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Diss Factsheets

Administrative data

Description of key information

Acute oral toxicity: LD50 is > 2000 mg/kg bw based on available information from its constituents and an analogue which were tested in studies similar to OECD TG 401 and OECD TG 423

Key value for chemical safety assessment

Additional information

Rosetal A and its acute oral toxicity using a constituent approach (Geraniol) supported with a read across


For Rosetal A two approaches are selected to assess reliably the acute oral toxicity and prevent animal testing for this endpoint. Rosetal A is a multi-constituent with a purity of > 90%. For some constituents the acute oral toxicity is available which can be integrated to assess the acute oral toxicity for Rosetal A using the ATE approach. For other constituents analogue information is used to assess acute oral toxicity. The LD50 results of the read across will be incorporated in the ATE approach.


Introduction and hypothesis for the constituent approach for block 0, 1 and 2


For Rosetal A no acute oral toxicity information is available. For the constituents in block 0, 1 and 2 this information is present (see below for the constituents in the blocks and in Annex 1), which is used for assessing acute oral toxicity. This is in accordance with Article 13 of REACH where it is said that lacking information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as in vitro tests, SARs, grouping and read-across.


Hypothesis: the acute oral toxicity of Block 0, 1 and 2 can be derived based on Geraniol as one of the key constituents in these blocks.  


Available information on Block 0, 1 and 2: For five constituents acute oral toxicity results can be derived from the disseminated ECHA dossiers (see Annex 1 for reference):


- Block 0 2‐phenylacetaldehyde: LD50 is 1550 mg/kg bw (Similar to OECD TG 401, Moreno 1977)


- Block 1 (2,2‐dimethoxyethyl)benzene: LD50 of >5000 mg/kg bw (OECD TG 423, 2015)


- Block 2: Citronellol: LD50 of 3450 mg/kg bw (Similar to OECD TG 401, Moreno, 1973)


- Block 2: Nerol: LD50 of 4500 mg/kg bw (Similar to OECD TG 401, Moreno, 1972)


- Block 2: Geraniol: LD50 of 3600 mg/kg bw (Similar to OECD TG 401, Jenner, 1964)


Geraniol is selected as key constituent for pragmatic reasons.


Target chemical and source chemical(s)


Chemical structures of the constituents are shown in Annex 1, including physico-chemical properties, thought relevant for acute oral toxicity.


Purity / Impurities


Rosetal A has a purity of > 90%. All constituents of > 1% are presented in Annex 1.


Constituent approach justification


A constituent approach is used to assess acute oral toxicity. When using the constituent approach, the result derived should be applicable for classification and labelling and/or risk assessment and it should be presented with adequate and reliable documentation, which is presented below.


Constituent selection: Based on the information on the Blocks as presented at ‘Available information’, all constituents including Geraniol have LD50s > 2000 mg/kg bw. Only 2-phenylacealdehyde (Block 0) can have an impact on EU CLP criteria because it has an LD50 < 2000 mg/kg bw. Due to the low concentration of this constituent, it has no impact on the classification and labelling of Rosetal A. See below:


LD50 of Rosetal A for Block 0, 1 and 2= (100/ATEmix) = (1.26/1550 (Block 0)) -> (100/ ATEmix) =  0.000813 -> ATEmix = (100/0.000813) =  123015 mg/kg bw (according EU CLP, part 3 health hazards, 3.1.3.6.1).


 


Structural similarities and differences are not considered applicable for this constituent approach.


Toxico-kinetics: Geraniol and all other constituents in Block 0, 1 and 2 are considered to be readily absorbed via the oral route based on their molecular weight and log Kow.


Toxico-dynamics: The toxico-dynamics are expressed in the respective acute oral toxicity LD50s.


Uncertainty of the prediction: For Block 0 the acute oral toxicity is assessed as part of Rosetal A with the ATE approach and results in LD50 > 2000 mg/kg bw. For Block 1 and 2 the actual LD50 are > 2000 and therefore the acute oral toxicity of Rosetal A will not be underestimated when using this > 2000 mg/kg bw value.


