Registration Dossier

Administrative data

Endpoint:
additional toxicological information
Type of information:
other:
Adequacy of study:
supporting study
Study period:
1970-1988
Reliability:
other:
Rationale for reliability incl. deficiencies:
other: A summary of primarily older but well-conducted and reliable studies designed to determine the potential liver toxicity of the test material in experimental animals and in humans.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1970
Report Date:
1970
Reference Type:
study report
Title:
Unnamed
Year:
1970
Report Date:
1970
Reference Type:
study report
Title:
Unnamed
Year:
1971
Report Date:
1971
Reference Type:
study report
Title:
Unnamed
Year:
1971
Report Date:
1971
Reference Type:
study report
Title:
Unnamed
Year:
1971
Report Date:
1971
Reference Type:
study report
Title:
Unnamed
Year:
1972
Report Date:
1972
Reference Type:
study report
Title:
Unnamed
Year:
1980
Report Date:
1980
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report Date:
1988

Materials and methods

Type of study / information:
In vivo studies in rats, monkeys and humans to determine the liver toxicity of the test material.
Principles of method if other than guideline:
Although generally not following modern protocols, the studies reviewed were well-conducted using procedures and protocols current at the time.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent

Results and discussion

Any other information on results incl. tables

Indocyanine green (ICG) plasma clearance in rats fed SAIB in the diet:

 

In this study, all rats consumed their diets and gained weight at a normal rate. The average dose of SAIB consumed for the duration of the feeding study was 2800 mg/kg bw/day. ICG clearance rates (1/2 lives) were measured on animals that had ingested accumulated doses of 2186 to 131,000 mg/kg bw of SAIB. Despite these extremely high doses of SAIB, elimination half-lives were not significantly different between treated and control animals. The mean of all clearance half-times for treated rats was 3.2 minutes, with extremes of 2.4 to 4.6 minutes, while control clearance half-times were 3.0 minutes, with extremes of 2.4 to 4.2 minutes.

 

Three (3) week studies on the effects of SAIB on the liver of rats:

 

All animals in this study survived the administration of test material. There were clinical signs of respiratory disease (wheezing and pulmonary congestion), but these decreased during the study. There were no adverse effects of SAIB administration on either body weights or food consumption. Gross necropsy revealed no treatment-related findings. There was also no evidence of liver enlargement at either dose level of SAIB following periods of 1, 2 or 3 weeks of feeding.

 

Subactute (6 or 12 week) study of liver effects in rats:

 

There were no clinical findings associated with SAIB administration in either 6-week or 12-week feeding studies in rats. However, all animals treated with phenobarbital experienced transient CNS depression lasting 4 to 6 h, as manifested by reduced motor activity, a sleepy appearance and mild ataxia. There was no evidence of adverse effects due to SAIB administration even at the highest dose level of 10.0%. In contrast, all animals treated with phenobarbital displayed effects including reduced weight gains, food consumption and food efficiency. Daily administration of phenobarbital resulted in increased urinary excretion of ascorbic acid whereas corresponding treatments with SAIB produced no similar increase. At study termination, no treatment related organ weight changes were recorded in adrenal glands, heart, kidneys or liver in SAIB-treated animals. Further extensive histopathological analyses revealed no treatment-related findings. A zoxazolamine muscle relaxant test, providing a second measure of liver enzyme induction, indicated no evidence of liver enzyme induction by SAIB. Liver biochemical studies conducted at study termination also revealed no liver enzyme induction and only slight increases in liver glycogen at the highest dose tested.

 

Characterization of serum alkaline phosphatase in dogs receiving high levels of SAIB in the diet:

 

Dogs fed SAIB in the diet for 28-days experienced elevated serum alkaline phosphatase activity. Disc electrophoresis studies indicated only 2 bands of alkaline phosphatase activity in serum from both control and experimental dogs. These bands were identical in both groups and identified as liver and bile alkaline phosphatase. In sera from experimental dogs, these bands were more intensely colored suggesting increased activity. Isoenzyme inactivation studies revealed that liver content of alkaline phosphatase was significantly different, with a two-fold increase evident in experimental dogs. Although elevated, serum alkaline phosphatase levels in dogs fed SAIB did not correspond with any other histological, histochemical or biochemical manifestations.

