Pentan-1-ol

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

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

Reference

Reference 1

Reference Type:

publication

Title:

Short-term toxicity of n-amyl alcohol in rats

Author:

Butterworth KR, Gaunt F, Heading CE, Grassot P and Gangolli SD

Year:

1978

Bibliographic source:

Fd Cosmet Toxicol 16: 203-207

Reference 2

Reference Type:

secondary source

Title:

1-Pentanol

Author:

Bevan C

Year:

2001

Bibliographic source:

Patty's Toxicology, Sixth Edition

Reference 3

Reference Type:

secondary source

Title:

No information

Author:

RIFM

Year:

2009

Bibliographic source:

RIFM database

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

15 animals per sex per dose, no ophthalmological examinations

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Pentan-1-ol

EC Number:

200-752-1

EC Name:

Pentan-1-ol

Cas Number:

71-41-0

Molecular formula:

C5H12O

IUPAC Name:

pentan-1-ol

Details on test material:

- Name of test material (as cited in study report): n-amyl alcohol
- Physical state: clear, colourless liquid
- Analytical purity: min 97%
- Impurities (identity and concentrations): arsenic, max 3 ppm; copper, max 50 ppm; iron, max 50 ppm; lead, max 10 ppm; total heavy metals (as lead), max 20 ppm.
- Specific gravity (20°/20°C), 0.815-0.816
- Refractive index (20°C), 1.410; mp, -78.9°C; b.p., 137.8°C

Test animals

Species:

rat

Strain:

other: ASH/CSE

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: from a specified-pathogen-free breeding colony
- Weight at study initiation: 91.8 ± 2.1
- Diet (ad libitum): Spillers' Laboratory Small Animal Diet
- Water (ad libitum): tap-water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 1
- Humidity (%): 40 - 60

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: in appropriate concentration so that all rats received a dosage of 5 ml/kg bw/day

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 w

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
50, 150, 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

15

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

BODY WEIGHT: Yes
- Time schedule for examinations: initially, then at days 1, 2 and 6 and at intervals of not more than 1 week up to thereafter (last weighing: days 91)

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

WATER CONSUMPTION: Yes
- Time schedule for examinations: food and water consumptions were measured over the 24-hour period preceding the day of weighing.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after final dose, the animals were killed by exsanguination from the abdominal aorta
- Anaesthetic used for blood collection: Barbiturate
- Animals fasted: Yes, the animals were deprived of food for 24 hour before sacrifice
- Parameters examined haemoglobin content, packed cell volume and counts of erythrocytes and leucocytes. Slides were prepared from all blood samples for the counting of reticulocytes and the different types of leucocytes, but the counts were confined to the controls and the animals on the highest level of treatment except at week 2, when leucocyte counts were also made on the 150-mg/kg groups.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after final dose, the animals were killed by exsanguination from the abdominal aorta
- Animals fasted: Yes, the animals were deprived of food for 24 hour before sacrifice
- Parameters examined: at week 13, serum was analysed for urea, glucose, total protein and albumin as well as for the activities of glutamic-oxalacetic transaminase, glutamic- pyruvic transaminase and lactic dehydrogenase.

URINALYSIS: Yes
- Time schedule for collection of urine: during week 2 and 6 and from the remaining rats during week 12.
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Yes, urine was collected over a 6-hour period of water deprivation from the rats about to be killed.
- Parameters were examined: the volumes and specific gravities of these samples were measured to determine the renal concentrating ability of the rats. In addition, the samples were examined for their appearance, number of cells and content of albumin, glucose, ketones, bile salts and blood. At week 6 and 12 the concentration test was extended to include measurements of the volume and specific gravity of urine produced in a 4-hr period commencing after 16 hr without water. In addition, the renal diluting capacity was investigated by measuring the volume and specific gravity of urine produced in the first 2 hr after a water load of 25 ml/kg.

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, at autopsy all the tissues were examined for gross abnormalities and the brain, heart, liver, spleen, kidneys, stomach, small intestine, caecum, adrenals, gonads, pituitary and thyroid were weighed.
HISTOPATHOLOGY: Yes, samples ot the above organs and of lung, lymph nodes, salivary gland, trachea, oesophagus, aortic arch, thymus, urinary bladder, colon, rectum, pancreas, uterus and skeletal muscle were preserved in 10% buffered formalin. Paraffin-wax sections of these tissues were stained with haematoxylin and eosin for microscopic examination, which was carried out on liver and kidney sections from all animals but on other types of tissue from only half of the control rats and from those given 1000 mg test substance/kg bw for 13 weeks.

Statistics:

Student's t test and the ranking test of White

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY
No abnormalities in appearance or behaviour were seen during the study.

