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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:
weight of evidence
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 BK, Brightwell WS, Khan A, Krieg Jr EF and Hoberman AM
Year:
1989
Bibliographic source:
J Am Coll Toxicol 8(2): 405-410
Reference Type:
secondary source
Title:
Developmental toxicology of industrial alcohols: a summary of 13 alcohols administered by inhalation to rats
Author:
Nelson KB et al.
Year:
1996
Bibliographic source:
Intl. Journal of Occupational Medicine, Immunology, and Toxicology, Vol. S, No. 1
Reference Type:
secondary source
Title:
Developmental toxicology of industrial alcohols: a summary of 13 alcohols administered by inhalation to rats
Author:
Nelson BK et al.
Year:
1990
Bibliographic source:
Toxicology and Industrial Health, Vol. 6, No. 3/4, 1990
Reference Type:
secondary source
Title:
ICH GUIDELINE - RESIDUAL SOLVENTS
Author:
Connelly JC et al.
Year:
1997
Bibliographic source:
PHARMEUROPA Vol. 9, No 1 - Supplement, April 1997
Reference Type:
secondary source
Title:
No information
Author:
RIFM
Year:
2009
Bibliographic source:
RIFM database

Materials and methods

Principles of method if other than guideline:
Developmental study, where rats were exposed on gestation days 1-19
GLP compliance:
no
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Analytical purity: >= 99%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, MI, USA
- Weight at study initiation: 200 - 300 g
- Housing: in standard metal cages equipped with automatic water dispensers
- Diet (e.g. ad libitum): NIH-07 lab chow (Ziegler Bros., Garden, MA); ad libitum
- Water (e.g. ad libitum): tap water, ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 40 - 60
- Photoperiod (hrs dark / hrs light): 12 / 12

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: Hinners-type chamber
- Method of holding animals in test chamber: in stainless steel wire mesh cages within the exposure chambers
- System of generating particulates/aerosols: A constant flow of test substance was mixed with a known volume of heated compressed air, resulting in instantaneous vaporization of the alcohol. This vapor-air mixture was introduced into the mainstream of the chamber airflow upstream from an orifice, and the resulting turbulence produced uniform mixing of the test chemical throughout the exposure chamber
- Temperature, humidity, pressure in air chamber: temperature of 25 ± 2°C; relative humidity of 50 ± 15%
- Air flow rate: ca. 0.5 m3/minute


TEST ATMOSPHERE
- Brief description of analytical method used: using a Miran 1A infrared-Analyzer at every hour
- Samples taken from breathing zone: no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Charcoal tube samples were drawn 2 days/week and analyzed by gas chromatography with partial verification of these methods using spiked samples of known concentration.
Means from the continuous monitoring were equal to the target value of 14 mg/L, with standard deviations not exceeding 5% of the means. Concentrations from the secondary monitoring method (gas chromatograph analysis of samples captured on charcoal tubes) were frequently 10-20% lower than the means from the primary method. However, results from spiked samples were often similarly below the concentrations supplied. Consequently, the figures from the primary monitoring method (infrared analyzer) are cited.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: no data
- Length of cohabitation: no data
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
days 1 - 19 of gestation
Frequency of treatment:
7 h/day
Duration of test:
20 d
Doses / concentrations
Remarks:
Doses / Concentrations:
14 mg/L
Basis:
nominal conc.
highest concentration technically achievable
No. of animals per sex per dose:
15
Control animals:
yes, sham-exposed

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: No data



DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: weighed daily for the first week and weekly thereafter


FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No


WATER CONSUMPTION: Yes
- Time schedule for examinations: on gestation days 7, 14, 20


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: uterus with ovaries
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- 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: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
Data were analyzed using multivariate analysis of variance (MANOVA) and analysis of variance (ANOVA); p< 0.05 was accepted as statistically significant. Three separate analyses were performed using exposure group as the independent variable. For the litter data (numbers of corpora lutea, resorptions, females per litter and males per litter, and weight of females per litter and of males per litter), a one-way ANOVA/ANOVA design was used. If a significant MANOVA was observed, individual ANOVAs were performed, and if these were significant, Bonferroni corrections were made comparing the individual exposure group with controls. A second analysis, for the weight data, used a litter per exposure group X day ANOVA. A third analysis, for the feed and water consumption data, used a litter per exposure group X week MANOVA/ANOVA design. For the ANOVAs, the probabilities of all within-litter main effects and interactions were corrected with the Greenhouse-Geisser estimate of Box's epsilon.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Comparing to the control group maternal body weights were decreased slightly, but this difference was not statistically significant. Food consumption was decreased, but water consumption unchanged.

Effect levels (maternal animals)

Dose descriptor:
NOAEC
Effect level:
14 mg/L air
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
Number of corpea lutea, resorptions, gender ratio and fetal weights were not affected by treatment.
Small, but nonsignificant, reversible delays in ossification of caudal vertebrae, sternum, metacarpals and hindpaw phalanges were reported.
No malformations were observed.

Effect levels (fetuses)

Dose descriptor:
NOAEC
Effect level:
>= 14 mg/L air
Basis for effect level:
other: developmental toxicity: no adverse effects observed

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Results:

1-Pentanol Control
Mean maternal weight (g)
day 0 260 ± 22 243 ± 25
day 7 297 ± 21 262 ± 24
day 14 291 ± 23 291 ± 26
day 20 348 ± 25 354 ± 32
overall gain 88 111
Mean feed consumption (g)
week 1 92 ± 14 108 ± 14
week 2 110 ± 10 124 ± 12
week 3 99 ± 12 118 ± 10
overall mean 100 ± 14 117 ± 13
Mean water intake (g)
week 1 222 ± 33 204 ± 46
week 2 223 ± 43 276 ± 93
week 3 288 ± 45 265 ± 123
overall mean 244 ± 51 248 ± 96
Mean corpora lutea/litter 13 ± 3 14 ± 4
Mean resorptions/litter 0.2 0.4
Mean no. females /litter 7 ± 1 8 ± 2
Mean no. males /litter 5 ± 2 7 ± 2
Mean fetal weight (g)
males 3.11 ± 0.31 3.19 ± 0.2
females 3.32 ± 0.26 3.28 ± 0.27

Applicant's summary and conclusion