A mixture of: thiobis(4,1-phenylene)-S,S,S',S'-tetraphenyldisulfonium bishexafluorophosphate; diphenyl(4-phenylthiophenyl)sulfonium hexafluorophosphate

Repeated dose toxicity: oral

Administrative data

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:

other: see 'Remark'

Remarks:

This study was included in the Notification dossier of the first Notifier (1989); since under Directive 67/548/EEC the studies of the first notifier were not included in the dossier, Lamberti has the letter of Access, but not the complete study report. The study can be considered reliable since already evaluated by the Authority.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

A mixture of: thiobis(4,1-phenylene)-S,S,S',S'-tetraphenyldisulfonium bishexafluorophosphate; diphenyl(4-phenylthiophenyl)sulfonium hexafluorophosphate

EC Number:

404-986-7

EC Name:

A mixture of: thiobis(4,1-phenylene)-S,S,S',S'-tetraphenyldisulfonium bishexafluorophosphate; diphenyl(4-phenylthiophenyl)sulfonium hexafluorophosphate

Cas Number:

74227-35-3

Molecular formula:

C36H28F12P2S3 (80%); C24H19F6PS2 (13%)

IUPAC Name:

A mixture of: thiobis(4,1-phenylene)-S,S,S',S'-tetraphenyldisulfonium bishexafluorophosphate; diphenyl(4-phenylthiophenyl)sulfonium hexafluorophosphate

Test animals

Species:

rat

Strain:

not specified

Sex:

not specified

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

Not available

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
6.81 mg/kg/day
Basis:
no data

Doses / concentrations 2

Remarks:

Doses / Concentrations:
21.5 mg/kg/day
Basis:
no data

Doses / concentrations 3

Remarks:

Doses / Concentrations:
68.1 mg/kg/day
Basis:

Doses / concentrations 4

Remarks:

Doses / Concentrations:
215 or 464 mg/kg/day
Basis:

No. of animals per sex per dose:

Not available

Control animals:

not specified

Details on study design:

In order to be certain about reaching the toxic range, the high dosage was increased on the 38th treatment day from 215 to 464 mg/kg/day.

Results and discussion

Results of examinations

Details on results:

No toxic effects were observed at doses of 21,5-68,1 mg/kg/day

Effect levels

Dose descriptor:

NOEL

Effect level:

6.81 mg/kg bw/day (nominal)

Based on:

not specified

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

After the dosage increase, 6 males died between the 7th and 13th weeks as did one female in the 9th week. A female from a medium dose group died as a result of incorrect application.

A clear impairment of the feed intake, clear weight-loss and impairment of the general state of health were observable in the high dosage group up to three weeks after the dosage increase. After this period the state of health of the surviving animals stabilised once more and the difference in the absolute body weights at the end of the test amounted to less than 10% when compared with the controls.

A slight decrease in the number of thrombocytes was established for both sexes in the high-dose group. Only the females in this dose group showed changes in the differential blood picture. The parameters measured in the 7th and 14th weeks revealed a slight increase in the activity of the transaminase as well as an inhibition of the cholinesterase. There were increased values for the total N as well as decreased values for bilirubin and triglyceride.

There were increases in the absolute and relative organ masses for the thyroid and adrenal glands as well as for the liver and kidney in the animals from the high-dose group. There were also increases in thyroid gland masses among animals from the 68.1 mg/kg group. There were some increases in liver masses among the females from this group. Enlarged thyroids were revealed macroscopically in the animals from the high-dose group.

The main finding of the histological investigation was likewise a marked hyperplasia of the thyroid follicular epithelia with a reduction in the area covered by colloidal follicles (Struma parenchymatosa diffusa) in the animals from the high-dose group and to a lesser extent also in some animals from the two medium-dose groups. An increased number of basophilic cells as well as vacuolar and enlarged basophilic cells were found in the pituitaries of the male animals in the high-dose group. Dose-related hypertrophies of the cells in the Zona granulosa and fasciculata were found in the adrenal glands of the animals from the high and up-per-middle dose group. These changes also occurred in low dosage groups and even in some control animals at a low level of markedness and at a low frequency.

Proliferating breast tissue and congested secretion parts in the proliferating glands could be found in all male animals. This finding was most frequent and most pronounced in terms of its degree of seriousness in the males from the high-dose group.

In addition, findings relating to the liver and kidneys (centrolobular hepatocellular vacuolization and hypertrophy or oil-red positive inclusions in proximal tubular epithelia of the kidney) were diagnosed in the animals from the high dose group. All of the other findings corresponded to the spontaneous pathological spectrum of the age group of the species.

Applicant's summary and conclusion

Conclusions:

According to the study results the NOEL for oral application to rats over 90 days amounts to 6.81 mg/kg/day.