BODY WEIGHT AND WEIGHT GAIN, FOOD CONSUMPTION AND WATER CONSUMPTION
There were no significant differences between the treated and control rats in body weight or in food and water consumption (see table 1).

HAEMATOLOGY AND CLINICAL CHEMISTRY (see table 2)
Only isolated differences from the controls were seen in the results of the haematological studies. These included a lower total leucocyte count at week 2 in the male rats given 150 or 1000 mg test substance/kg bw/day and lower haemoglobin concentrations at week 13 in the male animals given 50 or 1000 mg/kg bw/day. Also there were higher percentages of reticulocytes in the male rats given 1000 mg/kg bw/day at week 2 and in the females at week 13, as well as a slightly lower percentage of lymphocytes at week 6 in the females given 1000 mg/kg bw/day. The results of the serum analyses were similar in test and control rats.

URINALYSIS
The urine was free from bile, blood, glucuse and ketones, while the concentration of albumin was similar in all groups. At week 6 there were lower cell counts in the urine of the male rats given 150 or 1000 mg test substance/kg bw/day, the differences being statistically significant. Some statistically significant differences were also apparent in the concentration tests at week 12; the specific gravity of the samples collected at 16-20 hour from females given 1000 mg/kg bw/day was higher than the control value and the volume was lower. After the same period on test, the male rats given 50 or 1000 mg/kg bw/day produced less urine in the 6-hour period without water. No differences from the controls were found in the dilution test nor at week 2 and 6 in the concentration tests.

ORGAN WEIGHTS (see table 3)
Examination of the organ weights showed some isolated differences at week 2, but none thereafter. The stomach weights in the males and females given 1000 mg n-amyl alcohol/kg bw/day were higher than those of the controls, but the difference was confined to the male rats when the values were related to body weight. Also, a higher heart weight was found in the female rats given the top level of treatment, but this was not evident when the figure was related to body weight. Relative to body weight, the spleens from the female rats dosed with 1000 mg/kg bw/day showed a low value, as did the female kidney weights, both at this and at the 150 mg/kg bw/day level.

GROSS PATHOLOGY
At autopsy, no abnormalities were seen at any dose level

HISTOPATHOLOGY: NON-NEOPLASTIC
On histological examination, protein casts and foci of calcification were found in the kidney tubules, particularly from the male animals, but the incidences were similar in the treated animals and their corresponding controls. The incidence of fatty change and inflammatory cell infiltration in the liver was again comparable in the control and treated rats. No histological changes related to the period or level of treatment were seen in any of the organs examined.

Effect levels

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1: Mean body weights and food and water consumption values of rats given daily doses of 0 - l000 mg test substance/kg bw/day for l3 weeks

Dose level (mg/kg bw/day)	Body weight (g) at day				Mean food consumption (g/rat/day)	Mean water consumption (ml/rat/day)
	0	34	62	91
0 (males)	93	323	424	467	18.8	26.2
50	91	326	422	470	18.9	24.3
150	91	336	449	504	19.6	24.3
1000	96	316	426	479	18.0	24.3
0 (females)	91	211	256	281	14.7	20.6
50	91	211	259	286	14.9	20.5
150	89	217	268	293	15.1	21.6
1000	92	205	250	276	14.9	22.1

Table 2: Haematological values (aortic blood) for rats given daily doses of 0 -1000 mg test substance/kg bw/day

Sex and dose level (mg/kg bw/day)	Number of rats	Hb (g/100 ml)	PCV (%)	RBC (10^6/mm^3)	Retics (% of RBC)	Leucocytes
						Total (10^3/mm^3)	Differential (%)
							N	E	L		M
Week 2
0 (male)	5	12.7	41	5.40	1.4	7.1	11	1	85	3
150	5	12.7	41	5.80	-	5.5*	11	0	86	3
1000	5	13.0	42	5.15	2.3*	5.0*	12	1	85	2
0(female)	4	13.5	45	5.15	1.3	3.7	11	0	87	2
150	5	12.6	44	5.85	-	4.5	10	0	89	1
1000	5	13.0	44	5.74	1.0	4.6	11	1	86	2
Week 6
0 (male)	5	14.5	47	6.79	0.5	8.3	11	0	88	1
150	5	14.6	48	6.97	-	8.9	-	-	-	-
1000	5	14.0	46	6.76	0.4	5.6	7	0	91	2
0(female)	5	14.3	45	6.70	0.2	5.6	8	0	91	1
150	5	13.7	43	6.60	-	5.5	-	-	-	-
1000	5	14.1	44	6.76	0.1	6.6	18	1	79*	2
Week 13
0 (male)	14	14.1	45	6.90	0.6	5.6	17	1	80	2
50	15	13.4*	43	6.58	-	5.4	-	-	-	-
150	15	13.9	44	6.64	-	5.4	-	-	-	-
1000	15	13.6*	44	6.66	0.8	5.4	18	2	79	2
0(female)	13	14.0	43	6.56	0.3	4.7	10	1	87	2
50	14	13.5	43	6.51	-	4.4	-	-	-	-
150	14	13.8	43	6.45	-	4.4	-	-	-	-
1000	15	13.7	43	6.65	0.6*	3.9	12	1	85	2
Hb: haemoglobin, PCV: packet cell volume, RBC: red blood cells, Retics: reticulocytes, N: neutrophils, E: eosinophils, L: lymphocytes, M: monocytes, *: significantly different