 

Effects of SAIB administration on bromosulfophthalein plasma clearance from the squirrel monkey, rat and dog:

 

Single gavage treatments of squirrel monkeys (Saimiri sciureus) at 2 g SAIB/animal produced no change in bromosulfophthalein (BSP) clearance from plasma.

 

Similarly, 4% SAIB administration in the diet of male rats for 7 days produced no measurable effect on BSP clearance from plasma.

 

In a series of single feeding studies conducted in male and female beagle dogs, animals were given a single dose of 0.1% and 0.5% and 0.3% of SAIB. BSP serum retention was measured after 24 h and again after 48 h to determine reversibility. The 0.1% dose level was not associated with increased BSP retention. However, both the 0.5% and 0.3% resulted in marked increase retention of BSP at 24 h and which was reversible by 48 h.

 

Effects of SAIB administration on the liver excretory function in cynomolgus monkeys:

 

Daily observations of monkeys during the study period indicated no unusual findings other that an occasional soft stool, an effect commonly observed in cynomolgus monkeys under laboratory conditions. No marked changes in body weights were recorded. Serum alkaline phosphatase values were markedly decreased in a control and two treated monkeys, while a single treated animal showed a marked increase in this parameter. Such fluctuations are commonly observed in young adult cynomolgus monkeys.

 

Bromosulfophthalein (BSP) retention values generally showed no change from baseline values. A single high-dose animal and a control animal both showed decreased BSP retention values at 5 h versus baseline values. However, group mean BSP values for treated groups at 5 h were not markedly different from controls. Also, mean BSP retention values of treated animals were lower than respective control animal values.

 

Effects of single daily ingestion of SAIB on the hepatobiliary function of normal human volunteers:

 

A total of twenty-seven (27) healthy adults completed a 21-day study in which SAIB was administered daily in an orange juice beverage at 20 mg/kg bw for 14 days. The study was preceded by a one-week period of administration of orange juice beverage with test material. It was concluded that ingestion of 20 mg/kg bw over 14 days in healthy human volunteers produced no measurable changes in hematological parameters or effects on hepatobiliary functions.

Applicant's summary and conclusion

Conclusions:
Although displaying some limited toxicity to the liver in dogs, no similar effects are observed in other laboratory species or in humans.
Executive summary:

Feeding studies with SAIB in rats have failed to elicit any significant toxicological effects. However, in a 90-day feeding study in dogs, slight but significant increases in serum alkaline phosphatase levels and elevated liver weights at higher doses were reported. These changes were not accompanied by any histopathological changes in the liver or other organs in dogs. Similar effects in the liver were not reported in rats, two species of monkeys or in humans.

 

In feeding studies in rats, extremely high overall doses of SAIB did not result in significant changes in the clearance half-times for indocyanine green (ICG). Doses as high as 50,000 ppm (5%) of SAIB administered in the diet of rats for 3 weeks or as high as 10% in the diet for up to 12 weeks produced no evidence of liver toxicity. In addition, SAIB administered in the diet of male rats for 7 days produced no measurable effect on bromosulfophthalein (BSP) elimination.

 

In agreement with findings in the rat, a single gavage administration of 2 g SAIB/animal in the squirrel monkey (Saimiri sciureus) produced no change in BSP elimination from plasma. Similarly in the cynomolgus monkey (Macaca fasicularis), a 5.0 g/kg bw dose of SAIB produced no significant changes in liver function, as determined by serum alkaline phosphatase measurements or by BSP retention.

 

In twenty-seven (27) human volunteers, a 14-day administration of 20 mg/kg bw of SAIB in an orange juice beverage produced no measurable changes in hematological parameters or effects on hepatobiliary function.