Reaction products of decanoic acid and lauric acid with glycerol and polyglycerol

Toxicity to reproduction

Administrative data

Endpoint:

multi-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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 Chem Toxicol. 1998 Sep-Oct;36(9-10):739-41.

Materials and methods

Principles of method if other than guideline:

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.

GLP compliance:

no

Remarks:

study was conducted in the 1950s and 1960s

Test material

Test material information

Constituent 1

Reference substance name:

9-Octadecenoic acid, 12-hydroxy-, (9Z,12R)-, polymer with 1,2,3-propanetriol

Cas Number:

29894-35-7

IUPAC Name:

9-Octadecenoic acid, 12-hydroxy-, (9Z,12R)-, polymer with 1,2,3-propanetriol

Test material form:

liquid

Details on test material:

Hydroxyl value 85±100
Acid value 2.0 max.
Iodine value 80±90
Refractive index at 658C 1.4635±1.4665

"the polyglycerol moiety shall be composed of not less than 75 percent of the di-, tri- and tetraglycerols and shall contain not more than 10 percent of polyglycerols equal to or higher than heptaglycerol'' (FAO, 1992).

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Unilever Colworth Laboratory, Sharnbrook, Bedford, UK
- Age at study initiation: (P) x wks; (F1) x wks
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g
- Housing:
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:

oral: feed

Details on exposure:

DIET PREPARATION
Fresh mixes were prepared each week, and PGPR was incorporated into the ground diet first by hand, then well mixed in a mechanical mixer.

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.

Frequency of treatment:

continuously via diet

Details on study schedule:

All rats were weaned at 23 days and mated at 121 days.

Doses / concentrations

Dose / conc.:

1.5 other: % in diet

No. of animals per sex per dose:

control (11 males and 17 females),
treatment group (six males and 13 females)

Control animals:

yes, plain diet

Examinations

Statistics:

A Student's t-test was conducted in which the two groups were compared.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Description (incidence and severity):

There were no significant differences in clinical signs in treated or control rats which indicated an effect of treatment with PGPR. There was no evidence of abnormal behaviour or functional disorder associated
with the consumption of PGPR throughout the three generations of the study.

Mortality:

no mortality observed

Description (incidence):

There were no deaths during the experimental period.

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.

Food consumption and compound intake (if feeding study):

not examined

Description (incidence and severity):

Food intakes were not recorded in this study, but it has been previously shown that levels of 5% PGPR in the diet has no effect on food intake

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

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)

In general, breeding performance for both the control and PGPR groups appeared to be more successful in the first and third generations.
In the second generation, breeding performance was poor for both diets with the only significant difference being that control rats had a significantly greater percentage of litters weaned entirely, which was reversed in favour of the PGPR rats in the third generation. One further difference in the second generation was the higher proportion of males among the weaned rats fed PGPR. As rats were not sexed until weaning, it is not known if this is due to a higher proportion of males being born, or to the males surviving better than the females.
The developmental period from birth to weaning is considered extremely critical. In generations 1 and 3 a high percentage of the offspring were weaned for both groups. However, in the second generation there was a reduction in the percentage of animals weaned. As this reduction occurred in both groups and to a similar extent it is concluded that this was due to an unknown environmental factor.
In conclusion, the similarity observed between the data obtained for the first and third generations failed to provide any evidence of a cumulative effect due to long-term ingestion of PGPR over three successive generations.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Target system / organ toxicity (P0)

Critical effects observed:

not specified

Results: F1 generation

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

2 000 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Target system / organ toxicity (F1)

Critical effects observed:

not specified

Results: F2 generation

Effect levels (F2)

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

2 000 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Target system / organ toxicity (F2)

Critical effects observed:

not specified

Overall reproductive toxicity

Reproductive effects observed:

no

Any other information on results incl. tables

Table 1. Breeding performance

	1st generation		2nd generation		3rd generation
Reproductive parameter	Control	PGPR	Control	PGPR	Control	PGPR
No. of females	17	13	52	32	92	44
Females failing to breed (%)	0	0	15	16	17	16
Litters born (average/female)	4.7	4.6	4.4	3.2	3.5	4.0
Females producing five litters (%)	76	85	50	41	52	70
Average size of litters	8.4	7.4	7.2	7.2	7.0	7.4
Rats weaned/rats born (%)	79	79	54	44	70	83
Litters entirely weaned (%)	57	64	38	22	53	67
Average weight of weanling males (g)	37.8	37.3	33.7	33.7	36.8	35.4
Average weight of weanling females (g)	36.1	36.2	32.5	30.8	36.4	33.6
Weanling males/all weanling (%)	48	48	48	57	46	50

Table 2. Growth of rats from weaning to mating (females) or 65 days (males)

		Females			Males
Group	Generation	No. of females	Average weight at weaning [g]	Average weight gain at mating [g]	No. of males	Average weight at weaning [g]	Average weight gain 65 d [g]
Control	1	17	40	131	11	43	155
	2	42	38a	134a	52	39	150
	3	92	35	130	92	35	126
PGPR	1	13	38	127	6	40	143
	2	32	37	127	32	39	143
	3	44	33	119	44	35	112

a) Average of 50 animals.

*Indicates that the value is significantly greater (P = 0.05) than the other group in the same generation.

 

Table 3. Proportion of rats born and weaned

Treatment	Generation	No. of breeding females	Rats born	Rats weaned	% Weaned
Control	1	17	664	526	79.0
PGPR		13	447	353	78.9
Control	2	52	1312	710	54.0
PGPR		32	749	334	44.0
Control	3	92	2263	1595	70.0
PGPR		44	1325	1098	82.8

 

Applicant's summary and conclusion

Conclusions:

In the period of most rapid growth for the rats, polyglycerol polyricinoleate had no effect on the food intake during this period and had no subsequent effect on the growth of the rats.
During the three-generation study the breeding females consumed polyglycerol polyricinoleate 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 polyglycerol polyricinoleate in the diet at the fixed level of 1.5%). At this level of polyglycerol polyricinoleate consumption the breeding performance of the treated rats was similar to those rats fed the control diet. There was no effect of polyglycerol polyricinoleate on the suckling pups receiving polyglycerol polyricinoleate from their mothers' milk.
The ingestion of polyglycerol polyricinoleate at a dietary level of 1.5% did not produce any adverse effect on reproductive capacity or development of the offspring during three generations of continuous exposure.