Nonane-1,9-diol

Endpoint summary

Description of key information

Skin Sensitisation

A GLP and partially guideline compliant LLNA was conducted on 1,9 -Nonanediol.

1,9-Nonanediol was administered on 3 consecutive days to the dorsum of the ear of 6 female CBA mice/dose level. On each day of treatment the animals received an open application of 25 µL of the dose formulation. On day 6 all animals were sacrificed and each pair of draining auricular lymph nodes were collected from each animal. A single suspension of lymph node cells from each paired sample were prepared. Cell count was determined using a Casy-Counter.

The weight of ear punches taken from the areas of test article application as a measure of inflammatory ear swelling was determined, serving as an indicator for the irritant action of the test article.

A positive control study was conducted using hexylcinnamic aldehyde (HCA) approximately six-months before the study on 1,9 -Nonanediol and confirmed the specificity and sensitivity of the assay.

There were no clinical signs of toxicity observed, with all animals gaining weight. All animals receiving 1,9 -nonanediol at 10, 30 and 60% did not induce a statistically significant increase in either lymph node weight or lymph node cell counts.

A statistically significant increase in ear weight was observed in animals treated at 30%, this however was not deemed biologically relevant as it was not dose related.

Under the condition of the study, administration of 1,9 -Nonanediol to mice at concentrations of 10%, 30% or 60% resulted in lymph node cell counts and lymph node weights which were comparable to the vehicle control. In accordance with the criteria defined by Ulrich et al (2001) 1,9-Nonanediol was not considered to be a skin sensitizer. This study provides supportive information but it is not suitable for classification and labelling purposes.

 

QSAR analysis using the OECD Toolbox (v. 3.4.0.17) was undertaken to provide supporting data to the experimental data generated from the LLNA.

 Visual inspection of the data in this category showed it to be relevant and robust. This was then used in the read-across approach taking the highest mode values from the 5 nearest neighbours with structural similarity to 1,9 -Nonanediol to provide the estimate that 1,9 -Nonanediol is predicted to be negative for skin sensitisation potential when the likely mechanism of protein binding is considered. From the 19 category members, all are aliphatic carbon chains with terminal hydroxyl and/or methyl groups and Log Kow values bracketing that of 1,9-nonanediol. Thus it was concluded that the target chemical, 1,9-nonanediol met the applicability domain used to provide a read-across estimation.

The in silico estimates from the OECD Toolbox indicates that 1,9 -Nonanediol is predicted to be devoid of skin sensitization potential based on protein binding, deemed to be an applicable domain. When this in silico read across is assessed in conjunction with the limited LLNA data, 1,9 -Nonanediol is concluded to not be a skin sensitizer. No further work is considered necessary in addressing this endpoint. Therefore, according to Annex I for Regulation (EC) 1272/2008 the active ingredient, 1,9 -Nonanediol has no obligatory labelling requirement for skin sensitization and is unclassified.

 

Respiratory sensitisation

There are currently no validated animal tests that deal specifically with respiratory tract sensitisation, therefore this endpoint was not investigated.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2003-12-03 to 2003-12-08

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

Version / remarks:

2002

Deviations:

yes

Remarks:

Lymph node proliferation was assessed by total cell count and not via tritiated thymidine incorporation.

GLP compliance:

yes (incl. QA statement)

Type of study:

mouse local lymph node assay (LLNA)

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Chemical name: 1,9-Nonanediol
- CAS no.: 3937-56-2
- Source and lot/batch No.of test material: : BASF / 42638
- Expiration date of the lot/batch: March 2003
- Molecular weight: 160.254 g/mol
- Purity: 98.8%

Species:

mouse

Strain:

CBA/Ca

Sex:

female

Details on test animals and environmental conditions:

Weight at dosing: 19.5 - 25.0g
Age: 9 wks
Source: Charles River Deutschland GmbH, Sulzfeld, Germany
Acclimation period: 15 days
Diet: Kliba-Labordiat (Provimi), ad libitum
Water: Municipal water, ad libitum
Housing: Singly housed
Temperature: 20-24°C
Humidity: 30-70%
Air changes: not stated
Photoperiod: 12 hours light/dark

