Propane-1,3-diol

Toxicity to reproduction

Administrative data

Endpoint:

multi-generation reproductive toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

Additional documentation, provided within the IUCLID Assessment Reports (Section 13), supports the read-across approach.

Cross-reference

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

multi-generation reproductive toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

information beyond standard information requirements

Justification for type of information:

Additional documentation, provided within the IUCLID Assessment Reports (Section 13), supports the read-across approach.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

yes

Remarks:

estrous cycle, sperm evaluation, vaginal opening and preputial separation exams not conducted; study was conducted for 5 generations

GLP compliance:

not specified

Specific details on test material used for the study:

Test compound was obtained from the Celanese Chemical Company, New York.

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Not reported

Route of administration:

oral: feed

Details on exposure:

A semipurified diet with the following basal composition was used:
20% Caesin
8% Refined corn oil
4% Salt mix
1% Vitamin mix
33.5% Corn starch
33.5% Dextrose

The test diets were prepared by substituting the test material for equal amounts by weight of corn starch and dextrose.

Details on mating procedure:

F0 geneartion rats were paired after 4 weeks of treatment. At 1-2 weeks after weaning of the first litters, each female of the F0 generation was mated with a different male, and a second series of litters was produced. Insemination was confirmed by observation of a vaginal sperm plug; this observation date was designated as day 0 of pregnancy. If semination had not been confirmed by the seventh day, the female was paired to another male of the same group for an additional 7 days. Females which did not become pregnant within this time period were considered infertile and were discarded. The initial litters were reared to maturity as the F1A generation which was assigned to the longevity phase of the study and subjected to repeated reproduction cycles. All animals of the second series of litters (the F1B generation) were discarded at weaning except for 10 males per group which were reared and used in a dominant lethal test.

After 11 weeks of feeding, the F1A rats were paired to produce the F2 generation. In all, five succesive mating cycles were achieved iwth the F1A rats within a period of 77 weeks. Pups weaned fropm the first litters of the F1A females became the F2A parent, which were used to produce the F3 generation. Each set of F2A parents was mated twice to yield two litters of offspring. The F3A females were permitted to mature to term and cast litters of F4A and F4B generations. The procedure for confirmation of insemination were identical to those described for F0 females.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

4 weeks treatment prior to F0 generation being paired. Females of the F0 generation were fed their respective diets throughout mating, gestation, and lactation phase of the study. After 11 weeks of feeding, the F1A rats were paired to produce the F2 generation. In all, five successive mating cycles were achieved.

Frequency of treatment:

daily

Dose / conc.:

5 other: % (nominal in diet)

Dose / conc.:

10 other: % (nominal in diet)

Dose / conc.:

24 other: % (nominal in diet)

No. of animals per sex per dose:

25 per sex per group

Control animals:

yes

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: not reported

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): yes
- Time schedule: not reported

OTHER:
Blood samples were collected from 10 rats/sex/group for determination of alkaline phosphotase, glucose, hematocrit, hemoglobin, and total and differential leucocyte counts. Urine analysis of the same animals provided measurements of albumin, glucose, ketones, occult blood, pH, specific gravity, and miscroscopic examination of the sediment. The samples were collected from the F0 rats after 4 weeks on their respective diets. Samples were collected from the F1 rats after 11 weeks of feeding.

Litter observations:

PARAMETERS EXAMINED
The following parameters were examined:
number of pregnant females, number of pups cast alive or dead, pup weights and survival of progeny

Postmortem examinations (parental animals):

For the F1A rats, the gonads and pituitary glands were examined microscopically.

Reproductive indices:

Fertility: % matings resulting in pregnancies
Gestation: % pregnancies resulting in litters cast alive
Viability: % pups cast alive that survived to 4 days
Lacatation: % pups alive at 4 days that survived to 21 days

Remarks on result:

other: See "Remarks"

Remarks:

For four of five generations of rats treated at levels up to 24% of the diet, no adverse effects on reproduction and lactation parameters were observed. However, an apparent dose-related effect decrease in fertility occurred during five successive mating cycles of F1A rats.

Critical effects observed:

no

Remarks on result:

other: In rats treated at levels up to 24% of the diet, no adverse effects on reproduction and lactation parameters were observed. However, an apparent dose-related effect decrease in fertility occurred during five successive mating cycles of F1A rats.

Remarks on result:

other: In rats treated at levels up to 24% of the diet, no adverse effects on reproduction and lactation parameters were observed.

Reproductive effects observed:

no

Body weights: For four consecutive generations, female animals showed no significantly abnormal growth rates, but body weight gains of male rats in all four generations were slightly depressed, with an apparent dose relationship. However, efficiency of food utilization through 10 weeks of post-weaning remained constant for all generations of both sexes and was not affected by the level of 1,3-butanediol in the diet.

Clinical studies: Hematology, blood chemistry and urinalysis studies showed no trends associated with treatment of F0, F1, F2, and F3 generation animals.

During five successive mating cycles of F1A rats, a gradual decrease in the pregnancy rate was seen. Both the number of pregnant females and the fertility index appeared to be dose-related for several series of F2 litters, especially F2D and F2E. For the fifth series of litters, no pups were obtained in the high dose group. However, the gestation, viability, and lactation indexes, as well as the mean pup body weights at 4 and 21 days showed no significant differences between specific litter series or between control and test groups (excluding high-dose animals of the fifth series of litters). No significant treatment-related differences were noted on histopathologic examination of testes or ovaries and pituitary glands as a possible explanation of the observed reproductive failure during the fifth cycle.

