Propane-1,3-diol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

1,3-Propanediol is predicted to be of low concern for reproductive toxicity based on the lack of effects in a 90-day subchronic study for 1,3-propanediol, and reproductive results for structural analogues 1,2-ethanediol, 1,3-butanediol, and 1,4-butanediol.

Link to relevant study records

Reference

Reference 1

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

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:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

other: distilled water

Details on mating procedure:

Premating exposure period: Male: 14 days; Female: 14 days

Duration of treatment / exposure:

Male: For 2 weeks prior to mating and 2 weeks of mating
Female: For 2 weeks prior to mating, 2 weeks of mating, and throughout pregnancy until day 3 postpartum

Frequency of treatment:

Daily

Dose / conc.:

200 mg/kg bw/day (actual dose received)

Dose / conc.:

400 mg/kg bw/day (actual dose received)

Dose / conc.:

800 mg/kg bw/day (actual dose received)

Control animals:

yes, concurrent vehicle

Parental animals: Observations and examinations:

Food consumption and body weight

Reproductive indices:

copulation index, fertility index, gestation length, numbers of corpora lutea or implantation, implantation index, gestation index, delivery index, and behavior at delivery and lactation

Offspring viability indices:

pup viability, morphological examination of pups, pup body weight

Dose descriptor:

NOAEL

Effect level:

800 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: no adverse effects at highest dose tested

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

800 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects at highest dose level tested

Reproductive effects observed:

no

The parental animals exhibited no alteration in reproductive parameters including the copulation index, fertility index, gestation length, numbers of corpora lutea or implantation, implantation index, gestation index, delivery index, and behavior at delivery and lactation. Although neither the pup viability nor the incidence of morphological abnormalities was changed by the adminstration of the compound, pup body weight was slightly but significantly decreased in the 800 mg/kg group. This change was considered to be secondary to maternal toxicity (reduced food consumption and body weight gain).

Executive summary:

The parental animals exhibited no alteration in reproductive parameters including the copulation index, fertility index, gestation length, numbers of corpora lutea or implantation, implantation index, gestation index, delivery index, and behavior at delivery and lactation. Although neither the pup viability nor the incidence of morphological abnormalities was changed by the adminstration of the compound, pup body weight was slightly but significantly decreased in the 800 mg/kg group. This change was considered to be secondary to maternal toxicity (reduced food consumption and body weight gain).

Reference 2

Endpoint:

three-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

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 parameters, vaginal opening, and preputial separation examinations not conducted.

GLP compliance:

not specified

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch number of test material: Union carbide Corporation, Hahnville, Louisiana
- Purity: 99.3% by analysis at the time of shipment

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, Mass.
- Housing: 2 per cage in stainless-steel wire cages. During mating each male was housed with 2 females. After mating and during lactation, the female rats were housed individually in plastic shoebox cages with hardwood chips for nesting
- Age at study initiation: F0: ~7 weeks
- Diet (e.g. ad libitum): Purina Formulab 5008 chow ad libitum
- Water (e.g. ad libitum): city water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Photoperiod (hrs dark / hrs light): 12 hours light

Route of administration:

oral: feed

Details on exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): every 2 weeks
- Mixing appropriate amounts with (Type of food): percentage of test substance was adjusted base don group mean body weight and food consumption. However, concentration of test substance in diet was not changed during gestation or the first week of lactation, but was reduced 2- and 3-fold during the second and third weeks of lactation, respectively, to adjust for increased food consumption by the dams

Details on mating procedure:

At approximately 100 days of age, 10 males were mated to 20 females in each dosage gorup.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

gas chromatography

Duration of treatment / exposure:

Administration to the F0 rats began at approximately 7 weeks of age

Frequency of treatment:

Daily

Details on study schedule:

F1 rats were randomly selected within each dosage group for the next mating. Each litter was represented except for those conceived very late in the mating period. The F1 and F2 rats were treated as described for the F0 animals until approximately 100 days of age, at which time the animals were cohabited. Brother and sister matings were avoided for each generation.

Dose / conc.:

40 mg/kg diet

Dose / conc.:

200 mg/kg diet

Dose / conc.:

1 000 mg/kg diet

No. of animals per sex per dose:

20 females per group; 10 males per group

Control animals:

yes

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes, daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly except during gestation and lactation

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): yes
- Time schedule for examinations: Weekly except during gestation and lactation

Litter observations:

Date of parturition and the number of live and dead newborn were recorded for each litter. The appearance and behavior of dams and pups were observed daily. Litter size was randomly reduced to 10, if necessary, on post partum day 4. Offspring were weighed as litters at 4 and 14 days and individually at 21 days postpartum, the day they were weaned.

Postmortem examinations (offspring):

Necropsies were performed on 5 male and 5 females randomly selected from each dosage level of the F2 parents and the F3 weanlings. Microscopic examinations were performed on sections of liver, kidneys, lung, heart, adrenals, thyroid, trachea, accessory sex glands, adipose tissue, lymph nodes, pituitary, thymus, and testes and epididymis, or uterus and ovaries.

