altered at 0.003125% in the diet of rats for three months.

Therefore, the NOAEL was considered to be 0.003125 % (3.125 mg/kg/day) when Charles River CD male and female rats were treated with Diphenyl sulphide (CAS No. 139-66-2) orally in diet.

NOAEL (male) = 0.0125 % (12.5 mg/kg/day)

NOAEL (female) =0.003125 % (3.125 mg/kg/day)

 

On the basis of evidence from above studies for target substance in experimental animals, it can be presumed that there is no potential to be harmful to human health following repeated exposure. The substance Diphenyl sulphide (CAS No. 139-66-2) is unclassified because no specific target organ toxicity was seen. Thus, on the basis of CLP classification criteria the substance is not classified.

 

Repeated dose toxicity: inhalation

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance Diphenyl sulphide, which is reported as 0.00241 mm Hg. Thus, exposure to inhalable dust, mist and vapour of the chemical Diphenyl sulphide (CAS No. 139-66-2) is highly unlikely. Therefore this study was considered for waiver.

 

Repeated dose toxicity: dermal

The acute toxicity value for Diphenyl sulphide (CAS No. 139-66-2) (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, on the basis of the use of the chemical; repeated exposure by the dermal route is unlikely. Thus, it is expected that Diphenyl sulphide (CAS No. 139-66-2) shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no dermal absorption data as well as no data available that suggests that Diphenyl sulphide (CAS No. 139-66-2) shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Justification for classification or non-classification

Based on the available data for the assessment of repeated dose toxicity by oral, inhalation and dermal route and following CLP Regulation (EC) No 1272/2008, the substance Diphenyl sulphide (CAS No. 139-66-2) is not classified.