Vehicle:

propylene glycol

Concentration:

0, 10, 30, 60%

No. of animals per dose:

6

Details on study design:

1,9-Nonanediol was administered on 3 consecutive days to the dorsum of the ear of 6 female CBA mice/dose level. On each day of treatment the animals received an open application of 25 µL of the dose formulation. On day 6 all animals were sacrificed and each pair of draining auricular lymph nodes were collected from each animal. A single suspension of lymph node cells from each paired sample were prepared. Cell count was determined using a Casy-Counter.

Positive control substance(s):

hexyl cinnamic aldehyde (CAS No 101-86-0)

Statistics:

Wilcoxon test

Positive control results:

The positive control, alpha-hexylcinnamaldehyde, tech. 85% had a sensitising potential in the LLNA assay, thereby demonstrating the sensitivity and specificity of the assay.

Parameter:

other: Relative lymph node weight index

Value:

ca. 1

Test group / Remarks:

Vehicle control / 6 animals

Parameter:

other: Relative lymph node weight index

Value:

ca. 0.95

Test group / Remarks:

10% in propylene glycol / 6 animals

Parameter:

other: Relative lymph node weight index

Value:

ca. 0.87

Test group / Remarks:

30% in propylene glycol / 6 animals

Parameter:

other: Relative lymph node weight index

Value:

ca. 0.76

Test group / Remarks:

60% in propylene glycol / 6 animals

Parameter:

other: Relative lymph node cell count index

Value:

ca. 1

Test group / Remarks:

Vehicle control / 6 animals

Parameter:

other: Relative lymph node cell count index

Value:

ca. 1.05

Test group / Remarks:

10% in propylene glycol / 6 animals

Parameter:

other: Relative lymph node cell count index

Value:

ca. 0.92

Test group / Remarks:

30% in propylene glycol / 6 animals

Parameter:

other: Relative lymph node cell count index

Value:

ca. 0.88

Test group / Remarks:

60% in propylene glycol / 6 animals

Parameter:

SI

Test group / Remarks:

Vehicle control / 6 animals

Remarks on result:

not measured/tested

Parameter:

SI

Test group / Remarks:

10% propylene glycol / 6 animals

Remarks on result:

not measured/tested

Parameter:

SI

Test group / Remarks:

30% in propylene glycol / 6 animals

Remarks on result:

not measured/tested

Parameter:

SI

Test group / Remarks:

60% in propylene glycol

Remarks on result:

not measured/tested

Cellular proliferation data / Observations:

refer to Table 7.4.1/01

There were no clinical signs of toxicity observed, with all animals gaining weight. All animals receiving 1,9-Nonanediol at 10, 30 and 60% did not induce a statistically significant increase in either lymph node weight or lymph node cell counts.

A statistically significant increase in ear weight was observed in animals treated at 30%, this however was not deemed biologically relevant as it was not dose related.

Table 7.4.1/01:
Individual and group mean data

Group (%)	Lymph node weight (mg)	Lymph node weight index^1	Lymph node cell count	Lymph node index^1	Ear weight (mg)	Ear weight index^1
Untreated	4.3 ±0.7	0.89	6296833	0.89	27.8 ±2.3	0.97
Vehicle (propylene glycol)	4.9± 0.5	1.00	7082167	1.00	28.7 ±1.8	1.00
10%	4.6 ±0.4	0.95	7458833	1.05	30.4 ±1.3	1.06
30%	4.3 ±0.5	0.87	6546500	0.92	31.1 ±1.8	1.08*
60%	3.7 ±0.8	0.76	6232167	0.88	29.9 ±0.9	1.04
Positive control
Vehicle (acetone)	-	1.00	-	1.00	-	1.00
1% HCA in acetone	-	1.08	-	1.25	-	1.07*
3% HCA in acetone	-	1.21*	-	1.56*	-	1.14**
10% HCA in acetone	-	1.73**	-	2.58**	-	1.14**
* test group / vehicle control * p<0.05; ** p<0.01

Deficiencies:

Lymph node proliferation was assessed by total cell count and not via tritiated thymidine incorporation.