Statistics:

Continuous data such as body weights were compared by analysis of variance validated by Bartlett's test for homogenieity of variance. Duncan's multiple range test was used to identify individual mean differences when indicated by a significant F value. Where Bartlett's test indicated heterogeneous variances were used to delineate differences between groups. Pup weights were compared by the method of Weil. Discontinuous data such as implantations and reproductive indices were compared by a multiple sum of ranks test. Frequency data were compared by X2 test and by Fisher's exact test.

Reproductive indices:

Male and female fertility index, days from first mating to partutition, gestation index (fraction of pregnancies that resulted in litters with live pups), gestation survival index (fraction of newborn pups alive at birth), 0 to 4-day survival index, 4 to 14-day survival index, 4 to 21-day survival index.

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No reproductive effects were observed at any dose level tested.

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No reproductive effects were observed at any dose level tested.

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No reproductive effects were observed at any dose level tested.

Reproductive effects observed:

no

Diet consumption and Body weight:

Throughout the study, there was no effect on ethylene glycol treatment on body weight gain or diet consumption, nor was there any mortality among parental rats. The calculated dosages based on nominal concentrations of ethylene glycol in the diet were generally very close to the dosage goals. The weekly calculated dosages ranged from 1.0-1.3, 0.2-0.3, and 0.04-0.05 g/kg/day for males and from 0.9-1.2, 0.2-0.3, and 0.04-0.06 g/kg/day for females.

 

Reproductive indices:

No treatment-related effect was observed for any of the indices. Also, ethylene glycol treatment did not affect neonatal body weight at days 4, 14, or 21 postpartum.

 

Histopathologic Findings:

There were no treatment-related histopathological findings in F2 parents or in F3 weanlings. Although the kidney has been shown to be the primary target organ for ethylene glycol toxicity, there was no increase in the incidence or severity of kidney lesions in this study. One high dose F2 animal of each sex had mild focal interstitial nephritis. However, this condition was also seen in a control male and a control female. Unilateral hydronephrosis occurred in another high dose F2 male. In addition, mild focal tubular hyperplasia was observed in one high-dose male F3 pup was also diagnosed in two control male pups.

	1.0	0.2	0.04	0.0A	0.0B
F0-F1
Fertility Index (%) Male	100	90	100	90	90
Fertility Index (%) Female	95	90	90	75	90
Gestation index (%)	100	100	100	100	100
Gestation survival index (%)	100.0	99.4	100.0	100.0	99.4
0-4 day survival index (%)	99.5	98.1	100.0	99.3	99.4
4-14 day survival index (%)	97.9	97.6	100.0	93.4	92.2
4-21 day survival index (%)	97.9	97.6	100.0	91.9	92.2
Days from first mating to litter	27.1	28.5	28.3	28.3	27.3
F1-F2
Fertility Index (%) Male	100	100	90	90	90
Fertility Index (%) Female	85	95	85	90	85
Gestation index (%)	100	100	100	100	94
Gestation survival index (%)	100.0	97.5	99.5	96.1	94.1
0-4 day survival index (%)	94.1	97.4	97.3	94.0	99.4
4-14 day survival index (%)	99.4	100.0	97.7	99.4	100.0
4-21 day survival index (%)	99.4	100.0	97.7	92.3	100.0
Days from first mating to litter	27.6	28.2	29.6	27.7	28.5
F1-F2
Fertility Index (%) Male	100	90	100	80	80
Fertility Index (%) Female	90	75	85	80	70
Gestation index (%)	100	100	100	100	100
Gestation survival index (%)	98.9	99.0	96.3	100.0	100.0
0-4 day survival index (%)	98.9	100.0	100.0	98.3	98.4
4-14 day survival index (%)	100.0	97.8	100.0	100.0	100.0
4-21 day survival index (%)	100.0	97.8	100.0	100.0	100.0
Days from first mating to litter	29.5	28.6	27.0	30.9	27.1

 

Conclusions:

No evidence of reduced fertility or increased fetal death was observed in any of the groups receiving ethylene glycol at doses up to 1000 mg/kg.

Executive summary:

To assess the possible effects of ethylene glycol on reproductive performance, a three-generation reproduction study was performed in the Fischer 344 rat. Ethylene glycol was included in the diet at approximate dosages of 0, 0.04, 0.2, and 1.0 g/kg/day during three generations of reproduction. Each generation was bred was once. No evidence of reduced fertility or increased fetal death was observed in any of the groups receiving ethylene glycol.

Reference 3

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.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No reproductive toxicity study with the test substance is available. However, data for the structurally similar substances, 1,2-ethanediol, 1,3-butanediol, and 1,4-butanediol are available, and were used as read across to fulfil the data gap for the test substance. The underlying hypothesis supporting read-across is based on structural similarity of the target and source substances. The only difference between target and source molecules is the length of the carbon backbone and in one case the position of the second hydroxyl group. The target and source substances also have similar toxicokinetic properties. Additional documentation, provided within the IUCLID Assessment Reports section, supports the read-across approach.

