Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Peer reviewed publication of a study conducted following a method similar to OECD guideline 413. Study predates GLP.

Data source

Reference
Reference Type:
publication
Title:
The toxicity of allyl alcohol.
Author:
Dunlap, M.K., Kodama, J.K., wellington, J.S., Anderson, H.H., Hine, C.H.
Year:
1958
Bibliographic source:
AMA Archives of Industrial Health. 18:303-311

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Allyl alcohol
EC Number:
203-470-7
EC Name:
Allyl alcohol
Cas Number:
107-18-6
Molecular formula:
C3H6O
IUPAC Name:
prop-2-en-1-ol
Details on test material:
Allyl alcohol was 98.5% pure and was provided by the Shell Chemical Company. (Impurities are diallyl ether and water).

Test animals

Species:
rat
Strain:
Long-Evans
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Housing: Rats were housed in groups of two.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: No data
Details on inhalation exposure:
Rats were exposed to the test substance allyl alcohol in 200 litre capacity steel chambers and the desired concentrations of vapour produced with a constant metering device. The air flow was set at 10.9 to 21.1 litres per minute (three to six changes per hour). The temperature of the exposed room was maintained at 20 to 25 C.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Atmospheric samples drawn into water, reacted with bromine in acetic acid and titrated (analyses conducted by the Analytical Chemistry department, Shell Development company, Emeryville, Calif.) See table 2 in remarks on results section for the results of the analysis).
Duration of treatment / exposure:
12 weeks.
Frequency of treatment:
7 hours a day, for 5 days a week, for 12 weeks (but exposures limited by mortality to 10 at 150 ppm, 55 at 100 ppm)
Doses / concentrations
Remarks:
Doses / Concentrations:
1, 2, 5, 20, 40, 60, 100, 150 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
10 male rats/ dose
Control animals:
yes, concurrent no treatment
Details on study design:
Three experiments were conducted. Control groups were exposed to uncontaminated air (without test substance). The initial experiment, doses of 1, 2, 5 and 20 ppm did not produce any signs of gross toxicity and so a second experiment using doses of 40 and 60 ppm were used. A third experiment was conducted (using doses of 100 and 150 ppm).

Examinations

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

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly


Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
See details on results below
Mortality:
mortality observed, treatment-related
Description (incidence):
See details on results below
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
See details on results below
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
See details on results below
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
See details on results below
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
See details on results below
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
- Mortality: Four rats from the 150 ppm group died during the first exposure, a further 2 died the following morning and 2 died during the second exposure. The remaining 2 rats from the 150 ppm group died by the 10th exposure (end of the second week). There were 6 deaths in animals exposed to 100 ppm after 46 days and 1 death following 4 days exposure to 60 ppm allyl alcohol.
-Clinical signs: Clinical signs in the 150 ppm group included gasping, severe depression, nasal discharge, eye irritation and corneal opacity. Less intense clinical signs were present in animals exposed to 40-100 ppm. Clinical signs were absent in animals exposed to 20 ppm and below.

BODY WEIGHT AND WEIGHT GAIN
Mean percentage body weight gain was statistically significantly lower in animals exposed to 20 ppm (see table 1).

ORGAN WEIGHTS
Relative kidney weights increased by 8-10% in animals exposed to 40 ppm or 60 ppm allyl alcohol vapour for 12 weeks. Relative lung weight was increased after exposure to 40 ppm allyl alcohol vapour for 12 weeks. Relative liver weights for treated animals were indistinguishable from those of the controls. (see table 1).

GROSS PATHOLOGY
Livers from rats in the 150 ppm allyl alcohol group appeared haemorrhagic and lungs were pale and spotted. The kidneys appeared normal.

HISTOPATHOLOGY: NON-NEOPLASTIC
At the 150 ppm dose group microscopic examination revealed slight congestion of the lungs and liver. At the 100, 60 and 40 ppm groups, lesions and microscopic finding were similar to that of the 150 ppm dose group but less intense.

Effect levels

open allclose all
Dose descriptor:
NOAEC
Effect level:
20 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Limited reduction of bodyweight gain seen at this level: statistically significant but of uncertain biological significance
Dose descriptor:
LOAEL
Effect level:
40 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Increased lung weight is combined with clear retardation of weight gain at this level

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1. Mean bodyweight gains and organ/body weight ratios.

      Organ / Body weight ratios, %
Group PPM Mean % weight gain Liver Kidney Lung Mortality ratio
1 0 134 +/-29 3.74 +/-0.25 0.724 +/-0.06 - 0/10
1 133 +/-5.6 3.61 +/-0.2 0.706 +/-0.04 - 0/10
5 126 +/-17 3.52 +/-0.3 0.765 +/-0.06 - 0/10
20 110 +/-23* 3.61 +/-0.3 0.715 +/-0.08 - 0/10
2 0 128 +/-43 3.26 +/-0.3 0.582 +/-0.05 0.410 +/-0.1 0/10
40 90 +/-24* 3.19 +/-0.4 0.629 +/-0.03 0.435 +/-0.2* 0/10
60 75 +/-32*  3.08 +/-0.2 0.043 +/-0.04* 0.531 +/-0.2 1/10
3 0 135 +/-8 - - - 0/10
100 75 +/-4* - - - 6/10
150 - - - - 10/10

Table 2. Vapour analyses (higher test concentrations).

Nominal concentration Number of readings Mean value Standard deviation
40 24 40.7 3.24
60 24 61.1 2.37
100 22 103.2 8.68
150 14 166.7 17.66

Applicant's summary and conclusion

Conclusions:
In this study the NOAEL and LOAEL for repeated dose toxicity via the inhalatory route in rats were 20 ppm (47.5 mg/m3) and 40 ppm (95.1 mg/m3) respectively.
Executive summary:

In a subchronic inhalation toxicity study allyl alcohol was administered to 10 male rats (Long-Evans strain) per concentration group, by whole body exposure, at concentrations of 0, 1, 5, 20, 40, 60, 100 and 150 ppm for 7 hours per day, 5 days/week over 12 weeks. Treatment-related clinical signs were observed, beginning at 40 ppm, with treatment-related mortality observed at 60 ppm or higher.

 

The LOAEL was 40ppm, based on increased lung weight and clear retardation of weight gain.  The NOAEL is 20 ppm .