Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
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-MM-DD to 1960-MM-DD
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Sound scientific publication. This study was conducted during the late 1950s/early1960s and the methods represented the state of the art which existed during this period. They nevertheless allow an adequate assessment of the potential reproductive and chronic toxicity of PGPR.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
other: This study was conducted during the late 1950s/early1960s and the methods represented the state of the art which existed during this period. They nevertheless allow an adequate assessment of the potential reproductive and chronic toxicity of PGPR.
Principles of method if other than guideline:
A three-generation reproduction study was conducted on PGPR to investigate the potential adverse effects on reproduction. Breeding was conducted using a continuous breeding protocol in which pairs of animals were maintained until each female had produced five litters (or it became evident that breeding had ceased) and this was conducted over three generations. The main focus of the study design was to observe any effect on breeding. Parameters measured in each of the three generations included number of litters per dam, average litter size, average weaning weights of males and females, litters per group showing 100% survival and total survival (%) at day 21.
GLP compliance:
no
Remarks:
Studies were performed prior to implementation of GLP
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Colworth Wistar rats (obtained from the breeding facility at the Unilever Colworth Laboratory, Sharnbrook, Bedford, UK) were used in these stu-
dies.
TEST ANIMALS
- Source: Colworth Wistar rats (obtained from the breeding facility at the Unilever Colworth Laboratory, Sharnbrook, Bedford, UK) were used in these studies.
- Housing: Each pair occupied a single cage. Breeding was conducted using a continuous breeding protocol in which pairs of animals were maintained until each female had produced five litters (or it became evident that breeding had ceased) and this was conducted over three generations.)
- Diet (e.g. ad libitum): yes
- Water (e.g. ad libitum): yes
- Acclimation period: n.a.

ENVIRONMENTAL CONDITIONS
no inforamtion

IN-LIFE DATES: during late 1950's/early 1960's
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): Fresh mixes were prepared each week, and PGPR was incorporated into the ground diet first by hand,
then well mixed in a mechanical mixer.
- Mixing appropriate amounts with (Type of food): commercial pelleted stock diet (Spital)
- Storage temperature of food: n.a.

VEHICLE
none
Details on mating procedure:
The first-generation parents were selected from five litters which were assigned randomly into two groups: a control (11 males and 17 females) and a treatment group fed 1.5% PGPR (six males and 13 females). The dietary level of 1.5% PGPR was chosen to provide an intake by the pregnant and lactating rat which was in excess of 150 times the intake of a person consuming 5 mg PGPR/kg body weight/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 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.
In all instances the first litters were discarded after weaning and second-generation breeders were randomly selected (two males and two 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 32 of each sex in the PGPR group. The third-generation breeders were selected in a similar manner, by which the control and the PGPR groups were increased to 92 and 44 rats of each sex, respectively. The large control groups were considered necessary to get an indication of
the variations in breeding results that occur within a normal breeding colony. The control rats were fed a pelleted stock diet and the PGPR group were given the same diet ground with 1.5% PGPR.
The main focus of the study design was to observe any effect on breeding. Parameters measured in each of the three generations included number of litters per dam, average litter size, average weaning weights of males and females, litters per group showing 100% survival and total survival
(%) at day 21.
Analytical verification of doses or concentrations:
not specified
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
The PGPR group were given the same diet ground added with 1.5% PGPR.
Basis:
nominal in diet
The dietary level of 1.5% PGPR was chosen to provide an intake by the pregnant and lactating rat which was in excess of 150 times the intake of a person consuming 5 mg PGPR/kg body weight/day.
Remarks:
Doses / Concentrations:
The control rats were fed a pelleted stock diet
Basis:

No. of animals per sex per dose:
1st generation parents (P) were selected from five litters which were assigned randomly into two groups
Treatment group: 6 males and 13 females
Control group: 11 males and 17 females
In all instances the first litters were discarded after weaning and second-generation breeders were randomly selected (two males and two 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 32 of each sex in the PGPR group. The third-generation breeders were selected in a similar manner, by which the control and the PGPR groups were increased to 92 and 44 rats of each sex, respectively.
Control animals:
yes, plain diet
Statistics:
A Student's t-test was conducted in which the two groups were compared
Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Growth was monitored from weaning to mating during the first 4 months of each generation. Weight females recorded at weaning and mating. Males weight at weaning and day 65.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Growth was monitored from weaning to mating during the first 4 months of each generation. Weight females recorded at weaning and mating. Males weight at weaning and day 65.
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
not specified
Description (incidence and severity):
Test substance intake: During the three-generation study the breeding females consumed PGPR at levels of > 2 g/kg body weight (based on a food intake level of up to 40 g/day during lactation and the inclusion of PGPR in the diet of 1.5%)
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Dose descriptor:
NOAEL
Effect level:
> 2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Remarks on result:
other: Generation: for all three generations (migrated information)
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Description (incidence and severity):
There were no deaths during the experimental period and no evidence of abnormal behaviour or functional disorder associated with the consumption of PGPR throughout the three generations of the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The body weight data for test and control rats indicate that they both grew in a similar, normal pattern.
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Reproductive effects observed:
not specified
Conclusions:
Rats fed 1.5% (w/w) PGPR showed no evidence of a cumulative effect on breeding performance over three generations. Growth was comparable to controls throughout the three generations and there were no deaths or clinical signs associated with the consumption of PGPR. The only significant change in breeding performance was a reduction in the percentage of animals weaned in the second generation, but as this occurred in the control group to a similar extent it was concluded that this was due to an unknown environmental factor and was not treatment related. A 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.
Executive summary:

A publication is available where a series of toxicology studies were conducted in the 1950s and 1960s to investigate the toxicity of ADMUL WOL, a brand of polyglycerol polyricinoleate (PGPR). Included as part of these investigations was a three-generation reproduction study in rats. 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. A continuous breeding protocol was adopted, in which the breeding pairs were maintained until the female had produced five litters or when it became evident that breeding had ceased. The main focus of the study design was to observe any effect on breeding. The parameters measured in each of the three generations included number of litters per dam, average litter size, average weaning weights of males and females, litters per group showing 100% survival and total survival (%) at day 21.

Growth was comparable to controls throughout the three generations and there were no deaths or clinical signs associated with the consumption of PGPR. In conclusion, rats fed 1.5 % (w/w) PGPR showed no evidence of a cummulative effect on breeding performance over three generations.

During the three-generation study the breeding females consumed PGPR at levels of greater than 2 g/kg body weight (based on a food intake level of up to 40 g/day during lactation and the inclusion of PGPR in the diet at the fixed level of 1.5%). At this level of PGPR consumption the breeding performance of the treated rats was similar to those rats fed the control diet. There was no effect of PGPR on the suckling pups receiving PGPR from their mother's milk.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
As no study on reproductive toxicity is available for the target chemical, read across to PGPR (source chemical) was made. The read across is justified. Both chemicals are of comparable structures and can be characterized as esters of polyglycerol and fatty acids and undgo the same metabolism (Refer to "Read Across Justification" presented in Section 13).
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

As no study on reproductive toxicity is available for the target chemical Reaction products resulting from the esterification of C18 (unsaturated) fatty acid with glycerol oligomers, read across to polyglycerol polyricinoleate (PGPR), i.e. the source chemical, was made. Both chemicals are of comparable structures and can be characterized as esters of polyglycerols and fatty acid and undergo the same metabolism (Refer to "Read Across Justification" presented in Section 13). Thus the read across is justified.

A publication is available where a series of toxicology studies were conducted in the late 1950s and early 1960s to investigate the toxicity of the source chemical polyglycerol polyricinoleate (PGPR). In a three generation study 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. A continuous breeding protocol was adopted, in which the breeding pairs were maintained until the female had produced five litters or when it became evident that breeding had ceased. The main focus of the study design was to observe any effect on breeding. The parameters measured in each of the three generations included number of litters per dam, average litter size, average weaning weights of males and females, litters per group showing 100% survival and total survival (%) at day 21.

