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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (group sizes are smaller than recommended 8-10 pregnant females rather than 20).

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1997

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
group sizes are smaller than recommended; 8-10 pregnant females rather than 20
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): n-octanol
- Substance type: no data
- Physical state: no data
- Analytical purity: 99.9
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: no data
- Isomers composition: no data
- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: no data
- Other: n-octanol was freshly prepared daily

Test animals

Species:
rat
Strain:
other: Wistar outbred-strain Chbb/THOM
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Supplied by Dr K. Thomae, GmbH, Biberach, Germany.
- Age at study initiation: 68-85 days
- Weight at study initiation: 214-233 g
- Fasting period before study: no data
- Housing: DK III stainless steel wire-mesh cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): "fully air conditioned rooms"
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Doubly-distilled water containing about 0.005% Cremophor EL (as emulsifier)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Prepared daily in aqueousemulsions under rapid stirring


VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: Adjusted to give constant volume
- Amount of vehicle (if gavage): 5 ml/kg
- Lot/batch no. (if required): no data
- Purity: no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Gas chromatography
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: One to four untreated females were mated with one untreated fertile male
- Length of cohabitation: "overnight"
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
gestation days 6-15
Frequency of treatment:
daily
Duration of test:
20 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 130, 650, 975 and 1300 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
8-10 females
Control animals:
yes, concurrent vehicle
Details on study design:
no data

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: Daily


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Ovaries and uterus

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: half per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No
Statistics:
Dunnetts test for most reproductive parameters and Fischers exact test for evaluaton of conception rate and all foetal findings.
Indices:
Conception rates and pre & post implantation losses were calculated.
Historical control data:
Not presented

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
A dose-related increase in maternal toxicity with increasing severity of clinical signs (including lateral and abdominal position, unsteady gait, salivation, piloerection, nasal discharge and pneumonia) was observed in all treatment groups, compared to the controls. Two dams died in each of the groups (of ten rats) receiving the test material at 650, 975 and 1300 mg/kg bw/day, compared to no deaths in the dams receiving 130 mg n-octanol/kg bw/day or in the controls. A slight decrease in food consumption and body weight gain was observed in those female rats administered n-octanol at 650 mg/kg bw/day and above.

The number of pregnant dams per dose level was 10/10, 9/10, 8/10 and 8/10 in the dams administered the test material at 130, 650, 975, and 1300 mg/kg bw/day, respectively, compared to 9/10 in the water controls and 10/10 in the aqueous emulsifier. The number of resorptions, implantations, corpora lutea were comparable to controls (Number of resorptions (all)/dam (mean) 1.0, 1.4 (controls), and 1.2, 0.7, 0.8 and 1.3 in treated groups from low - high. Number of implantation sites/dam (mean) 14.7, 16.0 (controls), and 14.7, 15.4, 13.8 and 14.5 from treated groups low - high. Number of corpora lutea/dam (mean) 14.8, 16.3 (controls), and 15.0, 16.0, 14.9 and 14.5 in treated groups low - high.) Duration of pregnancy, and uterine and placental weights, were also comparable between treatment groups, and controls.

Effect levels (maternal animals)

Dose descriptor:
LOAEL
Effect level:
130 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No dead fetuses were observed and mean number of live foetuses/dam were unaffected by treatment ( 13.5, 14.7, 13.0 and 13.2 in treated groups receiving 130, 650, 975 or 1300 mg/kg bw/day, respectively, compared to 13.7 and 14.6 in controls). Litter size and weights were comparable in treated and control groups. Sex ratio was not reported. No treatment-related statistically significant and/or dose-related increases in the incidence of fetuses (or litters) with malformations, variations and retardations were observed, compared to controls. (Litters with malformations number 2 (22%), 3 (30%) (controls); 3 (30%), 3 (43%), 2 (25%) and 1 (17%) in treated groups low to high. Litters with variations number 8 (89%), 10 (100%) (controls); 10 (100%), 7 (100%); 7 (88%) and 5 (83%) in treated groups low to high. Litters with retardations number 8 (89%), 9 (90%) (controls);  9 (90%), 7 (100%), 8 (100%) and 5 (83%) in treated groups low to high. The authors note that "all foetal values were within the range of biological variation". A single cheiloschisis (cleft lip) and  one anophthalmy (eye loss) in the top-dose group was considered coincidental and not biologically relevant. 

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 300 mg/kg bw/day
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a reliable study, performed to OECD guideline 414, an LOAEL of 130 mg/kg bw/day (the lowest dose tested) was determined for maternal toxicity and an NOAEL of 1300 mg/kg bw/day for teratogenicity and foetotoxicity (the highest dose tested). The study was performed in compliance with GLP.