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Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14. October 2019 - 16 November 2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2020
Report date:
2020

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Version / remarks:
2018
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Nonane-1,9-diol
EC Number:
223-517-5
EC Name:
Nonane-1,9-diol
Cas Number:
3937-56-2
Molecular formula:
C9H20O2
IUPAC Name:
nonane-1,9-diol
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Batch no.: 03319B
- Purity, including information on contaminants, isomers, etc.: 99.4%

Test animals

Species:
rat
Strain:
Wistar
Details on species / strain selection:
Species: Rat
Strain: Wistar, Crl: WI(Han)
Age at dosing: Approximately 7-9 wks
Weight at dosing: M: 155-194 g; F: 130-157 g
Source: Charles River , Germany
Acclimation period: At least 5 days
Diet: Altromin 1324 ad libitum
Water: Municipal water, ad libitum
Housing: Housed in groups of 5/sex/group

Environmental conditions:
Temperature: 22 ±3°C
Humidity: 55 ± 10%
Air changes: 10 changes/h
Photoperiod: 12 hour light/dark

Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
methylcellulose
Details on oral exposure:
Stability data of the active ingredient formulated in 1% MC, along with homogeneity in the vehicle were determined prior to the start of the study at concentrations of 20 to 200 mg/mL. The results confirmed acceptable stability for 10 days at 2-8°C (refer to Eurofins Munich Study No. STUGC19AA2027 4).
The test article was grinded then weighed with an appropriate volume of 1% MC added to form a stock solution (200 mg/mL) and mixed by stirring on a magnetic mixer, from this serial dilutions were prepared at 60 and 20 mg/mL.
The dose preparations were stirred throughout the sampling and dosing procedures using a magnetic stir bar and plate. Dose preparations were prepared every 10 days. .
During the dosing period, samples were taken for confirmation of concentration and homogeneity during study weeks 1, 5 and 9.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
1,9-Nonanediol was homogenously distributed and chemically stable for 10 days within the range of 20 to 200 mg/mL. The analytical data verify that during the treatment period concentrations of the test article formulations ranged from 70% to 110% of nominal concentrations, 20, 60 and 200 mg/mL, which were within acceptable limits.
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
0 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10 male and 10 female rats per group.
Control animals:
yes
Details on study design:
After an acclimation period of 6 days, rats were randomly assigned to 4 test groups each consisting of groups of 10 male and 10 female Wistar. The test article was administered daily to the animals by oral gavage at dose levels of 0 (1% MC), 100, 300, 1000 mg/kg bw/day solution for 90 days. The dose volume for all groups was 5 mL/kg bw.
Rats were observed for clinical signs during the entire treatment period of 90 days. Bodyweights and food consumption were measured weekly. Haematology and clinical chemistry parameters were measured at the end of the treatment period. Ophthalmological examinations were made on all animals prior to the first administration and in the last week of the treatment period. Prior to the first exposure and towards the end of the exposure period behavioural observations were made outside the home cage using a functional observational battery of tests. These tests were conducted in all animals.

Positive control:
not relevant

Examinations

Observations and examinations performed and frequency:
General clinical observations were made at least once a day, preferably at the same time each day and considering the peak period of anticipated effects after dosing (approximately within 4 hours after administration). Detailed cage-side observations were conducted outside the home cage in a standard arena once before the first administration and at least once a week thereafter. All animals were observed twice daily for morbidity and mortality except on weekends and public holidays when observations were made once daily.

Animals were weighed at initiation of dosing and weekly during administration.

Food consumption was measured weekly during the treatment period, based on the difference between the mass of food provided and that, which remained unconsumed.
Mean daily food consumption = Food consumption (g rat per period) / Days per period
Food efficiency was not calculated

Ophthalmological examinations were conducted on all animals before the first administration and in the last week of the treatment period.

Neurological functional examinations: Once before the first exposure and towards the end of the exposure period multiple detailed behavioural observations were made outside the home cage using a functional observational battery of tests.