 

A 3-generation reproductive toxicity study according to OECD guideline 416 was performed to assess the effects of 1,2-ethanediol on reproductive performance in Fischer 344 rats. Rats were exposed to 1,2-ethanediol via the diet at concentrations up to 1000 mg/kg/day. No effect on fertility was observed during the study.

 

The fertility of rats (Fischer 344) exposed via diet in a 3-generation reproductive toxicity study (OECD 416) at doses up to 1000 mg/kg 1,2-ethanediol was not affected.

 

The fertility of rats (Wistar) exposed in a 2-generation reproductive toxicity study (OECD 416) up to a nominal concentration of 24% in the diet of 1,3-butanediol was not affected.

The fertility of rats (Crj: CD Sprague-Dawley) exposed via gavage in a screening reproductive toxicity study (OECD 422) at doses up to 800 mg/kg bw/day 1,4-butanediol was not affected.

 

Additionally, there were no pathological or histopathological indicators of reproductive toxicity in the 90-day toxicity study (reproductive organs and sperm parameters) observed following exposure to 1,3-propanediol in Sprague-Dawley rats at doses up to 1000 mg/kg/day.

 

Therefore, 1,3 -propanediol is predicted to be of low concern for reproductive toxicity based on the lack of effects in a 90-day subchronic study for 1,3-propanediol, and reproductive results for the structural analogues 1,2-ethanediol, 1,3-butanediol, and 1,4-butanediol.

Effects on developmental toxicity

Description of key information

1,3-Propanediol is predicted to be of low concern for developmental toxicity based on the lack of effects in a rat developmental toxicity with 1,3-propanediol, as well as lack of developmental effects in studies with structural analogues 1,2-ethanediol, 1,3-butanediol, and 1,4-butanediol.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

ACC PDO panel assigned reliability of 1. PDO from chemical process.

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hag: SD Breeder: Lippische Versuchstierzucht; HAGEMANN GmbH; D-4923 Extertal 1
- Age at study initiation: Approximately 56 days
- Weight at study initiation: 193-242 grams
- Fasting period before study: No
- Housing: Single MAKROLON cages type III (cleaned/changed once a week).
- Diet (e.g. ad libitum): ALTROMIN 1314 ad libitum
- Water (e.g. ad libitum): Tap (in bottles) ad libitum
- Acclimation period: Not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2°C
- Humidity (%): 50±15%
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

Route of administration:

oral: gavage

Vehicle:

other: 0.8% aqueous hydroxypropyl-methylcellulose gel

Details on exposure:

VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of approx. 10 ml were taken for each dose group immediately after preparation of the test suspensions as well as 8 and 24 hours after storage at room temperature (3 samples/dose-level). These samples were needed for determination of the concentration.

Details on mating procedure:

- Impregnation procedure: Co-housed.
- Proof of pregnancy: Sperm in vaginal smear referred to as day 0 of pregnancy.
- M/F ratio per cage: 1/1

Fertile ('proved') 4-12 month old male rats of the same breed served as partners. They were repeatedly employed, at the earliest three days after successful copulation. The female breeding partners were randomly chosen. Matings were monogamous.

Duration of treatment / exposure:

Treatment from day 6 to 15 of gestation.

Frequency of treatment:

Daily.

Dose / conc.:

250 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

20 (all female).

Control animals:

yes

Details on study design:

- Rationale for animal assignment (if not random): The rats were assigned to their respective group according to their mating day i.e. in a cyclic way following the listing of positive findings in the vaginal smear.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice/day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice/day

BODY WEIGHT: Yes
- Time schedule for examinations: Daily (morning)

FOOD CONSUMPTION: Yes
- Determined daily by weighing residue.

WATER CONSUMPTION: Yes
- Time schedule for examinations: Visually inspected daily

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: ovaries, uteri, other internal organs.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number and size resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

Fetal exams included:
-Count.
-Sex, viability.
-Weight, length.
-External exams for damages/malformations.
-Dissected and the number and type of possible variations (inc. retardations) or malformations was determined macroscopically.
-Location, size, and condition of the internal organs were determined.
-Skeletal system.
-Variations examined according to WILSON.

Statistics:

After randomisation of the animals an analysis of variance was carried out.
-Homogeneity of variances (Bartlett chi-square).
-If variances are homogeneous (one way analysis of variance was applied).
-When results indicated significant difference (DUNNETT test).
-Heterogeneity of variances (Student's t-test).
-Comparison of malformation, resorption, retardation and variation rates (Exact test of R.A. FISHER's or chi square test).

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weights remained within the normal range at 250 and 1000 mg/kg. Body weight gain showed no distinct influence of the test compound at 250 mg/kg. Body weight gain was slightly (-32%) but not significantly inhibited between gestation days 6 and 9 in the 1000 mg/kg group.

Food consumption and compound intake (if feeding study):

no effects observed

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

no effects observed

Gross pathological findings:

no effects observed

Details on results:

The fertility rate was 90.9% for all three groups.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Basis for effect level:

other: no adverse effects noted at highest dose level tested

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Description (incidence and severity):

In the control, one fetus had shortened hindlimbs and missing toes on the right foot.

