Pentane-1,2-diol

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Report date:

2006

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,2 hexanediol

IUPAC Name:

1,2 hexanediol

Test animals

Species:

rat

Strain:

other: Crl:CD (SD) IGS BR

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Limited
- Housing: individually in polypropylene cages with solid floors and stainless steel grid tops
- Diet (e.g. ad libitum): pelleted diet ad libitum
- Water (e.g. ad libitum): ad libitum



ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-23°C
- Humidity (%): 40-70%
- Air changes (per hr): at least 15 air changes per hour
- Photoperiod: 12hours light / 12 hours dark

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
dose administration was adjusted for most recent bodyweight using dose volume of 5ml/kg bodyweight

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentration of SYM051841129 in the test material formulations was determined by gas
chromatography (GC) using an external standard technique.

Details on mating procedure:

no data

Duration of treatment / exposure:

Animals were dosed with the appropriate concentration between days 5 and 19 of gestation.

Duration of test:

females were killed on day 20 of gestation.

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0 mg/kg bw
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
30 mg/kg bw
Basis:
nominal conc.

Doses / concentrations 3

Remarks:

Doses / Concentrations:
100 mg/kg bw
Basis:
nominal conc.

Doses / concentrations 4

Remarks:

Doses / Concentrations:
300 mg/kg bw
Basis:
nominal conc.

No. of animals per sex per dose:

24 females per dose

Control animals:

yes

Details on study design:

- Dose selection rationale:
Dose levels of 300, 100 and 30 mg/kg bw/day were selected for use on this study based on results of preliminary oral gavage prenatal developmental toxicity study in the rat. In this preliminary study, a dose level of 500 mg/kg bw /day was associated with clear adverse clinical signs ( noisy respiration, including decreased laboured respiration and gasping in one case), that excluded this dosage level from use in this main investigation. At 1000 mg/kg repiratory distress and mortality in two cases. A high dosage of 300 mg/kg bw /day was therefore chosen in anticipation of a degree of toxicity that would not impair the assessment of embryofoetal development. Lower dosages represent approximately three-fold reductions from this high dosage.

- Rationale for animal assignment (if not random):
The females were assigned to treatrnent groups using a randomisation procedure based on stratified body weight to ensure, as far as possible, similar group mean bodyweights for each twatment group.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for mortality/morbidity

CLINICAL OBSERVATIONS: Yes
- Time schedule:
All females were observed once daily, in the morriing throughout gestation and, additionally, one
hour after dosing, throughout the dosing period, for clinical signs of toxicity.


BODY WEIGHT: Yes
- Time schedule for examinations:
All females were weighed on Days 3, 5,6, 7,8,11, 14, 17 and 20 of gestation.

FOOD CONSUMPTION : Yes
Food consumption for individual animals was recorded for discrete periods throughout the study
on Day 3 to 5, Day 5 to 8, Day 8 to 1 l (or 9 to 1 l), Day 11 to 14, Day 14 to 17 and Day 17 to 20
of gestation.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
Each animal was examined externally and internally for macroscopic abnormalities.

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: Yes:[all per litter

Statistics:

Bodyweight, bodyweight change and food consumption: Barlett's test for homogeneity of variance and one way analysis of variance, followed by Dunnet's multiple comparison test or, if unequal variances were observed, on alternative multiple comparison test.

Litter data and litter , placental and foetal weights: Krskal-Wallis non-parametric analysis of variance; and a subsequent pairwise analysis of control value against treated values.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Effect levels (maternal animals)

1

Dose descriptor:

NOEL

Effect level:

300 mg/kg bw/day (nominal)

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOEL

Effect level:

300 mg/kg bw/day (nominal)

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The daily administration of the test item during the period of organogenesis, at dose levels up to 300 mg/kg, was not associated with any adverse effect on the pregnant rat or on the developing conceptus. The "No Observed Effect Level" (NOEL) for the pregnant female and for embryofoetal survival, growth and development was therefore considered to be 300 mg/kg/day.
The "No Observed Effect Level" (NOEL) is therefore considercd to be 300 mg/kg/day.