Plant Sterols

Toxicity to reproduction

Administrative data

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The OECD test guidelines specify that information relating to the total cauda epididymal sperm number, percent progressively mobile sperm, percent progressively motile sperm, percent morphologically normal sperm and percent of sperm with each identified abnormality should be included. These parameters were not addressed in the report. In addition there was no information relating to the lactation index.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1999

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

yes

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Phytosterol esters

IUPAC Name:

Phytosterol esters

Details on test material:

Table 3.1 Gross composition of the test material
Constituent Composition (%w/w)
Total sterol 62.0
Total fatty acid 38.2
Free sterol (as % of the total mixture) 8.4
Free fatty acid <0.3

Table 3.2 Sterol profile of the test material
Sterol profile Composition (%) Fatty acid profile Composition (%)
Cholesterol 0.4 C16:0 9.6
Brassicasterol 1.1 C18:0 4.1
Campesterol 25.8 C18:1 21.6
Stigmasterol 21.6 C18:2 64.6
β-Sitosterol 48.7
β-Sitostanol 1.8
Unknowns 0.8

Phytosterols were sourced from a variety of common edible vegetable oil distillates and then re-esterified with fatty acids from sunflower oil.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

7 days/week in diet for duration of study.

Frequency of treatment:

7 days/week in diet for duration of study.

Details on study schedule:

Rats received the test diets from the start of the premating period. At the end of the 10 week premating period, the males were then housed individually and a female placed with a male of the same dose group (F0 generation), Evidence of mating by the presence of sperm in the vaginal smear was considered to be day 0 of gestation.
After mating period the non mated females were housed individually until sacrifice.

During the lacatation period the females and their litters F1 were kept in the same cages assigned to that particular dose group. On postnatal day 21 the F1 pups were weaned and shortly thereafter 28 males and 28 females were randomly selected, with mating of siblings avoided.

10 male and 10 female pups of the F1 were subjected to necropsy.
Selected F1 pups were housed in groups of 4/sex in preparation for further mating. At the start of the premating period the animals were ca 5 weeks old. Animals selected to produce F2 litters were treated at the same dose levels as the parents. The procedures then to rear the F2 generation litters were identical as described for F0.

Doses / concentrations

Remarks:

Doses / Concentrations:
Administration of dietary PE during the study at concentrations of 0, 1.6, 3.2 and 8.1%
Basis:
nominal in diet

No. of animals per sex per dose:

117 males and 116 females split into four groups of 28 rats/sex/group (three test groups and one control).

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Dose descriptor:

NOAEL

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Remarks on result:

not measured/tested

Remarks:

Effect level not specified Generation: All generations and parents (migrated information)

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Food consumption

The effect of PE on the food consumption was inconsistent, but significantly different to the control group; both increasing and decreasing during different phases of the study.

 

Water consumption

No information.

 

Clinical signs

None noted that could be attributed to the test compound.

 

Effects on fertility and reproduction

None noted that could be attributed to the test compound.

 

Body weight

Body weights of the male rats of the high dose groups of the F0 and F1 generations were statistically significantly different when compared to the control groups. It is believed this was due to the energy content of the PE being lower than the control diet.

 

Organ weights

No statistically significant changes in organ weights in comparison to the control group.

 

Haematology

No specific information provided.

 

Clinical chemistry

No specific information provided.

 

Urinalysis

No specific information provided.

 

Macroscopic examination

No findings noted at necropsy.

 

Histopathology

No specific information provided.

Applicant's summary and conclusion

Conclusions:

A nominal dietary PE concentration of > 8.1% (equivalent to a dose of 2500 -9100 mg PE/kg body weight/day or 1540 – 5620 mg phytosterol/kg/body weight/day, dependent on the phase of the study) was considered to be the no observed adverse effect level in this study.

There were no effects on reproduction, on the development of the offspring, or on sexual maturation.

Executive summary:

In a well conducted OECD 416 oral feeding study in rats (with some deviations from the test guideline) a nominal dietary PE concentration of greater than 8.1% (equivalent to a dose of 2500 -9100 mg PE/kg body weight/day or 1540– 5620 mg phytosterol/kg/body weight/day, dependent on the phase of the study) was considered to be the no observed adverse effect level (NOAEL) in this study.There were no effects on reproduction, on the development of the offspring, or on sexual maturation.