The first generation parents were selected from five litters which were assigned randomly into two groups: controls (11 males/17 females) and treatment group (6 males/13 females) with a dietary level of 1.5 % PGPR. All rats were weaned at 23 days and mated at 121 days. Breeding was continuous. The percentage of females that failed to breed was comparable to the respective controls in all three generations. The number of females producing five litters is comparable in all three generations. Growth was comparable to controls throughout the three generations and there were no deaths or clinical signs associated with the consumption of PGRP. During the three-generation study the breeding females consumed PGPR at levels of greater than 2 g/kg body weight (based on a food intake level of up to 40 g/day during lactation and the inclusion of PGPR in the diet at the fixed level of 1.5%). At this level of PGPR consumption the breeding performance of the treated rats was similar to those rats fed the control diet. There was no effect of PGPR on the suckling pups receiving PGPR from their mothers' milk.

Thus it can be concluded, that the fertility is not disturbed by feeding 1.5 % PGPR during several generations.The same is assumed for the substance registered due to the analogue structure and comparability of the metabolic fate of the target as well as the source chemical (refer to Section 13, Read Across Justification).Furthermore, the source chemical PGPR is well assessed as food additive. Polyglycerol esters of fatty acids have been evaluated for acceptable daily intake by the Joint FAO/WHO Expert Committee on Food Additives in 1966. In its evaluation of PGPR in 1974, the Joint FAO/WHO Expert Committee on Food Addities (JECFA 17th report) considered that the rat reproduction study, with a dietary level of PGPR of 1.5%, should be used to estimate an acceptable daily intace (ADI) of PGPR for man since the study showed a no-effect level for liver enlargement. Accordingly, a rat intake equivalent to 750 mg PGPR/kg body weight was used to set the ADI for PGPR of 7.5 mg/kg body weight. This intake is more than maximum likely from the use of PGPR in tin-greasing emulsions or in block chocolate and chocolate couverture.

In conclusion, no effect on fertility is assumed for the substance registered due to the analogue structure and comparability of the metabolic fate of the target as well as the source chemical (refer to Section 13, "Read Across Justification").


Short description of key information:
In order to evaluate the fertility of the test substance (target chemical) read across to a three generation study performed with the PGPR (source chemical) was made. Both chemicals are of comparable structures and can be characterized as esters of polyglycerol and fatty acids and undergo the same metabolism (Refer to Read Across Justification presented in Section 13), thus read across is justified.

Effects on developmental toxicity

Description of key information
In order to evaluate the developmental toxicity of the test substance (target chemical) read across to a three generation study performed with the PGPR (source chemical) was made.  Both chemicals are of comparable structures and can be characterized as esters of polyglycerol and fatty acids and undgo the same metabolism (Refer to "Read Across Justification" presented in Section 13), thus read across is justified.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1950-MM-DD to 1960-MM-DD
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Sound scientific publication. This study was conducted during the late 1950s/early1960s and the methods represented the state of the art which existed during this period. They nevertheless allow an adequate assessment of the potential reproductive and chronic toxicity of PGPR.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
other: This study was conducted during the late 1950s/early1960s and the methods represented the state of the art which existed during this period. They nevertheless allow an adequate assessment of the potential reproductive and chronic toxicity of PGPR.
Principles of method if other than guideline:
A three-generation reproduction study was conducted on PGPR to investigate the potential adverse effects on reproduction. Breeding was conducted using a continuous breeding protocol in which pairs of animals were maintained until each female had produced five litters (or it became evident that breeding had ceased) and this was conducted over three generations. The main focus of the study design was to observe any effect on breeding. Parameters measured in each of the three generations included number of litters per dam, average litter size, average weaning weights of males and females, litters per group showing 100% survival and total survival (%) at day 21.
GLP compliance:
no
Remarks:
Studies were performed prior to implementation of GLP
Limit test:
yes
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
Colworth Wistar rats (obtained from the breeding facility at the Unilever Colworth Laboratory, Sharnbrook, Bedford, UK) were used in these stu-
dies.
TEST ANIMALS
- Source: Colworth Wistar rats (obtained from the breeding facility at the Unilever Colworth Laboratory, Sharnbrook, Bedford, UK) were used in these studies.
- Housing: Each pair occupied a single cage. Breeding was conducted using a continuous breeding protocol in which pairs of animals were maintained until each female had produced five litters (or it became evident that breeding had ceased) and this was conducted over three generations.)
- Diet (e.g. ad libitum): yes
- Water (e.g. ad libitum): yes
- Acclimation period: n.a.

