Propane-1,3-diol

Developmental toxicity / teratogenicity

Administrative data

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.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1992

Report date:

1992

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Propane-1,3-diol

EC Number:

207-997-3

EC Name:

Propane-1,3-diol

Cas Number:

504-63-2

Molecular formula:

C3H8O2

IUPAC Name:

propane-1,3-diol

Details on test material:

1,3-Propanediol, Polymer Grade (CAS 504-63-2) - abbreviated to '1,3-Propanediol' in this report.

Physical State: Liquid, colourless, odourless.
Storage Conditions: In a closed container.
Stability: Stable until June 1997.
Purity: 99.8%

Test animals

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

Administration / exposure

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.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

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

Doses / concentrations 2

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.

Examinations

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).

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

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.

Effect levels (maternal animals)

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

Results (fetuses)

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

Effect levels (fetuses)

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 abnormalities

Abnormalities:

no effects observed

Overall developmental toxicity

Developmental effects observed:

no

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.