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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
not stated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

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
Reference Type:
publication
Title:
Aliphatic alcohols (Monohydric alcohols)
Author:
Bevan C
Year:
2001
Bibliographic source:
In: Patty's Toxicology. John Wiley & Sons - online.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Hexanol administered by inhalation to pregnant rats from day 1 to day 19 of gestation and uterine contents examined on day 20
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Hexan-1-ol
EC Number:
203-852-3
EC Name:
Hexan-1-ol
Cas Number:
111-27-3
Molecular formula:
C6H14O
IUPAC Name:
hexan-1-ol
Test material form:
not specified

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system 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

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
No. of animals per sex per dose:
15 pregnant females
Control animals:
yes, sham-exposed
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)

Key result
Dose descriptor:
NOAEC
Effect level:
3 500 mg/m³ air (analytical)
Based on:
test mat.
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)

open allclose all
Dose descriptor:
NOAEC
Effect level:
3 500 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEC
Effect level:
> 3 500 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: developmental toxicity

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

The actual control value for total resorptions was at the lower end of the range of values found among 11 control groups used in a series of similar studies by these authors over a 5 year period (Nelson et al 1990b). The range of resorptions in these control  groups was  0.2 -1.5 per litter (mean 0.9) further suggesting that this was not a treatment  related effect.


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.