Skeletal malformations:

no effects observed

Description (incidence and severity):

The fetal incidence of all retardations was slightly and significantly increased at the skeletal examination for the 1000 mg/kg, particularly for the skull (retarded ossification). However, the significance observed was due to the low incidence of retarded skull ossification found in the control group in this study which was much below the background incidence. The incidence found for the dose level groups were within the range of the background hence no biological significance was attached to the finding.

Visceral malformations:

no effects observed

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Basis for effect level:

other: no adverse effects noted at highest dose level tested

Abnormalities:

no effects observed

Developmental effects observed:

no

Mean Maternal Body Weight Gain (g)

Gestation           Test Group (mg/kg bw)
Days               0               250            1000
===================================
0-3              12.4            11.0             11.6
 3-6              13.8            14.6             13.2
 6-9              11.1              9.2               7.5
 9-12            14.5            15.4             15.3
12-15          15.9             14.8            15.9
15-18          35.1             36.2            31.9
18-20          27.9             30.5            31.0
====================================

Fetal Skeletal Retardations
                                Test Group (mg/kg bw)
Parameter                        0     250  1000
====================================
Total 
Retardations
   Fetal Incidence (%)    63.9  63.5   77.4*
   Litter Incidence (%)    90.0  95.0  100.0 
Incomplete ossification of
the skull
    Fetal Incidence (%)    26.9  41.3* 41.9**
    Litter Incidence (%)    75.0  85.0   80.0
===================================
* p =< 0.05
** p =< 0.01

Conclusions:

1,3-Propanediol did not possess teratogenic properties.

Executive summary:

1,3 -Propanediol was administered to pregnant rats at concentrations of 0, 250, or 1000 mg/kg by oral gavage on gestation days 6-15. Maternal toxicity was evaluated via clinical observations, body weight, and food consumption. On gestation day 20, the surviving rats were laparotomized under ether narcosis. The ovaries and uterus were removed and a macroscopic examination of the internal organs was conducted. The number and size of resorptions were determined. The corpora lutea in the ovaries, implantations and location of the fetuses in the uterus were recorded. The gravid uterus weight and the weight of the placentae was recorded. The fetuses were removed from the uterus and were counted, sexed, assessed for viability, weighed and length measured, examined externally for malformations and dissected and examined for macroscopic malformations. In 50% of the fetuses/litter, the thoracic and peritoneal cavities were opened and the location, size and condition of the internal organs were determined. The skeletons were stained with Alizarin and the skeletal system was evaluated according to. Retardations, variations and/or malformations were examined and the number of occurrences recorded. In the remaining 50% of fetuses/litter, body sections were prepared and examined for variations according to.

 

No substance related mortality or clinical signs were observed in the dams.  Body weights remained within the normal range at 250 and 1000 mg/kg. Body weight gain showed no distinct influence of the test compound at 250 mg/kg. Body weight gain was slightly (-32%) but not significantly inhibited between gestation days 6 and 9 in the 1000 mg/kg group. Treatment did not influence drinking water or food consumption. No substance-related pathological changes were detected at autopsy. No distinct influence on the prenatal development was detected.  All fetal parameters were within the normal range of the control group. No substance-related variations and/or retardations were found. No malformed fetuses were detected in the substance-treated groups. No dead fetuses occurred in the substance treated and control dams. Therefore, the maternal and fetal NOAELs were determined to be 1000 mg/kg.

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Justification for type of information:

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

Principles of method if other than guideline:

Mice were exposed to the test material via gavage during the period of major organogenesis (gestation days 6-15) to determine potential developmental toxicity.

GLP compliance:

not specified

Species:

mouse

Strain:

Swiss

Remarks:

CD-1

Route of administration:

oral: gavage

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Timed-pregnant mice were used.

Duration of treatment / exposure:

gestation days 6-15

Frequency of treatment:

daily

Duration of test:

gestation day 17

Dose / conc.:

100 mg/kg bw/day

Dose / conc.:

300 mg/kg bw/day

Dose / conc.:

600 mg/kg bw/day

No. of animals per sex per dose:

28-32 females/dose

Control animals:

yes

Maternal examinations:

Body weight, clinical signs, and food/water intake were monitored at regular intervals throughout gestation.

Fetal examinations:

Implant survival, foetal weight, sex, and morphological development (external, visceral and skeletal) were examined on gestation day 17.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Daoms (60-100%/group/day) at teh mid and high doses exhibited symptoms of CNS intoxication (hypoactivity, immobility, loss of righting reflex and/or prone posture) during the first 4 hours following daily administration.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Reduced body weight and reduced weight gain (treatment period, gestation period, and corrected weight gain) were observed at mid and high doses.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Reduced food intake (treatment and post treatement periods) was observed at mid and high doses.

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

Abnormalities:

no effects observed

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Reduced average foetal body weight at the mid and high doses (92 and 83% of control, respectively)

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Details on embryotoxic / teratogenic effects:

The only definitive expression of developmental toxicity was the reduction in average foetal body weights at the mid and high doses.