ENVIRONMENTAL CONDITIONS
no inforamtion

IN-LIFE DATES: during late 1950's/early 1960's
Route of administration:
oral: feed
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): Fresh mixes were prepared each week, and PGPR was incorporated into the ground diet first by hand,
then well mixed in a mechanical mixer.
- Mixing appropriate amounts with (Type of food): commercial pelleted stock diet (Spital)
- Storage temperature of food: n.a.

VEHICLE
none
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
The first-generation parents were selected from five litters which were assigned randomly into two groups: a control (11 males and 17 females) and a treatment group fed 1.5% PGPR (six males and 13females). The dietary level of 1.5% PGPR was chosen to provide an intake by the pregnant and lactating rat which was in excess of 150 times the intake of a person consuming 5 mg PGPR/kg body weight/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 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.
In all instances the first litters were discarded after weaning and second-generation breeders were randomly selected (two males and two 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 32 of each sex in the PGPR group. The third-generation breeders were selected in a similar manner, by which the control and the PGPR groups were increased to 92 and 44 rats of each sex, respectively. The large control groups were considered necessary to get an indication of
the variations in breeding results that occur within a normal breeding colony. The control rats were fed a pelleted stock diet and the PGPR group were given the same diet ground with 1.5% PGPR.
The main focus of the study design was to observe any effect on breeding. Parameters measured in each of the three generations included number of litters per dam, average litter size, average weaning weights of males and females, litters per group showing 100% survival and total survival
(%) at day 21.
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
The PGPR group were given the same diet ground added with 1.5% PGPR.
Basis:
nominal in diet
The dietary level of 1.5% PGPR was chosen to provide an intake by the pregnant and lactating rat which was in excess of 150 times the intake of a person consuming 5 mg PGPR/kg body weight/day.
Remarks:
Doses / Concentrations:
The control rats were fed a pelleted stock diet
Basis:

No. of animals per sex per dose:
1st generation parents (P) were selected from five litters which were assigned randomly into two groups
Treatment group: 6 males and 13 females
Control: 11 males and 17 females
In all instances the first litters were discarded after weaning and second-generation breeders were randomly selected (two males and two 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 32 of each sex in the PGPR group. The third-generation breeders were selected in a similar manner, by which the control and the PGPR groups were increased to 92 and 44 rats of each sex, respectively
Control animals:
yes, plain diet
Statistics:
A Student's t-test was conducted in which the two groups were compared
Details on maternal toxic effects:
Maternal toxic effects:no effects
Dose descriptor:
NOAEL
Effect level:
> 2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
> 2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no data
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
No adverse effects were observed during a three generation study. The average weight of weanling males and females was comparable to respective control weanlings throughout the three generation study. The growth of rats from weaning to mating was comparable in each generation to the respective controls.
Executive summary:

A publication is available where a series of toxicology studies were conducted in the 1950s and 1960s to investigate the toxicity of ADMUL WOL, a brand of polyglycerol polyricinoleate (PGPR). Included as part of these investigations was a three-generation reproduction study in rats. 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. A continuous breeding protocol was adopted, in which the breeding pairs were maintained until the female had produced five litters or when it became evident that breeding had ceased. The main focus of the study design was to observe any effect on breeding. The parameters measured in each of the three generations included number of litters per dam, average litter size, average weaning weights of males and females, litters per group showing 100% survival and total survival (%) at day 21.

