Registration Dossier

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: Study not performed according to guideline. Only 15 fetuses were examined. Only one dose tested.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Developmental toxicology evaluation of 1-pentanol, 1-hexanol, and 2-ethyl-1-hexanol administered by inhalation to rats.
Author:
Nelson B K, Brightwell W S, Khan A, Krieg E F Jr, Hoberman A M
Year:
1989
Bibliographic source:
J. Am. Coll. Toxicol. 8(2): 405-410.
Reference Type:
publication
Title:
Developmental toxicology of industrial alcohols: A summary of 13 alcohols administered by inhalation to rats.
Author:
Nelson B K, Brightwell W S, Kreig E F
Year:
1996
Bibliographic source:
Tox. Ind. Hlth. 6(3/4): 373-387

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
no guideline followed
GLP compliance:
no
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name of test material (as cited in study report): 1-hexanol
- Substance type: no data
- Physical state: no data
- Analytical purity: >=99%
- 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

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, MI, USA
- Age at study initiation: no data
- Weight at study initiation: 200-300 g
- Fasting period before study:
- Housing: shoebox cages with cleaned heat-treated sawdust bedding
- Diet (e.g. ad libitum): NIH-07 lab chow, ad libitum except during exposure
- Water (e.g. ad libitum): tap water, ad libitum except during exposure
- Acclimation period: 1-2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +- 2
- Humidity (%): 50 +- 10
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: no data
Administration / exposure

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 0.5 m3 Hinners type chambers
- Method of holding animals in test chamber: stainless steel wire mesh cages within the exposure chambers
- Source and rate of air: constant flow of alcohol mixed with known volume of heated compressed air causing instant vapourisation; mixture introduced into mainstream of chamber airflow upstream from an orifice; resulting turbulance produced uniform mixing
- Method of conditioning air: no data
- Temperature, humidity, pressure in air chamber: 25 +- 1 deg C, 50 +- 15%, no data on pressure
- Air flow rate: 0.5 m3/minute
- Air change rate: no data
- Treatment of exhaust air: no data

TEST ATMOSPHERE
- Brief description of analytical method used: Miran 1A infrared analyser, concentrations recorded every hour; charcoal tube samples 2 days/week and analyzed by gas chromatography
- Monitored continuously

VEHICLE (if applicable)
- not applicable
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Miran 1A infrared analyser, concentrations recorded every hour; charcoal tube samples 2 days/week and analyzed by gas chromatography
Details on mating procedure:
- Sperm positive females used, no other information
Duration of treatment / exposure:
days 1-19 of gestation
Frequency of treatment:
7 hours/day
Duration of test:
20 days
Doses / concentrations
Remarks:
Doses / Concentrations:

Basis:
nominal conc.
equal to mean analytically, SD <=5% of mean
No. of animals per sex per dose:
15 pregnant females
Control animals:
yes
Details on study design:
Dose selection rationale: highest achievable concentration as a vapour at a temperature below 27 deg C (higher concentrations would have resulted in aerosol production)
- Rationale for animal assignment (if not random): "assigned without bias"

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes, no details (presumably daily) - "further, subjective observations of maternal animals did not provide evidence of toxicity"

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule: daily for the first week and weekly thereafter, means presented for days 0, 7, 14 and 20 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule: week 1, week 2, week 3 (days 7, 14 and 20 of gestation)

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule: week 1, week 3, week 3 (days 7, 14 and 20 of gestation)

POST-MORTEM EXAMINATIONS: No

OTHER:
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: No
- Number of late resorptions: No
- Other:
Total number of resorptions
Number of live foetuses
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: No
- Other:
foetal body weight and sex
Statistics:
Multivariate analysis of variance (MANOVA) and analysis of variance (ANOVA); statistical significance at p<=0.05; independent variable = exposure group; one-way MANOVA/ANOVA for litter data, with individual ANOVAs if significant MANOVA, with Bonferroni corrections for individual exposure groups if significant ANOVA; ANOVA for weight data using a litter per exposure group x day design; MANOVA/ANOVA for feed and water consumption data using a litter per exposure group x week design; for ANOVAs, Greenhouse-Geisser estimate of Box's epsilon used to correct within-litter main effects and interactions for ANOVAs
Indices:
no data
Historical control data:
resorption: up to 1.3 per litter

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No clinical signs of toxicity; no effect on maternal body weight or water intake; food intake significantly higher than controls (127 +- 12 g vs. 117 +- 13 g); no effect on number of corpora lutea (17 +- 1, treated; 14 +- 4 controls); presumably no effect on number of implantations (no data presented, but endpoint measured according to methods); slight but statistically significant increase in total resorptions (1.3/litter in treated group, 0.4/litter in controls) but the frequency was within the historical control range.

Effect levels (maternal animals)

Dose descriptor:
NOAEC
Effect level:
3 500 mg/m³ air (analytical)
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 effects on: litter size (mean, treated and control, 15), sex ratio (treated 8F,7M; controls 7F, 8M), grossly visible abnormalities, external or soft tissue abnormalities, male or female foetal weight (means, treated males 3.19 g, females 3.05g; control males 3.28 g, females 3.19 g); small, not statistically significant, effect on skeletal abnormalities - reversible delay in ossification of caudal vertebrae, sternum, metacarpals, and hindpaw phalanges (indicative of growth retardation but not accompanied by effects on foetal weight; data not presented).

Effect levels (fetuses)

Dose descriptor:
NOAEC
Effect level:
3 500 mg/m³ air (analytical)
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, an NOAEC of 3500 mg/m3 (the highest achievable concentration in the test system) was determined in the rat for maternal toxicity and developmental toxicity after administration by inhalation for 7 hours/day on gestation days 1 to 19.
Executive summary:

In a study performed with the analogue Hexanol, an NOAEC of 3500 mg/m3 (the highest achievable concentration in the test system) was determined in the rat for maternal toxicity and developmental toxicity after administration by inhalation for 7 hours/day on gestation days 1 to 19. No effects were observed in any reproductive paramaters. A NOAEL of 14000 mg/m3 was also set for Pentanol under the same experiment conditions in the same study with no effects on rat development.