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

NOAEL (maternal): 100 mg/kg/day
NOAEL (developmental): 100 mg/kg

Executive summary:

The test substance was evaluated for potential developmental toxicity. Pregnant mice were given 100, 300, or 600 mg/kg via gavage on gestation days 6-15. Maternal body weight, clinical signs, and food/water intake were recorded. On gestation day 17, implant survival, foetal weight, sex, and morphological development (external, visceral, and skeletal) were examined. There were no maternal deaths, and no maternal or developmental effects were observed at 100 mg/kg. Dams at≥300 mg/kg exhibited symptoms of CNS intoxication (hypoactivity, immobility, loss of righting reflex, and/or prone posture) during the first 4 hours following daily administration. Maternal effects at≥300 mg/kg also included reduced food intake, reduce body weight, and reduced weight gain. The only definitive expression of developmental toxicity was a reduction in average fetal body weight at≥300 mg/kg (92 and 83% of control, respectively). Thus, 100 mg/kg was the maternal and developmental NOAEL, and 300 mg/kg was the maternal and developmental LOAEL.

Reference 3

Endpoint:

developmental 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:

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

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 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Specific details on test material used for the study:

- Source and lot/batch number of test material: Southern Research Institute (SRI) (Birmingham, AL)
- Purity: 98% by packed column gas chromatography

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight: The range of actual body weights for females on GD 0 was 2470 to 4460 g
- Housing: Inseminated females were individually housed in stainless steel cages with mesh flooring
- Diet: Certified rabbit chow, ad libitum
- Water: Filtered water, ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.6°C
- Humidity (%): 54.1% (range of 26.8 to 81.9%)
- Photoperiod (hrs dark / hrs light): Animal room lights were on from 7 to 19 hr for females and from 7 to 21 hr for males

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Solutions of the test substance were created in deionized/distilled water.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Dosing formulations were homogenous and stable for at least 3 weeks. Predosing and postdosing formulations were 93.0-107.0 and 92.6-109.0% of theoretical, respectively.

Details on mating procedure:

To induce ovulation, females received an intravenous injection of Pregnyl (0.1 mL/kg) immediately prior to insemination. The day of insemination was designated as Gestational Day (GD) 0. Females were assigned to dose groups (23 -24 per group) by stratified randomization on GD 0 so body weights did not differ among groups within any replicate. The study was performed in two replicates (11-12 inseminated females per dose per replicate) with two consecutive breeding days in each replicate. There last breeding date for the first replicate and the first breeding date for the second replicate were 5 weeks apart.

Duration of treatment / exposure:

gestation day 6 to 19

Frequency of treatment:

daily

Duration of test:

until gestation day 30

Dose / conc.:

100 mg/kg bw/day

Dose / conc.:

500 mg/kg bw/day

Dose / conc.:

1 000 mg/kg bw/day

Dose / conc.:

2 000 mg/kg bw/day

No. of animals per sex per dose:

23-24 females

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: The doses chosen were based on preliminary studies with nonpregnant rabbits and information from rodents which indicated developmental effects at much lower doses than maternal effects.

Maternal examinations:

Inseminated females were weighed on GD 0, 6-19, 25, and 30. Females were observed and maternal water consumption was measured daily throughout gestation GD 0-30. All surviving inseminated females were killed at scheduled necropsy on GD 30 by iv injection of a euthanasia solution into the marginal ear vein. The maternal liver, kidneys and intact uterus were weighed and corpora lutea counted. Uteri which presented no visible implantation sites were stained with ammonium sulfide (10%) to detect very early resorptions. Maternal kidneys were bisected and fixed in 10% neutral buffered formalin. Kidneys from 10 randomly selected does from the control through the 1000 mg/kg/day groups and all the kidneys from the 2000 mg/kg/day group as well as kidneys from all does which died during study were sectioned, stained with haematoxylin/eosin and evaluated histologically. The sections were also examined under polarized light for oxalate crystals.

Fetal examinations:

Live foetuses were dissected from the uterus and euthanized. They were weighed, examined for external morphological abnormalities including cleft palate and dissected for visceral examination and determination of sex by a fresh tissue dissection technique. Half of the foetuses were decapitated after dissection: the heads were fixed in Bouin's solution and then examined by a freehand sectioning technique. All foetal carcasses were skinned, cleared, stained with Alcian blue/alizarin red S. and examined for skeletal malformations and variations.

Statistics:

Analyses were performed using the doe or the litter as the experimental unit. General Linear Trend Models procedures were applied for the analysis of variance (ANOVA) of maternal and foetal parameters. Prior to GLM analysis, an arcsine-square root transformation was performed on all litter-derived percentage data and Bartlett's test for homogeneity of variance was performed on all data to be analysed by ANOVA.

Clinical signs:

no effects observed

Mortality:

mortality observed, treatment-related

Description (incidence):

Maternal toxicity was observed at 2000 mg/kg/day, expressed as 42.1% mortality (8 of 17 pregnant animals). The 8 does which died at 2000 mg/kg/day died on GD 9 (one doe) and 11 (two does) and on GD 13, 14, 19, 21 and 25 (one doe each).