Haematology and clinical chemistry: Conducted at the end of the treatment period. Animals were fasted overnight prior to blood sampling.
Haematology: red blood cell parameters (haematocrit (commonly termed PCV), haemoglobin concentration (Hb), mean haemoglobin concentration (MHC), mean corpuscular haemoglobin concentration (MCHC), mean corpuscular volume (MCV), erythrocyte count, platelet count, reticulocyte count), white blood cell parameters (neutrophils, lymphocytes, eosinophils, basophils, monocytes) leukocyte count), coagulation parameters (activated partial thromboplastin time (APTT), and prothrombin time (PT)).
Clinical chemistry: electrolytes (sodium, potassium), kidney function test (creatinine, urea), glucose, liver function tests (albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT [commonly referred to as glutamic pyruvic transaminase (GPT)]), aspartate aminotransferase (AST [commonly referred to as glutamic oxaloacetic transaminase (GOT), total bilirubin (T.Bili), total protein (TP), lipid profile (total triglyceride, total cholesterol), total bile acids (TBA), low density lipoprotein (LDL), high density lipoprotein (HDL).
Serum thyroid hormones (T3, T4 and TSH) serum levels were determined at the end of the dosing period.

Urinalysis: Conducted on day 91 with overnight fasting. The following urinary parameters were measured: specific gravity, nitrite, pH, protein, glucose, ketones, bilirubin, urobilinogen, erythrocytes, leukocytes.

Organ weights: Adrenal glands, epididymides, heart, kidney, liver, brain, pituitary gland, ovary, spleen, thymus, thyroid/parathyroid, testis, uterus with cervix, prostate, seminal vesicles, coagulating glands.

No specific neurohistopathology with specific fixatives were performed in addition to the standard histopathology undertaken on neuronal tissues.
Sacrifice and pathology:
Conducted on day 91. Gross pathological examination was performed on all animals and included examination of the external surface, all orifices and associated tissues.
The following tissues from all animals were preserved in 4 % neutral-buffered formaldehyde except eyes, testes and epididymides which were fixed in Modified Davidson’s fixative for approximately 24 hours before they were transferred to 70 % ethanol.
Accessory sex glands (¿:epididymides, prostate, seminal vesicle (coagulating gland), testes; ¿: ovary, oviduct, uterus +cervix, vagina), cardiovascular/haematological system (thoracic aorta, bone (sternum or femur for marrow), heart, lymph nodes (mandibular, mesenteric, auxillary), spleen, thymus), gastrointestinal tract (oesophagus, tongue, stomach, intestine (caecum, colon duodenum, Peyer's patches, ileum, jejunum, rectum), liver, pancreas, salivary glands (submandibular, sublingual), neurological (brain (cerebellum, cerebrum, midbrain), eyes (+optic nerve, & Harderian glands), sciatic nerve, spinal cord (cervical, thoracic, lumbar), respiratory system (trachea, lung), urogenital system (kidneys, urinary bladder, ureter), other (skeletal muscle, skin, all gross lesions and masses)
Other endocrine producing/sensitive glands (adrenals, mammary gland, pituitary, thyroid (+parathyroid))
Statistics:
A statistical assessment of the results of the body weight, food consumption, parameters of haematology, blood coagulation and clinical biochemistry and absolute and relative organ weights were performed for each gender by comparing values of dosed with control animals using either a parametric one-way ANOVA and a post-hoc Dunnett Test or a non-parametric Kruskal-Wallis Test and a post-hoc Dunn’s Test, based on the results of homogeneity and normality tests. These statistics were performed with Ascentos 1.3.4 software or GraphPad Prism V.6.01 software (p<0.05 is considered as statistically significant).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
In the 1000 mg/kg bw/day group males, an increase was in Hb was observed when compared to the concurrent control group. An increase of Hb was also noted in the 100 mg/kg bw/day group and the 300 mg/kg bw/day group with achieving statistical significance compared to control in both groups. The increase in the male 1000 mg/kg bw/day group was seen without statistical significance, whereas the increase of Hb in the female 1000 mg/kg bw/day group was statistically significantly increased compared to the control.
An increase in Hb is suggestive of increased RBC turnover, however no changes in further RBC indices (MCH, MCHC, reticulocytes) were observed in the available haematology data indicating that the increase in Hb is of little toxicological significance. (see Table 2 below). Furthermore, the group mean values for Hb in all dose groups were within the historical control data range for males and females.
Differential white blood cell count showed statistically significant changes in the female 100 mg/kg bw/day group. Eosinophils and neutrophils were statistically significantly increased and lymphocytes were statistically significantly decreased when compared to the control group. This finding is considered of no toxicological significance as no effects on the total white cell count was observed and no dose-dependent increase or decrease occurred in higher dose levels.

Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
In the male dose groups, statistical significant differences were found for AST in the 300 mg/ kg bw/day group and 1000 mg/kg bw/day group. AST was statistically significantly decreased in the 1000 mg/kg bw/day group females. However, no dose dependency was noted for AST in males and females. An increase with statistical significance was noted for albumin in the 100 mg/kg bw/day males and 1000 mg/kg bw/day males, but in females, no statistical significance was found.
Glucose and creatinine were found with statistically significant decrease in the 300 mg/kg bw/day group and 1000 mg/kg bw/day group. In the 100 mg/kg bw/day group females. Total bilirubin showed a statistically significant increase when compared to control. No dose dependency occurred for this parameter. A toxicological effect on clinical chemical parameters was not considered, as the group mean values were within the historical control data range (see Table 3, below), with no associated histopathological findings.
In females, a statistically significant increase was found for T3 in the 300 mg/kg bw/day and 1000 mg/kg bw/day group when compared to the control group, whereas hormone analysis of T3, T4 and TSH showed no statistical significant differences in the male dose groups. Overall, the statistical significances were seen in one gender and without dose dependency. Additionally, the histopathological evaluation of the liver, kidney and thyroid showed no test article-related findings. Therefore, the statistically significant changes observed for clinical pathological parameters and hormone analysis are considered to be not test article-related. Furthermore, whilst no toxicological effect on hormone analysis (T3, T4 and TSH) was considered, with the group mean values within the historical control data range; it is prudent to acknowledge that the standard derivations were large (comparable to the reported group mean), which raises concerns over the specificity of the assay. However, with histopathology deemed the gold standard, no adverse histopathological findings were observed in the thyroid gland.
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant higher mean kidneys organ/body weight ratio was seen for the 1000 mg/kg bw/day group male when compared to the respective control (+10.86%). In females, the mean absolute weight of kidney and mean organ/body weight ratio was statistically significantly increased in the 300 mg/kg bw/day (absolute +7.13%, relative +7.41%) and 1000 mg/kg bw/day (absolute +7.67%, relative +8.74%) group compared to control. The mean relative liver weight in the female 1000 mg/kg bw/day group was statistically significantly increased compared to control (+l8.03%). Furthermore, the absolute, organ/body weight ratio for the adrenal glands was statistically significantly increased when compared to control in the female 100 mg/kg bw/day group (+20.37%, +18.95% respectively) (see Table 4 below).
The statistical significant differences observed in the 100 mg/kg bw/day group were found without dose dependency and are therefore deemed to be incidental and not to be treatment-related. There were no corresponding possible findings, such as degenerative, inflammatory, hypertrophic and hyperplastic changes, as well as retention or deposits of substances noted at histopathological evaluation for the differences in organ weight of the kidney and liver. Therefore, the statistical significant changes when compared to the respective control group are considered to be without toxicological relevance.
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no advesrse effects observed

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

Table 1:
Overview of sub-chronic toxicity study in rats treated orally (via gavage) with 1,9-nonanediol: study design and dose received

Parameters

male (mg/kg bw/d)

female (mg/kg bw/d)

0

100

300

1000

0

100

300

1000

Animals assigned/sex

10

10

10

10

10

10

10

10

 