Ear erythema was not assessed by thickness at the end of treatment, but via ear weight. A defined area of 0.8 cm was punched out of the apical part of each ear and for each animal the weight of the pooled punches was determined in order to obtain an indication of possible skin irritation.

Evidence of skin sensitisation was based on statistically significant increases in lymph node cell count and/or lymph node weight compared to the vehicle control. Whilst it is recognised that this study is insufficient in addressing the endpoint sufficiently, a weight of evidence approach has been taken to address this endpoint conclusively.

Interpretation of results:

study cannot be used for classification

Conclusions:

Under the condition of the study, administration of 1,9-Nonanediol to mice at concentrations of 10%, 30% or 60% resulted in lymph node cell counts and lymph node weights which were comparable to the vehicle control. In accordance with the criteria defined by Ulrich et al (2001) 1,9-Nonanediol was not considered to be a skin sensitizer. This study provides supportive information but it is not suitable for classification and labelling purposes.

Executive summary:

1,9-Nonanediol was administered on 3 consecutive days to the dorsum of the ear of 6 female CBA mice/dose level. On each day of treatment the animals received an open application of 25 µL of the dose formulation. On day 6 all animals were sacrificed and each pair of draining auricular lymph nodes were collected from each animal. A single suspension of lymph node cells from each paired sample were prepared. Cell count was determined using a Casy-Counter. 

The weight of ear punches taken from the areas of test article application as a measure of inflammatory ear swelling was determined, serving as an indicator for the irritant action of the test article.

A positive control study was conducted using hexylcinnamic aldehyde (HCA) approximately six-months before the study on 1,9-Nonanediol and confirmed the specificity and sensitivity of the assay.

There were no clinical signs of toxicity observed, with all animals gaining weight. All animals receiving 1,9-Nonanediol at 10, 30 and 60% did not induce a statistically significant increase in either lymph node weight or lymph node cell counts.

A statistically significant increase in ear weight was observed in animals treated at 30%, this however was not deemed biologically relevant as it was not dose related.

Under the condition of the study, administration of 1,9-Nonanediol to mice at concentrations of 10%, 30% or 60% resulted in lymph node cell counts and lymph node weights which were comparable to the vehicle control. In accordance with the criteria defined by Ulrich et al (2001) 1,9-Nonanediol was not considered to be a skin sensitizer. This study provides supportive information but it is not suitable for classification and labelling purposes.

Reference 2

Endpoint:

skin sensitisation, other

Remarks:

QSAR analysis

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

1. OECD Toolbox

2. OECD Toolbox (v. 3.4.0.17)

3. Input into model via CAS number / SMILES

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Workflow:
Profiling the structure of Nonane-1,9-diol from the chemical databases in the Toolbox produced positive results for:
- Aquatic toxicity classification by ECOSAR (primary grouping)
The following categories were therefore formed using this information

Mechanistic:
- Protein binding by OASIS v1.4

Sub-categorization
- Chemical elements (subcategorization)
- Organic functions groups
- Norbert Haider


Organic function group similarity and protein binding categories were then combined to give a category that was both structurally and mechanistically similar so as to increase the robustness of the estimations, resulting in the group of 28 analogues.


