Registration Dossier

Toxicological information

Repeated dose toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
repeated dose toxicity: inhalation, other
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1990
Report Date:
1990

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD TG 414
Principles of method if other than guideline:
Exposure to max. attainable vapor concentration of 1-octanol, 1-nonanol, and 1-decanol
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:

- Analytical purity: reagent-grade chemicals were purchased from commercial sources
- Lot/batch No.:
1-octanol and 1-decanol: both lot No. A15B; Eastman Kodak Co. Rochester, NY
1-nonanol: lot No. 7328 from EM Science, Cherry Hill, NJ:
- Other: samples of each chemical were analyzed for purity by gas chromatography using modifications of the NIOSH analytical methods 1401 and 1402

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 0.5 m³ Hinners-type chamber
- Method of holding animals in test chamber: animals were placed in stainless steel wire mesh cages
- Source and rate of air: compressed air
- Method of conditioning air: vapor generation equipment, housed in a sealed glove box
- System of generating particulates/aerosols: a constant flow of alcohol was mixed with a known volume of heated compressed air. Th eresulting vapor/air mixture was introduced into the chamber airflow system upstream from the orifice plate. The resulting turbulence downstream from the orifice plate produced a uniform mixing of the test chemcial throughout the exposure chamber.
- Temperature in air chamber: 70-80°F (21-27°C)
- Air flow rate: no data
- Air change rate: no data
- Method of particle size determination: no data
- Treatment of exhaust air: no data


TEST ATMOSPHERE
- Brief description of analytical method used:
(1) infrared analyzer (Miran 1A) continously recorded concentrations near the rats breathing zone
() charcoal tube samples were collected 2 days per week and analyzed using gas chromatography. Spiked samples were also used to evaluate the accuracy of the GC results.
- Samples taken from breathing zone: yes


VEHICLE : no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
(1) infrared analyzer (Miran 1A) continously recorded concentrations near the rats breathing zone
() charcoal tube samples were collected 2 days per week and analyzed using gas chromatography. Spiked samples were also used to evaluate the accuracy of the GC results.
Duration of treatment / exposure:
gestation days 1-19
6 h/day (1-decanol)
7 h/day (1-octanol and 1-nonanol)
Frequency of treatment:
7/week
Doses / concentrations
Remarks:
Doses / Concentrations:
400 (octanol), 150 (nonanol), 100 (decanol) mg/m³
Basis:
analytical conc.
No. of animals per sex per dose:
15
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: maximum concentrations that could be generated as a vapor at an average chamber temperature of 70-80°F. Generation of higher exposure concentrations resulted in aerosol production inside the inhalation chamber.

- Rationale for animal assignment: random
Positive control:
Yes; in total 13 alcohols with carbon chain skeltons of C1- to C10 were tested.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily



DETAILED CLINICAL OBSERVATIONS: No data



BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: group means reported


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No


WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly


OPHTHALMOSCOPIC EXAMINATION: No data


HAEMATOLOGY: No data


CLINICAL CHEMISTRY: No data



URINALYSIS: No data


NEUROBEHAVIOURAL EXAMINATION: No data


Statistics:
One-way multivariate analysis of variance/ analysis of variance (MANOVA/ANOVA): number of corpora lutea, resorptions, male and female pups, mean male and female pup weight.
ANOVA: maternal weights, feed and water intake data,
ANOVA: fetal incidence data; also Variance Test for homogeneity of the binominal distribution; Kuskal-Wallis test was used if nonparametric analysis was more appropriate.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Vapour pressure and maximum attainable vapour concentrations of aliphatic alcohols decrease rapidly with increasing chain length. Therefore, toxic atmospheres cannot be generated with alcohols with carbon chain lengths of 5 and more. This implicates for isononanol (and other long chain alcohols):
(1) acute inhalation toxicity testing may scientifically be unjustified, due to low attainable vapour concentrations
(2) repeated inhalation toxicity testing: as above
(3) isononanol: repeated inhalation toxicity testing scientifically unjustified
Executive summary:

The effects of repeated inhalation exposure to 1-octanol, 1-nonanol, and 1-decanol was tested in female rats (15 per group) at the maximum attainable vapour concentrations of 400, 150, and 100 mg/m³, respectively. The rats were exposed during days 1 -19 of gestation for 6h (decanol) or 7 h/day (octanol and nonanol). Dams were sacrificed on gestation day 20, and dams and pups were examined for signs of maternal toxicity, toxicity to reproduction, and developmental toxicity.

Results:

(1) the maximum attainable vapour concentrations at inhalation chamber temperatures between 21 -27°C were 400, 150, and 100 mg/m³ for octanol, nonanol, and decanol, respectively. Concentrations are bases on analytical data.

(2) No treatment related effects were seen.

dams:

- maternal toxicity: no signs of toxicity, no mortality, maternal body weight, mean food and mean water consumption unchanged compared to sham-treated controls

- toxicity to reproduction: mean numbers of corpora lutea/litter, resorptions/litter, male or female pups/litter all unchanged compared to sham-treated controls

pups

- developmental toxicity: male and female pup weights unchanged compared to controls

- teratogenicity: frequency of skeletal or visceral malformations unchanged

(Nelson et al., Tox Ind Health 6:373 -387, 1990; Nelson et al., J Am Coll Tox 9:93 -97, 1990 (T04167 and T04176)

Conclusions:

Maximum attainable vapour concentrations of aliphatic alcohols decrease rapidly with increasing chain length. Max. inhalation concentration of 1-nonanol was 150 mg/m³. No maternal toxicity, nor toxicity to reproduction, was noted in dams exposed during gestation days 1-19 (7h/day). No developmental toxicity or teratogenicity was seen in the progeny. In total 13 alcohols were tested, with carbon chain lengths ranging from C1 to C10. Maternal toxicity was only seen with C1 to C4 alcohols at ≥5000 ppm, but not with higher alcohols, probably due to the rapid decline of the vapour pressure with increasing chain length.

This implicates for isononanol (and other long chain alcohols):

(1) acute inhalation toxicity testing may scientifically be unjustified, due to low attainable vapour concentrations

(2) repeated inhalation toxicity testing: as above

Overall, repeated inhalation toxicity testing of isononanol is scientifically unjustified