Registration Dossier

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
three-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
Study period:
1950/1960
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted during late 1950 and early 1960 and the methods represented the state of the art which existed during this period. They nevertheless allow in adequate assessment of the potential reproductive toxicity of PGPR.

Data source

Reference
Reference Type:
publication
Title:
A three-generation reproduction study on polyglycerol polyricinoleate (PGPR) in Wistar rats.
Author:
Wilson R; Smith M
Year:
1998
Bibliographic source:
Food and chemical toxicology : VOL: 36 (9-10); p. 739-41 /1998 Sep-Oct/

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: no guideline followed
Deviations:
not applicable
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name: Polyglycerol polyricinoleate (PGPR) - commercially available
ADMUL-WOL brand

PGPR was prepared by the estrification of condensed castor oil fatty acids (primary ricinoleic acid) with polyglycerol. The polyglycerol was first made by heating glycerol under vacuum with potassium hydroxide as catalyst while the condensed acids were made by heating castor oil fatty acids at elevated temperatures under vacuum and in an atmosphere of CO2 to prevent oxidation.

Composition of the test substance and its synthesis can be found in the complementary article "Overview of the preparation, use and biological studies on PGPR", Wilson 1998).

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS: Colworth Wistar rats
- Source: breeding facility at the Unilever Colworth Laboratory, UK
- Age at study initiation: see below
- Weight at study initiation: see below
- Fasting period before study: not applicable
- Housing: Each pair of rats occupied a single cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
no data

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
The control rats received a commercial pelleted stock diet and the treated rats were given the same diet ground with 1.5% (w/w) PGPR. Fresh mixes were prepared each week and PGPR was incorporated into the ground diet first by hand and then well mixed in a mechanical mixer.
Details on mating procedure:
FIRST GENERATION:
The first generation parents were selected from five litters which were assigned randomly into two control groups: a control (11 males, 17 females) and a treatment group fed 1.5% (w/w) PGPR (6 males, 13 females).
The dietary level of 1.5% was chosen to provide an intake by the pregnant lactating rat which was in excess of 150 times the intake of a person consuming 5 mg PGPR/kg b.w./day. All rats were weaned at 23 days and mated at 121 days. Breeding was continuous and the males were only separated from the females when it was apparent that the female was pregnant. Ecah pair of rats occupied a single cage and they were maintained until the female had produced five litters or until such time as it became evident that breeding had ceased.

SECOND GENERATION:
In all cases the first litter was discarded after weaning and second-generation breeders were randomly selected (2 males, 2 females) from each of the second and fourth litters. By selecting from two first-generation litters the number of animals was increased to 52 of each sex in the control and to 32 of each sex in the PGPR group.

THIRD GENERATION:
The third generation breeders were selected in a similar manner and the control group was increased to 92 rats and the PGPR group to 44 rats, each sex.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
3-generation study
Frequency of treatment:
daily
Details on study schedule:
see above
Doses / concentrations
Remarks:
Doses / Concentrations:
1.5% (w/w) PGPR
Basis:
nominal in diet
No. of animals per sex per dose:
1st generation: control (11 males, 17 females) and a treatment group fed 1.5% (w/w) PGPR (6 males, 13 females).
2nd generation: 52 of each sex in the control and to 32 of each sex in the PGPR group.
3rd generation: 92 of each sex in the control and to 44 of each sex in the PGPR group.
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: the dietary level of 1.5% was chosen to provide an intake by the pregnant lactating rat which was in excess of 150 times the intake of a person consuming 5 mg PGPR/kg b.w./day.

FIRST GENERATION
The parents were selected from five litters which were assigned randomly into two control gropus: a control (11 males, 17 females) and a treatment group fed 1.5% (w/w) PGPR (6 males, 13 females). The dietary level of 1.5% was chosen to provide an intake by the pregnant lactating rat which was in excess of 150 times the intake of a person consuming 5 mg PGPR/kg b.w./day. All rats were weaned at 23 days and mated at 121
days. Breeding was continuous and the males were only separated from the females when it was apparent that the female was pregnant. Each pair of rats occupied a single cage and they were maintained until the female had produced five litters or until such time as it became evident that breeding had ceased.

SECOND GENERATION
In all cases the first litter was discarded after weaning and second-generation breeders were randomly selected (2 males, 2 females) from each of the second and fourth litters. By selecting from two first-generation litters the number of animals was increased to 52 of each sex in the control and to 32 of each sex in the PGPR group.

THIRD GENERATION
The third generation breeders were selected in a similar manner and the control group was increased to 92 rats and the PGPR group to 44 rats, each sex.
Positive control:
not required

Examinations

Parental animals: Observations and examinations:
In each generation: number of litters per dam, average litter size, average waning weights of males and females, litter per group showing 100% survival and total survival (%) at day 21.
Oestrous cyclicity (parental animals):
not performed
Sperm parameters (parental animals):
not performed
Litter observations:
In each generation: number of litters per dam, average litter size, average waning weights of males and females, litter per group showing 100% survival and total survival (%) at day 21.
Postmortem examinations (parental animals):
performed but no details available
Postmortem examinations (offspring):
performed but no details available
Statistics:
A Student's t-test was conducted in which two groups were compared.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
reported but data not shown
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

see below

Effect levels (P0)

Dose descriptor:
NOAEC
Effect level:
> 2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Remarks on result:
other: Generation: all 3 generations (migrated information)

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
no effects observed

Details on results (F1)

see below

Effect levels (F1)

Dose descriptor:
NOAEL
Effect level:
> 2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Growth: was monitored from weaning to mating during the first 4 months of each generation. The weights of the females were recorded at weaning and mating while the weight of the males was recorded at weaning and at day 65. There were no significant differences between weights in treated or control rats.

Food intake: was not recorded in this study, but a previous study indicates that levels of 5% PGPR in the diet had no effects on food intake.

Survival and clinical signs: the rats were observed daily. There were no deaths and no evidence of abnormal behaviour or functional disorders in all 3 generations.

Breeding performance:

in general for both grups the breeding performance was better in the 1st and 3rd generation. In the 2nd generation the breeding was poor in the control and PGPR group. The only significant difference was a greater percentage in the controls of litters weaned entirely which was reversed in favour of the PGPR rats in the third generation. Besides, the 2nd generation had a larger proportion of males among the weaned rats fed PGPR.

In the generation 1 and 3 a high percentage of the offspring were weaned for both groups. In the 2nd generation were was a reduction

in both groups in the percentage of the animals weaned. Since this reduction occurred in both groups and to similar extend, it was caused by an unknown environmental factor. Histology

histological examination of selected tissues from those rats continued for 1 year failed to show any lesions which could be ascribed to the consumption of PGPR.

Applicant's summary and conclusion

Conclusions:
The similarity observed between data from the first and third generation did not prove any evidence of a cumulative effect due to long-term ingestion of PGPR over three successive generations. No effects on animal growth or food intake were observed. There were no effects of PGPR on the sucking pups receiving this substance from mother's milk. The ingestion of 1.5% PGPR in diet did not produce any adverse effects on reproductive capacity or development of the offspring during three generations of continuous exposure.

In spite of lack of information on implantation sites, uterus weight etc, no significant effects were observed in the reproduction performance in rats during 3 generations. Therefore, the NOAEL (reproduction) is considered to be >= 2g/kg b.w./day for both females and males.