Table 2:
Overview of sub-chronic toxicity study in rats treated orally (via gavage) with 1,9-nonanediol: selected haematological parameters

Parameters

male (mg/kg bw/d)

female (mg/kg bw/d)

0

100

300

1000

0

100

300

1000

Hb (g/dL)

15.53 ±0.68

16.31 ±0.47*

16.36 ±0.50*

16.22 ±0.79

14.55 ±0.44

15.06 ±0.70

14.94 ±0.64

15.48 ±0.52**

RBC (1012/L)

9.28 ±0.39

9.55 ±0.51

9.81 ±0.64

9.63 ±0.68

8.37 ±0.37

8.33 ±0.45

8.45 ±0.27

8.61 ±0.59

WBC (1012/L)

4.90 ±2.49

4.84 ±1.31

4.98 ±1.72

4.69 ±0.68

2.33 ±0.86

1.97 ±0.62

2.60 ±1.22

2.44 ±0.35

MCH (pg)

16.73 ±0.57

17.13 ±1.08

16.72 ±0.73

16.88 ±0.85

17.40 ±0.64

18.09 ±0.44

17.65 ±0.47

18.02 ±0.87

MCHC (g/dL)

32.27 ±0.99

32.41 ±0.88

32.23 ±0.74

32.41 ±1.02

32.0 ±0.94

33.13 ±0.97

32.38 ±0.80

32.39 ±1.00

PT (sec)

26.18 ±1.74

25.45 ±0.66

24.92 ±1.49

26.64 ±1.46

27.64 ±1.24

27.48 ±1.31

27.48 ±1.26

27.05 ±0.74

APTT (sec)

10.81 ±1.18

10.49 ±1.74

12.25 ±1.83

10.06 ±1.59

13.47 ±1.51

12.79 ±1.47

12.49 ±1.19

12.45 ±1.12

Platelet (104 µL)

656.10 ±139.31

640.90 ±119.37

626.50 ±74.53

650.70 ±65.96

671.60 ±76.15

601.20 ±99.26

659.00 ±75.38

600.70 ±80.95

Lymp (%)

70.72 ±14.61

77.97 ±3.19

71.09 ±4.70

77.06 ±4.188

84.02 ±3.67

66.21 ±20.98**

82.71 ±3.96

84.34 ±4.70

Neut. (%)

24.82 ±13.58

18.85 ±3.21

25.44 ±4.44

19.97 ±3.99

13.24 ±3.34

25.93 ±13.53***

14.39 ±3.72

12.93 ±4.57

Ret. (%)

1.61 ±0.82

1.39 ±0.24

1.39 ±0.26

1.44 ±0.25

1.87 ±0.12

1.80 ±0.39

1.82 ±0.33

1.58 ±0.24

Laboratory historical control data (Wistar rat, 2016 – 2020)

Hb (g/dL)

n:
Mean ±SD:
Obs. range:

401
15.9 ±0.9
12.5 - 18.3

n:
Mean ±SD:
Obs. range:

406
14.8 ±0.8
11.3 - 18.0

RBC (1012/L)

n:
Mean ±SD:
Obs. range:

387
9.0 ±0.6
6.9 - 10.9

n:
Mean ±SD:
Obs. range:

391
8.0 ±0.6
1.5 - 9.6

WBC (1012/L)

n:
Mean ±SD:
Obs. range:

400
4.2 ±1.4
1.4 - 8.7

n:
Mean ±SD:
Obs. range:

406
2.4 ±1.0
0.4 - 6.1

MCH (pg)

n:
Mean ±SD:
Obs. range:

401
17.7 ±1.2
13.5 - 23.3

n:
Mean ±SD:
Obs. range:

406
18.5 ±1.1
12.1 - 23.8

MCHC (g/dL)

n:
Mean ±SD:
Obs. range:

401
33.3 ±2.0
24.7 - 41.8

n:
Mean ±SD:
Obs. range:

406
33.4 ±1.9
28.4 - 41.9

Platelet (104 µL)

n:
Mean ±SD:
Obs. range:

401
668.3 ±125.2
217.0 - 1231.0

n:
Mean ±SD:
Obs. range:

406
701.4 ±112.9
302.0 - 1329.0

Lymp (%)

n:
Mean ±SD:
Obs. range:

401
75.2 ±8.3
3.5 - 90.7

n:
Mean ±SD:
Obs. range:

405
77.9 ±11.5
4.3 - 93.3

**p <0.01; ***p <0.001

Hb: haemoglobin

RBC: red blood cells

WBC: white blood cells

MCH: Mean corpuscular haemoglobin

MCHC: Mean corpuscular haemoglobin concentration

PT: prothrombin time

 

APTT: activated partial thromboplastin time

Lymp.: lymphocytes

RBC: Red blood cells

Neut.: neutrophils

Reti. reticulocytes

Table 3:
Overview of sub-chronic toxicity study in rats treated orally (via gavage) with 1,9-nonanediol: selected clinical chemistry parameters

Parameters

male (mg/kg bw/d)

female (mg/kg bw/d)

0

100

300

1000

0

100

300

1000

T.prot (g/L)

60.52±1.95

61.75±2.61

61.79±3.71

62.92±4.10

61.44±2.91

61.93±2.20

62.35±3.44

63.27±3.09

Alb (g/L)

31.68±1.61

33.01±1.51*

33.19±1.70

33.92±1.82**

35.19±1.84

35.04±1.65

35.80±2.09

36.44±1.52

Gluc (mmol/L)

11.55±2.29

11.78±1.83

10.67±2.31

11.25±1.71

7.82±1.49

6.95±1.73

5.56±0.97**

5.99±1.34*

Urea (mmol/L)

6.94±1.07

6.94±0.63

6.59±0.58

6.89±1.67

7.51±0.47

7.30±0.46

7.29±0.51

7.07±1.09

Crea (µmol/L)

20.60±3.03

21.50±3.10

20.50±2.37

24.30±17.27

23.20±1.81

20.90±3.11

19.00±3.71**

16.44±2.07***

Trig. (mmol/L)

1.04±0.23

1.17±0.40

1.05±0.45

1.10±0.30

0.52±0.21

0.46±0.15

0.60±0.39

0.67±0.15

T.bili (µmol/L)

1.91±0.29

1.96±0.33

1.83±0.37

1.88±0.44

2.56±0.46

2.14±0.17*

2.64±0.49

2.55±0.27

T.chol. (mg/dL)

1.70±0.22

1.62±0.23

1.75±0.24

1.73±0.34

1.30±0.18

1.36±0.33

1.36±0.23

1.29±0.35

AST (U/L)

86.84±12.64

81.49±10.90

70.98±10.20**

72.33±8.52*

80.69±10.86

69.08±6.64

81.07±33.18

63.32±10.07**

T3 (ng/ml)

3.28±0.33

3.33±0.42

3.76±1.80

3.68±1.31

2.79±0.55

3.16±0.77

4.37±1.16***

4.26±0.61***

T4 (mg/ml)

150.05±53.81

133.77±15.90

116.17±21.31

118.57±14.97

84.07±30.53

97.76±23.04

110.49±25.36

117.58±38.32

TSH (ng/ml)

1.26±0.86

1.01±0.58

0.94±0.31

1.35±0.76

1.44±1.00

1.65±1.10

1.54±1.03

1.01±0.70

Laboratory historical control data (Wistar rat, 2016 – 2020)

T.prot (g/L)

n:
Mean ±SD:
Obs. range:

416
55.6 ±5.8
27.5 - 75.6

n:
Mean ±SD:
Obs. range:

408
59.3 ±6.6
3.8-75.1

Alb (g/L)

n:
Mean ±SD:
Obs. range:

415
31.0 ±3.6
15.3 - 41.0

n:
Mean ±SD:
Obs. range:

411
34.6 ±4.3
16.9 - 44.9

Gluc (mmol/L)

n:
Mean ±SD:
Obs. range:

416
10.2 ±2.9
3.4 - 19.3

n:
Mean ±SD:
Obs. range:

4110
7.7 ±2.4
2.5 - 18.4

Urea (mmol/L)

n:
Mean ±SD:
Obs. range:

416
6.6 ±1.7
2.3 - 18.0

n:
Mean ±SD:
Obs. range:

410
6.8 ±1.5
2.4 - 20.0

Crea (µmol/L)

n:
Mean ±SD:
Obs. range:

412
25.7 ±11.3
8.0 - 141.0

n:
Mean ±SD:
Obs. range:

410
28.5 ±9.9
7.0 - 131.0

Trig. (mmol/L)

n:
Mean ±SD:
Obs. range:

144
0.8 ±0.4
0.2 - 2.1

n:
Mean ±SD:
Obs. range:

148
0.5 ±0.3
0.1 - 1.6

T.bili (µmol/L)

n:
Mean ±SD:
Obs. range:

395
34.1 ±20.2
0.1 - 7.7

n:
Mean ±SD:
Obs. range:

410
2.6 ±0.6
1.5 - 4.6

T.chol. (mg/dL)

n:
Mean ±SD:
Obs. range:

413
1.7 ±0.4
0.8 - 3.8

n:
Mean ±SD:
Obs. range:

405
1.3 ±0.3
0.4 - 2.3

AST (U/L)

n:
Mean ±SD:
Obs. range:

417
97.0 ±82.4
16.4 - 1667.0

n:
Mean ±SD:
Obs. range:

412
86.8 ±24.8
27.9 - 195.1

T3 (ng/ml)

Date range:
n:
Mean ±SD:
Obs. range:

2019 - 2020
179
3.004 ±1.998
0.33 - 18.8

Date range:
n:
Mean ±SD:
Obs. range:

2019 - 2020
137
2.486 ±2.057
0.25 - 14.19

T4 (mg/ml)

Date range:
n:
Mean ±SD:
Obs. range:

2019 - 2020
31
159.891 ±92.641
70.96-  465.34

Date range:
n:
Mean ±SD:
Obs. range:

2019 - 2020
4
146.111 ±138.198
42.74 - 663.04

TSH (ng/ml)

Date range:
n:
Mean ±SD:
Obs. range:

2019 - 2020
180
1.428 ±0.872
0.28 - 3.85

Date range:
n:
Mean ±SD:
Obs. range:

2019 - 2020
136
1.349 ±1.100
0.21 - 6.16

* p <0.05; ** p <0.01; *** p <0.001

T.prot.: total protein

Alb.: albumin

Gluc: Glucose

Crea: Creatinine

Trig.: triglycerides

T.bili.: total bilirubin

 

T.chol.: total cholesterol

AST: aspartate aminotransferase

T3: triiodothyronine

T4: thyroxine

TSH: thyroid stimulating hormone

Table 4:
Overview of sub-chronic toxicity study in rats treated orally (via diet) with 1,9-nonanediol : selected organ weights

Parameters

male (mg/kg bw/d)

female (mg/kg bw/d)

0

100

300

1000

0

100

300

1000

Terminal bwt (g)

394.70±23.89

391.30±33.76

385.50±43.35

389.30±38.69

224.80±12.24

228.20±11.58

224.20±12.39

222.60±8.93

Liver

Abs (g)
Rel. (g%)

9.74±1.07
2.46±0.19

9.89±0.98
2.52±0.12

9.40±1.54
2.45±0.16

10.22±1.29
2.62±0.17

5.72±0.27
2.54±0.06

5.92±0.40
2.59±0.12

5.92±0.39
2.64±0.11

6.13±0.44
2.75±0.1***

Thyroid

Abs (mg)
Rel. (g%)

0.03±0.0
0.00±0.0

0.03±0.0
0.08±0.0

0.03±0.0
0.08±0.0

0.03±0.0
0.08±0.0

0.02±0.0
0.01±0.0

0.02±0.0
0.01±0.0

0.02±0.0
0.01±0.0

0.02±0.0
0.01±0.0

Kidney

Abs (g)
Rel. (g%)