 

For the other three generations of dams and pups, no significant dose-related trends were observed for the reproduction and lactation parameters.

			Average no. of pups per litter		Indexes
Generation/ Dietray Level (%)	No of matings	No of pregnant females	Cast alive	Cast dead	Fertility	Gestation	Viability	Lactation
F2A
0	25	18	9.3	1.4	72	94	84	83
5	25	20	9.9	0.5	80	100	85	90
10	25	23	9.7	0.2	92	100	75	90
24	25	19	8.4	0.8	76	100	93	99
F2B
0	25	11	10.1	0.5	44	100	76	90
5	25	11	9.7	0.1	44	100	98	90
10	25	16	10.2	0.3	64	100	98	100
24	25	13	10.2	0.4	52	100	88	99
F2C
0	25	16	8.1	0.8	64	94	88	75
5	25	19	9.8	0.2	76	100	96	99
10	25	17	10.0	0.0	68	94	97	94
14	25	11	8.1	0.1	44	100	97	79
F2D
0	25	15	9.1	0.1	60	100	81	95
5	25	15	9.6	0.1	60	100	99	100
10	25	10	9.8	0.1	40	100	99	100
14	25	7	7.7	0.4	28	100	87	100
F2E
0	25	10	5.4	0.8	40	90	85	98
5	25	4	7.0	0.5	16	100	100	100
10	25	5	7.4	0.4	20	100	84	100
14	25	0	0	0	0	-	-	-

 

 

			Average no. of pups per litter		Indexes
Generation/ Dietray Level (%)	No of matings	No of pregnant females	Cast alive	Cast dead	Fertility	Gestation	Viability	Lactation
F1A
0	25	23	10.0	0.6	92	100	98	98
5	25	21	10.4	0.3	84	100	91	99
10	25	19	10.3	0.3	76	100	96	96
24	25	20	9.3	0.3	80	100	84	96
F1B
0	25	20	8.8	0.5	80	100	94	95
5	25	17	8.8	0.8	68	100	85	95
10	25	13	9.6	0.5	52	100	95	96
24	25	16	8.1	0.3	64	100	88	91

 

 

			Average no. of pups per litter		Indexes
Generation/ Dietray Level (%)	No of matings	No of pregnant females	Cast alive	Cast dead	Fertility	Gestation	Viability	Lactation
F3A
0	24	18	10.3	0.4	75	100	98	99
5	25	22	8.9	0.1	88	96	95	97
10	25	17	9.9	0.1	68	100	95	91
24	25	23	9.7	0	92	96	95	100
F3B
0	7	6	11.2	1.0	86	100	100	100
5	8	7	9.3	0.4	88	96	95	92
10	8	7	9.6	0	88	100	100	83
24	6	4	11.8	0.3	68	100	92	100

 

			Average no. of pups per litter		Indexes
Generation/ Dietray Level (%)	No of matings	No of pregnant females	Cast alive	Cast dead	Fertility	Gestation	Viability	Lactation
F4A
0	25	22	10.9	0.7	88	100	98	97
5	25	18	9.8	0.1	72	100	81	97
10	25	20	10.5	0.1	80	100	94	97
24	25	22	9.7	0.6	88	96	88	99
F4B
0	25	22	11.3	0.4	88	100	97	99
5	25	21	9.7	0.3	84	100	99	89
10	25	21	10.1	0	84	100	99	90
24	25	20	9.2	0.2	80	100	96	96

 

Conclusions:

For four of five generations of rats treated at levels up to 24% of the diet, no adverse effects on reproduction and lactation parameters were observed. However, an apparent dose-related effect decrease in fertility occurred during five successive mating cycles of F1A rats.

Executive summary:

The effect of 1,3-butanediol on reproductive performance were studied in five generations of Wistar rats. Animals of both sexes were fed either control diet or diet supplemented with 1,3-butanediol at dose levels of 5, 10, or 24% of the diet by weight. Reproduction and lactation parameters were comparative to controls for four or five generations of dams and pups. In contrast, the pregnancy rate of F1A rats decreased during five successive mating cycles; no pups were obtained in the high dose-group of the fifth series of litters (F2E generation). Excluding this group, the viability of F2 generation pups revealed no significant differences between litters or between control and test groups.

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Butane-1,3-diol

EC Number:

203-529-7

EC Name:

Butane-1,3-diol

Cas Number:

107-88-0

IUPAC Name:

butane-1,3-diol

Constituent 2

Reference substance name:

1,3-Butanediol

IUPAC Name:

1,3-Butanediol

Details on test material:

- Purity: Not reported

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Remarks on result:

other: see 'Remark"

Remarks:

For four of five generations of rats treated at levels up to 24% of the diet, no adverse effects on reproduction and lactation parameters were observed. However, an apparent dose-related effect decrease in fertility occurred during five successive mating cycles of F1A rats.

Results: F1 generation

Effect levels (F1)

Remarks on result:

other: In rats treated at levels up to 24% of the diet, no adverse effects on reproduction and lactation parameters were observed. However, an apparent dose-related effect decrease in fertility occurred during five successive mating cycles of F1A rats.

Results: F2 generation

Effect levels (F2)

Remarks on result:

other: In rats treated at levels up to 24% of the diet, no adverse effects on reproduction and lactation parameters were observed.

Overall reproductive toxicity

Reproductive effects observed:

no