5. APPLICABILITY DOMAIN
The target chemical, scopolamine met the applicability domain used to provide a read-across estimation

The applicability domain is defined by following scheme
a) Referential boundary:
The target chemical should be classified as Neutral Organics by Aquatic toxicity classification by ECOSAR

b) Referential boundary:
The target chemical should be classified as Group 14 - Carbon C AND Group 16 - Oxygen O by Chemical elements

c) Referential boundary:
The target chemical should be classified as Group 15 - Nitrogen N OR Group 15 - Phosphorus P OR Group 16 - Sulfur S OR Group 17 - Halogens Br OR Group 17 - Halogens Cl OR Group 17 - Halogens F OR Group 17 - Halogens F,Cl,Br,I,At OR Group 17 - Halogens I by Chemical elements

d) Referential boundary:
The target chemical should be classified as Alcohol AND Hydroxy compound AND Primary alcohol by Organic functional groups, Norbert Haider (checkmol)

e) Referential boundary:
The target chemical should be classified as 1,2-diol OR Acetal OR Alkene OR Alkylarylether OR Aromatic compound OR Carbonic acid derivative OR Carbonyl compound OR Carboxylic acid OR Carboxylic acid derivative OR Dialkylether OR Ether OR Hemiacetal OR Heterocyclic compound OR Ketone OR No functional group found OR Secondary alcohol OR Tertiary alcohol by Organic functional groups, Norbert Haider (checkmol)

f) Referential boundary:
The target chemical should be classified as Organic Functional groups

g) Referential boundary:
The target chemical should be classified as Alkane, branched with tertiary carbon OR Alkene OR Allyl OR Cycloalkane OR Cycloalkene OR Isopropyl OR Terpenes by Organic Functional groups

h) Parametric boundary:
The target chemical should have a value of log Kow which is >= 0.838

i) Parametric boundary:
The target chemical should have a value of log Kow which is <= 3.3


6. ADEQUACY OF THE RESULT
The predicition is based on 6 neighbours' values, 5 of them equal to prediction. Prediction confidence is measured by the p value = 0.0156

Qualifier:

no guideline available

Principles of method if other than guideline:

QSAR analysis

GLP compliance:

no

Run / experiment:

other: other: Refer to report 0312799-TOX1 attached

Parameter:

other:

Remarks:

Refer to report 0312799-TOX1 attached

Vehicle controls validity:

not applicable

Negative controls validity:

not applicable

Positive controls validity:

not applicable

Remarks on result:

no indication of skin sensitisation

Interpretation of results:

study cannot be used for classification

Conclusions:

In conclusion, the in silico estimates from the OECD Toolbox indicates that 1,9-nonanediol is predicted to be devoid of skin sensitization potential based on protein binding, deemed to be an applicable domain. When this in silico read across is assessed in conjunction with the limited LLNA data, 1,9-nonanediol is concluded to not be a skin sensitizer. No further work is considered necessary in addressing this endpoint. Therefore, according to Annex I for Regulation (EC) 1272/2008 the active ingredient, 1,9-nonanediol has no obligatory labelling requirement for skin sensitization and is unclassified.

Executive summary:

In conclusion, thein silicoestimates from the OECD Toolbox indicates that 1,9-nonanediol is predicted to be devoid of skin sensitization potential based on protein binding, deemed to be an applicable domain. When thisin silicoread across is assessed in conjunction with the limited LLNA data, 1,9-nonanediol is concluded to not be a skin sensitizer. No further work is considered necessary in addressing this endpoint. Therefore, according to Annex I for Regulation (EC) 1272/2008 the active ingredient, 1,9-nonanediol has no obligatory labelling requirement for skin sensitization and is unclassified.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Comparison with the CLP criteria

The in silico estimates from the OECD Toolbox indicates that 1,9-nonanediol is predicted to be devoid of skin sensitization potential based on protein binding, deemed to be an applicable domain. When this in silico read across is assessed in conjunction with the limited LLNA data, 1,9-nonanediol is concluded to not be a skin sensitizer. No further work is considered necessary in addressing this endpoint. Therefore, according to Annex I for Regulation (EC) 1272/2008 the active ingredient, 1,9-nonanediol has no obligatory labelling requirement for skin sensitization and is unclassified.

 

There are currently no validated animal tests that deal specifically with respiratory tract sensitisation, therefore this endpoint was not investigated.