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EC number: 246-562-2
CAS number: 25013-15-4
Acute oral toxicity:
LD50 (rat) = 2321.58 mg/kg bw (QSAR; 3-methylstyrene, CAS no. 100-80-1)
LD50 (male rat) = 4000 mg/kg bw (No guideline; Vinyl toluene, CAS No. 25013-15-4)
LD50 (rat) = 2255 mg/kg bw (No guideline; 4-Methylstyrene, CAS No. 622-97-9)
Acute inhalation toxicity: LC50 (male/female) = >5.02 mg/L (OECD 403/GLP)
4. Defining the algorithm - OECD Principle 2
4.2. Explicit algorithmHierarchical method: The toxicity for a given query compound is estimated using the weighted average of the predictions from several different models. The different models are obtained by using Ward’s method to divide the training set into a series of structurally similar clusters. A genetic algorithm based technique is used to generate models for each cluster. The models are generated prior to runtime. FDA method: The prediction for each test chemical is made using a new model that is fit to the chemicals that are most similar to the test compound. Each model is generated at runtime. Nearest neighbour method: The predicted toxicity is estimated by taking an average of the 3 chemicals in the training set that are most similar to the test chemical. Consensus method: The predicted toxicity is estimated by taking an average of the predicted toxicities from the above QSAR methods (provided the predictions are within the respective applicability domains).
5. Defining the applicabilitv domain - OECD Principle 3
5.1. Description of the applicability domain of the model:Hierarchical method: The applicability domain is defined using several different constraints. The first constraint, the model ellipsoid constraint, checks if the test chemical is within the multidimensional ellipsoid defined by the ranges of descriptor values for the chemicals in the cluster (for the descriptors appearing the cluster model). The second constraint, the Rmax constraint, checks if the distance from the test chemical to the centroid of the cluster is less than the maximum distance for any chemical in the cluster to the cluster centroid. The last constraint, the fragment constraint, is that the compounds in the cluster have to have at least one example of each of the fragments contained in the test chemical. For example if one was trying to make a prediction for ethanol, the cluster must contain at least one compound with a methyl fragment (- CH3 [aliphatic attach]), one compound with a methylene fragment (-CH2 [aliphatic attach]), and one compound with a hydroxyl fragment (-OH [aliphatic attach]). This constraint was added to avoid situations where a chemical might have a similar backbone structure to the chemicals in a given cluster but has a different functional group attached. For example if a given cluster contained only short-chained aliphatic amines one would not want to use it to predict the toxicity of ethanol. If a chemical contains a fragment that is not present in the training set, the toxicity cannot be predicted. The fragment constraint can be removed before execution.
FDA method: For a prediction to be valid, the cluster must not violate the model ellipsoid and fragment constraints described above (for Hierarchical method). In addition, the predicted toxicity value must be within the range of experimental toxicity values for the chemicals used to build the model.
Nearest neighbour method: In order to make a prediction, each of the structural analogs must exceed a certain minimum cosine similarity coefficient (SCmin). SCmin was set at 0.5 so that the prediction coverage was similar to that of the other QSAR methods.
Consensus method: In the consensus method, the predicted toxicity is simply the average of the predicted toxicities from the other QSAR methodologies (taking into account the applicability domain of each method).
The predicted LD50 is 2321.58 mg/kg based on Consensus, which can be concluded as not classified for acute oral toxicity. The results of the model can be considered reliable in terms of numerical value because the closest neighbours in the test set and training set predicted accurately and both MAE of similar compounds in the test/training set lower than the error observed for the whole dataset. Although the predicted value of the most similar chemical CAS No. 622- 97-9 is slightly lower than experiment value, the difference ≤0.5, which is acceptable.
The following signs of systemic toxicity occurred in all 3 male and 3 female animals immediately after end of the 4-hour exposure and lasted for up to test day 3:
Moderately to severely reduced motility and ataxia were noted in all male and female rats until 60 minutes p.a., and slightly reduced motility and ataxia until 3 hours p.a.
Slightly reduced respiratory rates, tonic and clonic convulsions and slight tremor were observed in all 3 male and 2 of 3 female animals until 3 hours p.a. Slight lacrimation was observed for all animals up to 3 hours p.a. One female rat (no. 5 f) revealed a pronounced sedation until 60 minutes p.a. and was sacrificed prematurely 2 hours after end of exposure due to animal welfare reasons.
Slight pilo-erection was noted up to test day 2 (all 3 females) or test day 3 (all 3 males) p.a.
Furthermore, the following sign of systemic toxicity occurred in 1 of 3 female animals in test week 2 p.a.:
Ptosis and corneal oedema was noted in female no. 6 f on test day 8 or 9 and lasted until test day 11 or 13, respectively.