2.34±0.1
0.59±0.0

2.44±0.2
0.62±0.0

2.34±0.3
0.60±0.0

2.56±0.2
0.66±0.0**

1.49±0.0
0.66±0.0

1.57±0.1
0.69±0.0

1.59±0.0*
0.71±0.0**

1.60±0.0*
0.72±0.0**

Adrenals

Abs (g)
Rel. (g%)

0.05±0.0
0.01±0.0

0.06±0.0
0.01±0.0

0.06±0.0
0.01±0.0

0.06±0.01
0.01±0.0

0.06±0.01
0.02±0.0

0.08±0.0**
0.03±0.0*

0.07±0.0
0.03±0.0

0.07±0.0
0.03±0.0

Testes

Abs (g)
Rel. (g%)

3.25±0.46
0.82±0.14

3.42±0.42
0.87±0.11

3.51±0.31
0.91±0.07

3.57±0.21
0.92±0.07

-

-

-

-

Ovaries

Abs (g)
Rel. (g%)

-

-

-

-

0.15±0.03
0.07±0.01

0.14±0.03
0.06±0.01

0.14±0.03
0.06±0.01

0.12±0.03
0.05±0.01

* p <0.05; ** p <0.01; *** p <0.001

Abs.: absolute

Rel.: relative to body weight

 

 

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study, the NOAEL for 1,9-nonanediol following 90 days of oral (via gavage) treatment is deemed to be 1000 mg/kg bw/day (the maximum recommended concentration in accordance with current sub-chronic repeat dose toxicity test guidelines) in the absence of any adverse findings.
Executive summary:

In this 90-day study the effect of 1,9-nonanediol on rats was investigated using groups of 10 male and 10 female Wistar rats. The test article was administered daily to the animals by oral gavage at dose levels of 0, 100, 300, 1000 mg/kg bw/day of 1,9-Nonanediol dissolved in 1% (w/v) methyl cellulose solution for 90 days. The dose volume for all groups was 5 mL/kg bw. The test article formulation was prepared at least every 10 days and dose volumes were adjusted individually based on weekly body weight measurements.

During the period of administration, the animals were observed precisely each day for signs of toxicity. At the conclusion of the test, all animals were sacrificed and observed macroscopically. Body weight and food consumption were recorded weekly. Functional observational battery was undertaken prior to dosing and in the last week of dosing. Haematological and clinical chemistry parameters were examined at the end of the treatment prior to or as part of the sacrifice of the animals. A urinalysis was performed with samples collected after overnight fasting from all animals prior to or as part of the sacrifice of the animals. At the conclusion of the treatment period, all animals were sacrificed and subjected to necropsy. The wet weight of a subset of tissues was taken and a set of organs/tissues was preserved. A full histopathological evaluation of the tissues was performed on high dose and control animals. These examinations were not extended to animals of all other dosage groups as no treatment-related changes were observed in the high dose group. Any gross lesion macroscopically identified was examined microscopically in all animals.

Treatment with 1,9-nonanediol had no toxicological effects on mortality, clinical signs, functional observation, body weight and body weight gain, food consumption, haematology, blood coagulation and clinical chemistry including thyroid hormones. Macroscopic examination of organs at necropsy including organ weight parameters showed no toxicologically relevant findings. There were no histopathological findings in any organ that could be related to the treatment with the test item. The dose formulation analysis confirmed the nominal concentrations for all dose groups, as measured mean recoveries were in the range of 70-110%. All samples were homogenous, as RSD was below or equal 20%.

Under the conditions of this study, the NOAEL for 1,9-nonanediol following 90 days of oral (via gavage) treatment is deemed to be 1000 mg/kg bw/day (the maximum recommended concentration in accordance with current sub-chronic repeat dose toxicity test guidelines) in the absence of any adverse findings.

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