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

no effects observed

Description (incidence and severity):

Maternal water consumption, expressed as g/animal/day or as g/kg/day was also statistically equivalent across all groups for all intervals, although water consumption appeared slightly increased for all test substance groups during the treatment period but not in a manner related to dose.

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:

effects observed, treatment-related

Description (incidence and severity):

Maternal absolute kidney weight (but not relative weight) was slightly increased at 2000 mg/kg/day to 106.3% of the control value for the right kidney (left kidney value was 107.6% of control).

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histologic evaluation of maternal kidneys revealed treatment-related renal lesions only at 2000 mg/kg/day. The lesions were limited to the cortical renal tubules and included intraluminal crystals (appearance consistent with oxalate), epithelial necrosis, and tubular dilatation and degeneration. The most severe findings, crystals (designated "marked") and necrosis, were observed in the does which died on study, but the renal tubular necrosis observed in these animals was not a postmortem event. The cause of death in these animals was determined to be renal failure.

Histopathological findings: neoplastic:

not examined

Number of abortions:

effects observed, non-treatment-related

Description (incidence and severity):

An increase in early deliveries with three does at 2000 mg/kg bw (and one each at all other doses) was observed. One dose at 2000 mg/kg/day aborted on GD 20 (no litters were aborted at any other doses). lncreases in early deliveries and abortion are usually considered indicative of maternal stress in rabbits.

Pre- and post-implantation loss:

effects observed, non-treatment-related

Description (incidence and severity):

There was a statistically significant increase in the number of corpora lutea at 500 mg/kg/day associated, as expected, with a slight increase in the number of implantation sites/litter and a slight increase in live litter size. This finding was not observed at higher doses and is considered most likely due to biologic variation. The values at 500 mg/kg/day were well within historical control values for these parameters.

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

not examined

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

Pregnancy rate was high and equivalent across all groups from 0 - 1000 mg/kg/day (95.5, 95.7, 91.3, and 95.2%, respectively); pregnancy rate was slightly lower (8 1.8%) at 2000 mg/kg/day.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

mortality

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

External malformations:

no effects observed

Description (incidence and severity):

There were no treatment-related alterations in incidence of malformations pooled as external, visceral (including craniofacial), or skeletal, or as total malformations or variations. Examination of foetal malformations and variations by individual findings also indicated no findings which were treatment- or dose-related and none which appeared predominantly or exclusively at higher doses.

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects observed at highest dose

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

NOAEL (maternal): 1000 mg/kg/day
NOAEL (foetus) 2000 mg/kg/day

Executive summary:

Artificially inseminated New Zealand white (NZW) rabbits were administered the test substance by gavage on Gestational Days (GD) 6 through 19 at doses of 0, 100, 500, 1000, or 2000 mg/kg/day, with 23-24 inseminated animals per group. Clinical signs were recorded and water consumption was measured daily; does were weighed on GD 0, 6-19, 25, and 30. At necropsy (GD 30), maternal liver, kidney, and gravid uterine weights were recorded. Histopathologic examination was performed on kidneys from 10 does/dose and for all unscheduled deaths. Ovarian corpora lutea were counted and uterine implantation sites (total sites, resorptions, dead and live fetuses) were recorded. All live fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations and variations. The test substance resulted in profound maternal toxicity at 2000 mg/kg/day (42% mortality; three early deliveries and one spontaneous abortion) associated with renal pathology and unaccompanied by any other indicators of maternal toxicity. Renal lesions at 2000 mg/kg/day involved the cortical renal tubules and included intraluminal oxalate crystals, epithelial necrosis, and tubular dilatation and degeneration. No dose-related maternal toxicity occurred at ≤1000 mg/kg/day. There was no indication of developmental toxicity at any dose tested, including no effects on pre- or post-implantation loss, number of foetuses, foetal body weight, or sex ratio (% male fetuses) per litter, and no evidence of teratogenicity. The "no observable adverse effect level" (NOAEL) for maternal toxicity was therefore 1000 mg/kg/day and the NOAEL for developmental toxicity was at least 2000 mg/kg/day in this study.

Reference 4

Endpoint:

developmental 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

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 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Long-Evans

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Blue Spruce Farms in Altamont, NY
- Weight at study initiation: 200-300 g

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Freshly prepared

VEHICLE
- Concentration in vehicle: 35.30, 21.18, or 3.53% w/v

Analytical verification of doses or concentrations:

no

Details on mating procedure:

- Impregnation procedure: cohoused
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

Days 6 to 15 of gestation

Frequency of treatment:

Daily

Duration of test:

Day 20 of pregnancy

Dose / conc.:

706 mg/kg bw/day (actual dose received)

Dose / conc.:

4 236 mg/kg bw/day (actual dose received)

Dose / conc.:

7 060 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

10 females/dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: exposure levels chosen as fractional doses (24, 14.4, and 2.4%) of LD50 value, similar to previous studies with other alcohols