Feasibility test results summary
Cumulative mass of particles
< 1 µm
< 4 µm
5.20 mg/L air
2.06 mg/L air
Limit study test results summary
and standard deviation
Mass median aerodynamic diameter
Geometric standard deviation
Relation of actual to nominal concentration
5.02 ± 0.02
In an acute inhalation toxicity study (OECD 403/GLP), a group of young adult Crl: CD(SD) rats (3/sex) were exposed to a test atmosphere of Vinyltoluene (99.66%; 3-Vinyltoluene CAS No. 100-80-1: 64.3 %; 4-Vinyltoluene CAS No. 622-97-9: 35.7 %) in air (aerosol) for 4 hours (nose only) at the target concentration of 5 mg/L air (limit test). Animals were then observed for 14 days.
LC50 male/female > 5.02 mg/L air.
The determination of the aerosol particle distribution did not reveal the range for MMAD (1 - 4 µm) and GSD (1.5 - 3.0) as recommended in the guideline. The feasibility tests revealed that the MMAD at a concentration of 2 mg/L air (9.768 µm) was even slightly worse compared to a concentration at 5 mg/L air (9.124 µm).The cumulative mass of particles less than 4 µm was approximately 31% at a concentration at 5 mg/L air and only 11% at a concentration at 2 mg/L air. Hence, the use of 5 mg/L air is from a toxicological point of view more suitable than employing 2 mg/L air, as at a concentration of 5 mg/L air the absolute concentration of smaller particles reaching the alveoli is considered to be larger than at 2 mg/L air. The gravimetric (actual) concentration in the limit test was 5.02 ± 0.02 mg/L air. The mean MMAD and GSD were 9.205 μm and 4.913, respectively.
The test item led to mortality/morbidity in only 1 of the 6 animals. One female rat revealed a pronounced sedation until 60 minutes p.a. and was sacrificed prematurely 2 hours after end of exposure due to animal welfare reasons. Systemic toxicity was noted in in form of reduced motility, ataxia, tremor, a reduced respiratory rate, tonic and clonic convulsions, and/or lacrimation immediately after end of exposure up to 3 hours after end of exposure in all 3 of 3 male and up to 3 of 3 female animals. Pilo-erection was noted up to 48 hours after end of exposure. The body weight did not reveal test item-related changes in any of the rats at the end of the study.The macroscopic examination at necropsy did not reveal any changes. Hence, no histopathological examination was performed. No influence on the lung weights was observed.
Acute oral toxicityThere is one QSAR report for 3-methylstyrene (CAS No. 100-80-1), one in vivo study in rats for Vinyltoluene (CAS No. 25013-15-4) and one in vivo study in rats for 4-Methylstyrene (CAS No. 622-97-9) available. The QSAR report was selected as the key study as the results were derived from a valid QSAR model and fell into its' applicability domain, with adequate and reliable documentation.
In vivo data
In an acute oral toxicity test (no guideline/EPA), 42 male Wistar rats were administered Vinyltoluene (98%; combined 55%-70% meta-isomer and 30%-45% para-isomer), either as the undiluted material or as an olive-oil or corn-oil solution emulsified with a 5-10% aqueous solution of acacia (gum arabic) by oral gavage. All the surviving rats were observed until recovery was assured (usually about two weeks). Several experimental details (i.e., doses used, number of animals per dose, statistical methodology, detailed sublethal observations, etc.) were not reported in the study. When the rats were autopsied, slight liver changes and, in some instances, some kidney involvement of questionable significance was observed. The approximate LD50 in male rats is 4.0 g/kg.
In an acute oral toxicity test (no guideline/ChemIDPlus), rats were administered 4-Methylstyrene (CAS No. 622-97-9) orally. No further details were provided. Behavioral tremors, respiratory depression and unspecified gastrointestinal changes were noted. The LD50 in rats of 4-Methylstyrene (CAS No. 622-97-9) is 2255 mg/kg.
Based on the results of the QSAR report and 2 in vivo studies, the LD50 is >2000 mg/kg bw.
Acute inhalation toxicity
There is one acute inhalation toxicity study in the rat available.
The test item led to mortality/morbidity in only 1 of the 6 animals. One female rat revealed a pronounced sedation until 60 minutes p.a. and was sacrificed prematurely 2 hours after end of exposure due to animal welfare reasons. Systemic toxicity was noted in in form of reduced motility, ataxia, tremor, a reduced respiratory rate, tonic and clonic convulsions, and/or lacrimation immediately after end of exposure up to 3 hours after end of exposure in all 3 of 3 male and up to 3 of 3 female animals. Pilo-erection was noted up to 48 hours after end of exposure. The body weight did not reveal test item-related changes in any of the rats at the end of the study.The macroscopic examination at necropsy did not reveal any changes. Hence, no histopathological examination was performed. No influence on the lung weights was observed. The LC50 male/female was > 5.02 mg/L air.
Based on the available information in the dossier, the substance Vinyltoluene (CAS No. 25013-15-4) is not classified for acute toxicity or specific target organ toxicity, when the criteria outlined in Annex I of 1272/2008/EC are applied.
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