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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
reproductive toxicity, other
Remarks:
subchronic repeated dose toxicity study
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:
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 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:
1-Pentanol
Author:
Bevan C
Year:
2001
Bibliographic source:
Patty's Toxicology, Sixth Edition

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
15 animals per sex per dose, no ophthalmological examinations
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 and environmental conditions:
TEST ANIMALS
- Source: from a specified-pathogen-free breeding colony
- Weight at study initiation: 91.8 ± 2.1
- Diet (e.g. ad libitum): Spillers' Laboratory Small Animal Diet
- Water (e.g. 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 exposure:
VEHICLE
- Concentration in vehicle: in appropriate concentration so that all rats received a dosage of 5 ml/kg/day

Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks
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

Parental animals: Observations and examinations:
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
Postmortem examinations (parental animals):
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.

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

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/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 (P0)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects on reproductive organs (gross pathology, histopathology)

Results: F1 generation

Effect levels (F1)

Remarks on result:
not measured/tested

Overall reproductive toxicity

Reproductive 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

dose level (mg/kg bw/day)

Number of rats

Hb (g/100 ml)

PCV (%)

RBC (106/mm3)

Retics (% of RBC)

Leucocytes

Total (103/mm3)

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/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

Applicant's summary and conclusion