 


Introduction and hypothesis for the analogue approach for Block 3 and 4


For block 3 and 4 of Rosetal A no data on acute oral toxicity was found. For assessing the acute oral toxicity of Rosetal A, block 3 and block 4, the analogue approach is selected because for a closely related analogue acute oral toxicity information is available which can be used for read across. In accordance with Article 13 of REACH, lacking information should be generated whenever possible by means other than vertebrate animal tests  i. e. applying alternative methods such as in vitro tests, QSARs, grouping and read across.


Hypothesis: Rosetal A, block 3 and block 4, have similar acute oral toxicity compared to 2,2-Bis(3-methylbutoxy)ethyl)benzene resulting in the same LD50, based on similarity in structure and functional groups indicating similar mode of action.


Available information: The analogue of Block 3 and 4: 2,2-Bis(3-methylbutoxy)ethyl)benzene has been tested in a well conducted acute oral toxicity test, LD50 of > 12600 mg (Symrise 2002).


Target chemical and source chemical(s)


Chemical structures of the constituents are shown in Annex 1, including physico-chemical properties, thought relevant for acute oral toxicity and read across. In data matrix table the source substance is presented


Purity / Impurities


Rosetal A has a purity of > 90%. All constituents of > 1% are presented in Annex 1.


Analogue approach justification


According to Annex XI 1.5 read across can be used to replace testing when the similarity can be based on a common backbone and a common functional group. When using read across the result derived should be applicable for classification and labelling and/or risk assessment and it should be presented with adequate and reliable documentation, which is presented below.


Analogue selection: For Rosetal A (block 3 and block 4) the analogue 2,2-Bis(3-methylbutoxy)ethyl)benzene is selected based on similarity in chemical structure and for 2,2-Bis(3-methylbutoxy)ethyl)benzene acute oral toxicity information is available.


Structural similarities and differences: Rosetal A (block 3 and block 4) and 2,2-Bis(3-methylbutoxy)ethyl)benzene have the same backbones and the same functional acetal group. The difference in the backbone is the chain length attached to the acetal as presented in data matrix table and Annex 1.


Toxico-kinetic:. All constituents and the analogue have a molecular weight below 500 which is favourable for oral absorption, where 2,2-Bis(3-methylbutoxy)ethyl)benzene is the smaller molecule and expected to have higher absorption.


Toxico-dynamics: All functional groups of Block 3 and 4 are also present in the analogue and therefore the same mode of action is anticipated and the same acute oral toxicity.


Result of the analogue approach: The acute oral toxicity of block 3 and 4 is > 12600 mg/kg bw based the LD50 of the analogue 2,2-Bis(3-methylbutoxy)ethyl)benzene


 


Conclusions on acute oral toxicity – Overall prediction – constituent ATE approach using Block 0, 1and 2 with the inclusion of the analogue approach representing Block 3 and 4


There are no acute oral toxicity data for Rosetal A. The acute oral toxicity of the substance is derived from the constituents of Rosetal A for block 0, 1 and 2 and an analogue of block 3 and 4. For Geraniol (block 2) a well conducted acute oral toxicity test is available (similar to OECD TG 401, Klimisch 2) with a LD50 of 3600 mg/kg bw. For block 3 and 4 acute oral toxicity data from an analogue is used for derivation of the ATEmix the % of block 3 and 4 are added together. Based on the LD50 for the constituents of Rosetal A an LD50 can be derived: (100/ATEmix) = (1.26/1550 block 0))+(13.1/5000 (block 1))+(3.04/3450 (Citronellol)+(1.46/4500 (Geraniol)+(5.34/3600 (Nerol)+(70.12/12600 (analogue) -> (100/ ATEmix) =  0.011712 -> ATEmix = (100/0.011712) =  8538,31 mg/kg (CLP, part 3 health hazards, 3.1.3.6.1)


Final conclusion: Rosetal A and its constituents gathered in block 1, 2, 3 and 4 the LD50 is > 2000 mg/kg


 


 


 


The relevant information on the analogue substance is presented in the Data Matrix table below.