Growth was comparable to controls throughout the three generations and there were no deaths or clinical signs associated with the consumption of PGPR. No adverse effects were observed during a three generation study. The average weight of weanling males and females was comparable to respective control weanlings throughout the three generation study. The growth of rats from weaning to mating was comparable in each generation to the respective controls.

In conclusion, rats fed 1.5 % (w/w) PGPR showed no evidence of a cumulative effect on breeding performance over three generations.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
As no study on reproductive toxicity is available for the target chemical read across to PGPR was made. The read across is justified. Both chemicals are of comparable structures with minor deviations and can be characterized as esters of polyglycerol and fatty acids and undgo the same metabolism (Refer to "Read Across Justification" presented in Section 13).
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

As no study on developmental toxicity is available for the target chemical Reaction mass C18 (unsaturated) esters with glycerin oligomers, read across to polyglycerol polyricinoleate (PGPR), i.e. the source chemical, was made. Both chemicals are of comparable structures and can be characterized as esters of polyglycerol and fatty acids and undergo the same metabolism (Refer to Read Across Justification presented in Section 13). Thus the read across is justified.

A publication is available where a series of toxicology studies were conducted in the late 1950s and early 1960s to investigate the toxicity of the source chemical polyglycerol polyricinoleate (PGPR). In a three generation study 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. A continuous breeding protocol was adopted, in which the breeding pairs were maintained until the female had produced five litters or when it became evident that breeding had ceased. The main focus of the study design was to observe any effect on breeding. The parameters measured in each of the three generations included number of litters per dam, average litter size, average weaning weights of males and females, litters per group showing 100% survival and total survival (%) at day 21.

During the three-generation study the breeding females consumed PGPR at levels of greater than 2 g/kg body weight (based on a food intake level of up to 40 g/day during lactation and the inclusion of PGPR in the diet at the fixed level of 1.5%). At this level of PGPR consumption the breeding performance of the treated rats was similar to those rats fed the control diet.

The body weight data for test and control rats indicate that they both grew in a similar, normal pattern.There was no effect of PGPR on the suckling pups receiving PGPR from their mothers' milk. Thus, it is assumed that the PGPR has no influence on the development of pups when PGPR was fed for three generations. The same is assumed for the target chemical.

Thus it can be concluded, that there are no effects on development of pups by feeding 1.5 % PGPR during several generations.

The same is assumed for the substance registered due to the analogue structure and comparability of the metabolic fate of the target as well as the source chemical (refer to Section 13, Read Across Justification). Further testing on a second species (e.g. rabbit) is unjustified considering scientific as well as animal welfare reasons.

Furthermore the source chemical PGPR is well assessed as food additive. Polyglycerol esters of fatty acids have been evaluated for acceptable daily intake by the Joint FAO/WHO Expert Committee on Food Additives in 1966. In its evaluation of PGPR in 1974, the Joint FAO/WHO Expert Committee on Food Addities (JECFA 17th report) considered that the rat reproduction study, with a dietary level of PGPR of 1.5%, should be used to estimate an acceptable daily intake (ADI) of PGPR for man since the study showed a no-effect level for liver enlargement. Accordingly, a rat intake equvalent to 750 mg PGPR/kg body weight was used to set the ADI for PGPR of 7.5 mg/kg body weight. This intake is more than maximum likely from the use of PGPR in tin-greasing emulsions or in block chocolate and chocolate couverture.

Justification for classification or non-classification

Based on the results from the available toxicity data on reproduction, it is concluded that the registered substance is not subject to classification and labelling according to the criteria of the EU Dangerous Substances Directive (67/548/EEC) (DSD) and of the EU Classification, Labelling and Packaging Regulation (1972/2008/EC) (CLP).