Table 3: Mean relative organ weights of rats given daily doses of 0 -1000 mg test substance/kg bw/day for 2 or 13 weeks

Sex and dose level (mg/kg bw/day)	Number of rats	Relative organ weight (g/100 g body weight)												Terminal body weight (g)
		Brain	Heart	Liver	Spleen	Kidneys	Stomach	Small intestine	Caecum	Adrenals (mg/100g)	Gonads*	Pituitary (mg/100g)	Thyroid (mg/100g)
Week 2
0 (male)	5	1.04	0.45	3.59	0.36	0.88	0.62	4.75	0.47	24.24	1.25	3.5	8.0	164
150	5	0.99	0.47	3.68	0.38	0.90	0.70	4.89	0.49	25.42	1.21	3.5	6.9	164
1000	5	0.98	0.46	3.75	0.37	0.92	0.72*	4.47	0.49	27.87	1.28	4.0	6.7	164
0(female)	5	1.14	0.44	4.13	0.38	0.96	0.70	4.45	0.42	35.36	61.7	6.3	8.4	137
150	5	1.11	0.46	3.83	0.33	0.86*	0.64	4.14	0.43	35.84	60.9	6.1	9.2	144
1000	5	1.05	0.47	3.74	0.31*	0.85*	0.68	3.84	0.44	36.71	54.8	5.9	9.2	150
Week 13
0 (male)	15	0.42	0.31	2.68	0.17	0.64	0.41	2.02	0.22	15.66	0.83	2.9	4.7	546
50	15	0.42	0.30	2.73	0.18	0.63	0.42	2.19	0.21	15.05	0.81	2.6	4.8	561
150	15	0.40	0.30	2.72	0.19	0.61	0.41	2.21	0.23	14.76	0.80	2.7	4.4	491
1000	15	0.41	0.31	2.69	0.19	0.64	0.43	1.98	0.23	15.19	0.81	2.8	4.9	474
0(female)	15	0.66	0.34	2.49	0.25	0.63	0.53	2.52	0.29	28.10	54.9	5.2	7.0	270
50	15	0.66	0.34	2.49	0.24	0.65	0.53	2.53	0.31	29.45	53.2	5.3	6.5	268
150	15	0.63	0.35	2.49	0.25	0.64	0.53	2.59	0.29	27.74	54.7	5.1	6.6	276
1000	15	0.66	0.37	2.36	0.24	0.62	0.50	2.43	0.31	28.36	54.0	4.7	7.5	268
*mg/100 g body weight for female gonads; *: significantly different

CONCLUSION

Only isolated changes with no consistent pattern were found in the hematological studies, either with respect to dose-response, sex or time relationships. The reductions of hemoglobin concentration in the male rats at week 13 suggest a mild anemia, but this is not supported by other measurements. The packet cell volumes mean corpuscular hemoglobin concentrations and erythrocyte and reticulocyte counts were all within the normal limits and there were no variations in spleen weight. The low total white cell counts observed in the male animals after 2 week treatment (with 150 or 1000 mg/kg bw/day) were probably accidental findings for 2 reasons: 1) the corresponding female rats did not show a similar effect and 2) the differential white cell counts were very similar to those of the controls. The few variations observed in the reticulocyte counts were within the normal range for rats of this strain.

No specific gravity or volume measurements of the urine indicated any adverse effect on renal function in the treated groups. The two isolated reductions in relative kidney weights (after 2 weeks treatment) were neither consistent with absolute kidney weight measurements nor associated with any histopathological findings, or present after a more prolonged treatment.

The increased stomach weights found at week 2 in some rats given the top dose may be associated with a mild irritation since the test substance was administered by gastric intubation. In any case, the effect did not persist throughout the study.

The few other changes in organ weights were isolated, followed no consistent pattern and were considered to be unrelated to treatment.

The highest dose level tested can therefore be considered as the NOAEL under the conditions of the study.