Diphenyl sulphone

Endpoint summary

Description of key information

Assessment of toxicokinetics based on the physicochemical properties indicates that absorption from the gastro-intestinal tract is relevant, as confirmed by the  oral acute and chronic toxicity data. Toxicokinetics on plasma samples of the 90-day oral rat toxicity study demonstrated clear plasma levels, however without dose-proportionally between 100, 200 and 2000 ppm. In week 12 the 2000 ppm dosed males, a fall in plasma level was seen compared to week 1, whilst 2000 ppm dosed females showed a slight rise against week 1. Although dermal absorption may also be indicated by physicochemistry, acute toxicity was low; inhalation route was not considered relevant due to low evaporation rate. In conclusion, the oral route was considered  most appropriate  for toxicity testing.
Distribution in the body was further confirmed by the changes seen in the repeated dose oral toxicity study. At the end of the 3-month toxicity study, liver  Aminopyrine N-demethylase (APDM) activity was shown to be increased in males and females at 2000 ppm only, indicating clearly induced metabolism, which might be responsible for the non-dose proportionality of the plasma levels. As plasma levels did not significantly increase between week 1 and 12, no accumulation is further assumed and elimination is expected to take place by biliary or urinary route.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

40

Additional information

Plasma samples (5animals/sex/group) were collected from 100, 200 and 2000 ppm diphenyl sulphone dosed treatment groups, including control groups, after 1 and 12 weeks of treatment (this study was part of the 90 -day toxicity study in rats; ICI, 1981). These samples were then stored at –20° C whilst a reverse phase HPLC method was developed and validated . Pooled samples were then analysed for test article using this analytical procedure. The plasma diphenyl sulphone levels of treated animals showed a positive but non-linear correlation with dose. Circulating levels of diphenyl sulphone were comparable at the week 1 and 12 investigations for the 100 and 200 ppm dosed group. However, during week 12 group 2000 ppm dosed males showed a fall in plasma level when compared to week 1, whilst the plasma diphenyl sulphone level of 2000 ppm dosed females rose against the week 1 value. Consequently, on this occasion the plasma concentration shown by females was some four times higher than that of the males.

Assessment of oral toxicokinetics based on the physicochemical properties according to ECHA Guidance on information requirements and chemical safety assessment (Chapter R.7c) provides the following indications

(molecular weight 218,27; water solubility 14 mg/L; partition coefficient log Kow = 2.6):

ABSORPTION

-         The physicochemical characteristics (log Pow 1-4) and the molecular mass (< 500) are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion. This assumption is confirmed by the data of acute oral toxicity (LD50 300-500 mg/kg bw) and chronic oral toxicity (NOAEL 16-19 mg/kg bw/day). Therefore oral route is considered most appropriate (default) route for toxicity testing.

-         The physicochemical characteristics (log Pow 2-3) and the molecular mass (< 500) are in a range suggestive of dermal absorption, however dermal acute toxicity is low (LD50 > 2000 mg/kg), therefore this route is not selected for further toxicity testing. A more quantified assessment was made for dermal absorption comparted to oral absorption in terms of DNEL calculation and route-to-route extrapolation, indicating that dermal absorption is at least 2,5 times lower than oral absorption (separately attached).

-         The vapour pressure (0.00075 Pa at 50°C and 9.3649 Pa at 120°C) and the molecular mass (< 500) is not in a range suggestive of respiratory absorption, therefore it is not considered appropriate.

DISTRIBUTION and METABOLISM

-         As a small molecule a wide distribution is expected. This assumption is confirmed by the changes shown in the repeated dose toxicity studies following oral application.

-         As demonstrated by increased aminopyrine N-demethylase (APDM) activities at 2000 ppm, metabolism was considered to be stimulated.

ELIMINATION

-         The n-Octanol/water partition coefficient (log Pow of 2.61) may be suggestive of accumulation in fatty tissues subsequent to absorption from gastrointestinal tract or from lungs.

-         However, on the basis of the fact that circulating levels of diphenyl sulphone were comparable in week 1 and 12 for the 100 and 200 ppm dosed groups, no accumulation is assumed and elimination is expected to take place by biliary or urinary route. In the highest group of 2000 ppm, no dose proportional increases in plasma levels were seen and induction of enzymes was demonstrated, therefore a higher catabolism is assumed.

Aminopyrine N-demethylase (APDM) activities were further determined on individual liver samples (6 animals/sex/group) at the termination of the study using a colorimetric method supplied by the sponsor. A significant increase in mean APDM activities was apparent for rats of both sexes given 2000 ppm diphenyl sulphone when compared to corresponding contro1 values (p<.01). There was no effect on APDM activity in rats given 100 or 200 ppm diphenyl sulphone. The level of APDM activity in female controls was about half that of male controls.

These results corresponded with morphological findings in the liver at this dose level, including increases in mean liver weight, hepatocellular hypertrophy and proliferation of liver smooth endoplasmic reticulum in both sexes.