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: No
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes (visual inspection of diet remaining in
calibrated metal feed cups)
WATER CONSUMPTION AND COMPOUND INTAKE: No data
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterine weight

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes: [all per litter ]
- Soft tissue examinations: Yes: [all per litter ]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: No

Statistics:

All data generated in the course of the study were entered, archived, and statistically analyzed on an IBM personal computer (IBM PC-XT). Statistical analyses of the data were performed using an interactive, disc-based software package (Crunch Interactive software, version 83.1, Crunch Software, Inc.), using the litter as the experimental unit. The parametric analysis of variance and Newman-Keuls posthoc analyses were used to compare maternal bodyweights, uterine weights, litter weights, pup weights, crown-rump lengths, corpora lutea, implantations, percent of males per litter, intrauterine deaths per litter, malformed pups per litter, and pup bodyweights by contiguity classification on an absolute and relative (percent of control) basis. Contigency table analysis (Chi-square and Fisher exact test) were applied to litters bearing malformed pups. Linear regression analysis of butanediol dose against pup bodyweight was performed.

Details on maternal toxic effects:

Signs of mild maternal narcosis (lethargy, decreased response to light cage tap) were noted in rats at the 2 highest dose levels within 1 hour of dosing. All animals appeared normal within 8 hours. Feed consumption, total gestation weight gains, and maternal weight gains were similar for all groups.

Dose descriptor:

NOAEL

Effect level:

7 060 mg/kg bw/day (actual dose received)

Basis for effect level:

clinical signs

Abnormalities:

no effects observed

Details on embryotoxic / teratogenic effects:

Runting (defined as a pup weighing <2.7 g) occurred in 6 of 95 pups at 7060 mg/kg (no control pups were runted). Sternebral variations (missing, incomplete, or incompletely calcified) were noted in 15 of 95 pups at 7060 mg/kg as compared to 7 of 112 control pups. These changes were considered to reflect the birthweight reductions and are not indicative of a teratogenic effect.

Dose descriptor:

NOAEL

Effect level:

7 060 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

fetal/pup body weight changes

other: Runting pup weighing <2.7 g) occurred in 6/95 pups at highest dose (none in controls). Sternebral variations (missing, incomplete, incompletely calcified) in 15/95 pups of highest dose (7/112 control) due to reduced weights and not teratogenic effect.

Abnormalities:

effects observed, treatment-related

Localisation:

skeletal: sternum

Description (incidence and severity):

Sternebral variations (missing, incomplete, or incompletely calcified) were noted in 15 of 95 pups of the highest dose, compared to 7 of 112 control pups considered to reflect reduction in birthweight and not indicative of teratogenic effect

Developmental effects observed:

no

Conclusions:

The test substance was not teratogenic. Fetotoxicity was evidenced as dose-dependent decrease in foetal weight.

Executive summary:

The embryotoxic of high doses of the test substance were evaluated in pregnant Long-Evans rats during the critical period of organogenesis. Rats were exposed to butanediol via gavage at doses of 706, 4236, and 7060 mg/kg/day. Maternal sedation was observed at 4236 and 7060 mg/kg, but feed consumption and maternal body weight were unaffected. Runting (defined as a pup weighing <2.7 g) occurred in 6 of 95 pups at 7060 mg/kg (no control pups were runted). Sternebral variations (missing, incomplete, or incompletely calcified) were noted in 15 of 95 pups at 7060 mg/kg as compared to 7 of 112 control pups. These changes were considered to reflect the birthweight reductions and are not indicative of a teratogenic effect.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Additional information

Female Sprague-Dawley rats were exposed to the test substance in accordance with OECD guideline 414 at doses up to 1000 mg/kg/day on gestation days 6-15. No maternal or foetal effects were observed at 1000 mg/kg, the highest concentration tested. The test substance was not uniquely toxic to the developing foetus at any concentration tested.

 

Since data for only one species (rat) were available for the target substance, additional data for structurally similar substances (1,2-ethanediol, 1,3-butanediol, and 1,4-butanediol) were used as read across to fulfil the data gap (second species developmental toxicity requirement). The underlying hypothesis supporting read-across is based on structural similarity of the target and source substances. The only difference between target and source molecules is the length of the carbon backbone and in one case the position of the second hydroxyl group. The target and source substances also have similar toxicokinetic properties. Additional documentation, provided within the IUCLID Assessment Reports section, supports the read-across approach.

 

Rats were exposed to 1,3-butanediol via gavage at doses of 706, 4236 or 7060 mg/kg/day from days 6 to 15 of gestation. Maternal toxicity was limited to narcosis ≥4236 mg/kg/day. Foetal effects were limited to a reduction in foetal weight for a group of specific male offspring only at 7060 mg/kg/day. The intrauterine position was seen as a factor in effects on male pups only. The affected offspring also showed anomalies of skeletal development, which were considered to be due to the reductions in weight and not indicative of a teratogenic effect.