 


Data matrix: Analogue important for assessment of acute oral properties




























 



Name



CAS



EC



Structure



MW



Log kow



LD50 (mg/kg bw)



ECHA reference



Analogue for block 3 and 4



[2,2-bis(3-methylbutoxy)ethyl]benzene;Benzene, [2,2-bis(3-methylbutoxy)ethyl]-;Phenylacetaldehyde diisoamyl acetal



68555-28-2



271-41-96


 

278



5.71 (Episuite)



> 12600 (Symrise 2002)


 



Substance Information - ECHA (europa.eu)



 


Annex 1: Structural information










































































































































 



Name



CAS



%



Structure



MW



Log kow



LD50


(mg/kg bw)



ECHA reference



Block 0



2‐phenylacetaldehyde



122-78-1



1.26


 

120



1.44


(25C, OECD TG 117)



1550 (Similar to OECD TG 401, Moreno 1977)



Substance Information - ECHA (europa.eu)



Block 1



(2,2‐dimethoxyethyl)benzene



101-48-4



13.10


 

166



2.23


(24.7C, OECD TG 117)



>5000 mg/kg bw (OECD TG 423, 2015)


 



Substance Information - ECHA (europa.eu)



Block 2



3,7‐dimethyloct‐6‐en‐1‐ol (Citronellol)



106‐22‐9



3.04


 

156



3.41


(25C, EC A.8)



3450 (Similar to OECD TG 401, Moreno, 1973)


 



Substance Information - ECHA (europa.eu)



Block 2



(Z)‐3,7‐dimethylocta‐2,6‐dien‐1‐ol (Nerol)



106-25-2



1.46


 

154



Ca. 2.76


(30C, EC A.8)



4500 (Similar to OECD TG 401, Moreno, 1972)


 



Substance Information - ECHA (europa.eu)



Block 2



(E)‐3,7‐dimethylocta‐2,6‐dien‐1‐ol (Geraniol)



106-24-1



5.43



See Z-isomer above



154



2.6


(25C, OECD TG 117)



3600 (Similar to OECD TG 401, Jenner, 1964)


 



Substance Information - ECHA (europa.eu)



Block 3



(2‐((3,7‐dimethyloct‐6‐en‐1‐yl)oxy)‐2‐methoxyethyl)benzene



 



10.91


 

290



6.12 (Episuite)



From analogue: LD50 of > 12600 mg (Symrise 2002)


 



-



Block 3



(Z)‐(2‐((3,7‐dimethylocta‐2,6‐dien‐1‐yl)oxy)‐2‐methoxyethyl)benzene



 



5.05


 

288



6.03 (Episuite)



From analogue: LD50 of > 12600 mg (Symrise 2002)


 



-



Block 3



(E)‐(2‐((3,7‐dimethylocta‐2,6‐dien‐1‐yl)oxy)‐2‐methoxyethyl)benzene



 



19.10



See Z-isomer above



288



6.03 (Episuite)



 



-



Block 4



{2,2‐bis[(3,7‐dimethyloct‐6‐en‐1‐yl)oxy]ethyl}benzene



 



6.30


 

414



10.31 (Episuite)



From analogue: LD50 of > 12600 mg (Symrise 2002)


 



-



Block 4



(E)‐(2‐((3,7‐dimethyloct‐6‐en‐1‐yl)oxy)‐2‐((3,7‐dimethylocta‐2,6‐dien‐1‐yl)oxy)ethyl)benzene



 



17.19


 

412



10.22 (Episuite)



From analogue: LD50 of > 12600 mg (Symrise 2002)


 



-



Block 4



(2,2‐bis(((E)‐3,7‐dimethylocta‐2,6‐dien‐1‐yl)oxy)ethyl)benzene



67634‐02‐0



11.57


 

410



10.14 (Episuite)



From analogue: LD50 of > 12600 mg (Symrise 2002)


 



-



 

Justification for classification or non-classification

Based on the available information Rosetal A does not have to be classified for acute oral toxicity according to EU CLP (EC 1272/2008 and its amendments).