 

Mice were exposed to 1,4-butanediol via gavage doses of 100, 300 and 600 mg/kg/day from days 6-15 of gestation. Maternal toxicity was observed at ≥300 mg/kg/ day. At the same dose levels there was evidence of reduced foetal weight only with no obvious foetal anomalies. The NOAEL for adults and developmental effects was 100 mg/kg/day.

 

Although 1,2-ethanediol has been evaluated for prenatal developmental toxicity in multiple species (rat, mouse, rabbit), it was determined in the REACH registration for this substance (https://echa.europa.eu/registration-dossier/-/registered-dossier/15973/7/9/1) that rabbits are the most appropriate species for determining developmental effects. A prenatal developmental toxicity study with 1,2-ethanediol in rabbits via oral gavage at dose levels of 100, 500, 1000 or 2000 mg/kg/day dosed on days 6 to 19 of gestation resulted in profound mortality at 2000 mg/kg/day as a consequence of renal lesions, but with no obvious developmental effects on offspring and a NOAEL was set at 2000 mg/kg for developmental toxicity.

Toxicity to reproduction: other studies

Description of key information

No effects observed in reproductive organs in a 90-day rat study.

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction: other studies

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Reliability assigned by ACC HPV Document

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: OECD 408 and EPA TSCA 798.2650

GLP compliance:

yes

Species:

rat

Strain:

other: Crl: CD(SD)BR

Sex:

male

Route of administration:

oral: gavage

Vehicle:

other: deionized water

Duration of treatment / exposure:

91-92 days

Frequency of treatment:

Daily

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

10 sex/group

Control animals:

yes, concurrent vehicle

Details on study design:

General methods for the standard repeated dose methods can be found in Section 7.5.1.

Sperm parameters (parental animals)
Spermatogenic endpoints were evaluated for all males at termination. This included a motility/viability assessment, a morphology assessment and the enumeration of epididymal and testicular sperm numbers and sperm production rate. Immediately following euthanization, the right epididymis of each male was excised and weighed separately. An incision was made in the distal region of the cauda epididymis, which was removed and placed in Dulbecco's phosphate buffered saline (PBS). A sample of the diluted sperm was then loaded into a 100 μm cannula for determination of motility. Anything that came into contact with the sperm was maintained at approximately 37ºC as to not adversely affect motility. Motility determinations were performed under constant temperature (37ºC) using the Hamilton-Throne HTM-IVOS Cersion 10 computer-assisted sperm analysis (CASA) system. At least 200 motile and nonmotile spermatozoa/animal were analyzed.

A sample of sperm for morphology assessment was obtained from the right cauda epididymis of each male. Sperm morphology was evaluated using a modification of the wet-mount technique. Abnormal forms of sperm (double heads, double tails, micro- or megacephalic, etc) were recorded from a differential count of 200 spermatozoa/animal.

The left testis and epididymis from each male were weighed, frozen, homogenized and evaluated for sperm production rate using the Hamilton-Thorne CASA system.

Statistics:

All data analyses were conducted using two-tailed tests, p < 0.01 and p < 0.05, comparing the treated groups to the control group. Standard deviations were calculated for all means. Epididymal and testicular sperm numbers and sperm production rates were subjected to a one-way analysis of variance, followed by Dunnett's test. The percentage of motile spermatozoa and the percentage of sperm with normal morphology were analyzed by the Kruskal-Wallis test. Statistical analysis was not performed if the number of animals was 2 or less. All statistical tests were performed by a computer with appropriate programming.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Sex:

male

Remarks on result:

other: There were no treatment-related effects on spermatogenic endpoints (mean testicular and epididymal sperm numbers, sperm production rate and sperm motility and morphology) at any dose level.

No effects on reproductive organs (organ weight or histopathology) were observed in the study. There were no treatment-related effects on spermatogenic endpoints (mean testicular and epididymal sperm numbers, sperm production rate and sperm motility and morphology) at any dose level.

Conclusions:

There were no treatment-related effects on spermatogenic endpoints (mean testicular and epididymal sperm numbers, sperm production rate and sperm motility and morphology) at 1000 mg/kg (highest dose tested).

Executive summary:

Crl:CD (SD) BR rats (10/sex/group) were administered 1,3-propanediol by oral gavage daily for 91 or 92 days at concentrations of 100, 300 and 1000 mg/kg/day. A concurrent control group (10/sex) was administered the vehicle, deionized water. Spermatogenic endpoints were evaluated for all males at termination. This included a motility/viability assessment, a morphology assessment and the enumeration and epididymal and testicular sperm numbers and sperm production rate.

 

No effects on reproductive organs (organ weight or histopathology) were observed in the study. There were no treatment-related effects on spermatogenic endpoints (mean testicular and epididymal sperm numbers, sperm production rate and sperm motility and morphology) at any dose level. The male reproductive NOEL of orally administered 1,3-propanediol under the conditions of the study was determined to be 1000 mg/kg/day.

Justification for classification or non-classification

The test substance is predicted not to adversely affect reproductive function and was not uniquely toxic to the developing fetus. The substance does not need to be classified for reproductive toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.