α,α,6,6-tetramethylbicyclo[3.1.1]hept-2-ene-2-propionaldehyde

Endpoint summary

Description of key information

Acute oral toxicity using read across from Floralozone (tested in a study similar to OECD TG 401): LD50 > 5000 mg/kg bw

Acute dermal toxicity using read across from Floralozone (tested in a study similar to OECD TG 402): LD50 > 5000 mg/kg bw

Acute inhalation toxicity using route to route extrapolation from the oral route: > 13000 mg/m3.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

The acute oral and dermal toxicity of Pinyl Isobutyraldehyde was assessed by using read across from Floralozone (CAS no. 67634-15-5). First the experimental acute toxicity information of Floralozone will be summarised. Thereafter the read across justification is presented. The accompanying files are attached in the Endpoint summary.

Acute oral toxicity of Floralozone

Floralozone is tested for acute oral toxicity in a study performed similar to OECD TG 401. Ten male Wistar rats were exposed to the test substance via oral gavage. Animals received a dose of 5000 mg/kg bw. After an observation period of 14 days animals were necropsied. In this study 2 animals died at day 2, one at day 6 and one at day 12. Lethargy and oily anogenital area was noted in 5 or more animals. The survivors were normal until day 11 and 12 when piloerection was noted in several animals. Ptosis was noted in 1 animal on day 13. The surviving animals were normal on day 14. No effects were observed upon necropsy in the animals that were sacrificed on day 14. In the animals that died the following effects were seen: stained brown anogenital area, congested lung, dilated heart, excess fluid in pleural cavity, stomach and intestines distended, intestines grey and/or purple and pale exudate contained in pleural cavities and pericardium.The LD50 was determined to be higher than 5000 mg/kg bw.

Acute dermal toxicity of Floralozone

Floralozone was tested in an acute dermal toxicity study similar to OECD TG 402 under GLP. Ten New Zealand White rabbits were exposed to the test substance via dermal application. Six males and four females were exposed to 5000 mg/kg bw. After an observation period of 14 days animals were necropsied. All animals survived the study in generally good health. Changes in body weights were generally normal. Internal organs, on superficial examination, appeared normal. Skin reactions were generally slight on days 1 and 7 and generally cleared by day 14. One animal had severe edema on day 1 and crusted skin at necropsy on day 14. Scaly skin was observed in 6 out of 10 animals at necropsy. The LD50 was determined to be higher than 5000 mg/kg bw.

Acute inhalation toxicity

The acute inhalation toxicity of Pinyl Isobutyraldehyde is predicted based on the acute oral toxicity in accordance with the ECHA CLP guidance document (2017, page 250, 3.1.3.3.5: 1 mg/kg bw = 0.0052 mg/l (5.2 mg/m3). This means that an LD50 of 5000 mg/kg bw * 0.0052 = 26 mg/L = 26000 mg/m3. The acute inhalation is predicted to be >13000 mg/m3 for Floralozone (using 100% inhalation and 50% oral absorption and an LD50 oral of > 5000 mg/kg bw). The calculated saturated vapour pressure is 288.4 mg/m3 (MW in mg*VP in Pa/ 8.3 (gas constant*293°K)(206290 * 3.4 /(8.3 *293)). This means that the acute inhalation concentration cannot be reached and therefore no acute inhalation toxicity is anticipated.

Read across justification

Theacute oral and dermal toxicity of Pinyl Isobutyraldehyde (CAS 33885-52-8; Target) using read across from Floralozone (CAS 67635-15-5 and 67634-14-4, main and minor constituent, respectively; Source)

Introduction and hypothesis for the analogue approach

Pinyl Isobutyraldehydecontains analpha pinene unit attached to the 2-position of isobutanal via its allylic 2-methyl group. The pinene unit is 2,6,6-trimethylbicyclo [3.1.1]hept-2-ene, a bicyclic monoterpene.For this substance no acute oral and dermal toxicity data are available. Therefore additional information is used in accordance with Article 13 of REACH where it is said thatlacking 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. For assessing the acute oral and dermal toxicity of Pinyl Isobutyraldehyde the analogue approach is selected because for one closely related analogue,Floralozone, acute oral and dermal toxicity data are available which can be used for read-across.

Hypothesis:Pinyl Isobutyraldehyde has the same acute oral toxicity as Floralozone.

Available information: The source chemical Floralozone has been tested in a well conducted acute oral and dermal toxicity tests (method similar to OECD TG 401 and 402, under GLP) up to 5000 mg/kg bw and the test result receives a reliability of 2 because the information is retrieved from a similar but pre-guideline protocol.

Target chemical:The chemical structure of the Pinyl Isobutyraldehyde is shown in the data matrix including the physico-chemical properties and toxicological information.

Purity / Impurities:

Pinyl Isobutyraldehyde is a mono-constituent with a purity generally > 90%. The impurities are not known but are below 3%.

Analogue approach justification

According to REACH Annex XI an analogue approach and structural alert information can be used to replace testing when information from different sources provides sufficient evidence to conclude that this substance has or does not have a particular dangerous property. The result derived should be applicable for C&L and/or risk assessment and be presented with adequate and reliable documentation.

Analogue selection:Analogues were identified in the RIFM database. Hereafter, analogues were identified in the OECD QSAR Toolboxby using structural similarity with Tanimoto (MSC) 80%.Pino Aceteald andFloralozone were considered as potential analogues with >80% similarity and > 50% similarity, respectively.Floralozone’s functional aldehyde group is more structurally related to Pinyl Isobutyraldehyde: both have the adjacent quaternary carbon, while Pino Acetald has a propyl aldehyde without such a quaternary carbon. This means Pinyl Isobutyraldehyde and Floralozone can be oxidised into the respective acid (gut and liver) but cannot be beta-oxidised in the mitochondrion. Pino Aceteald also oxidises into the acid in gut or liver but will thereafter also be beta-oxidised in the mitochondrion. The pKa values of the propyl acids of Pinyl Isobutyraldehyde and Floralozone are calculated to be 4.7, while the methyl acid of Pino Aceteald results in a pKa of 4.4 being more acidic and therefore more reactive compared to the other two. Therefore for acute toxicity the analogue Floralozone is selected.

Structural similarities and differences:Pinyl Isobutyraldehyde andFloralozone both have a hydrocarbon backbone to which a propyl-aldehyde, with a quaternary carbon next to the aldehyde, is attached. The difference is that Pinyl Isobutyraldehyde has a cyclic pinene type of structure while Floralozone has an aromatic ring. Pinyl Isobutyraldehyde has 2 methyl groups directly attached to its ring structure while Floralozone has an ethyl group attached on a para position (main constituent) and ortho-position (minor constituent).These differences between the target and source chemical are not expected to behave differently because these CH methyl or ethyl groups are part of the hydrocarbon backbone and as such do not change the reactivity in a different way.

Toxico-kinetics: Pinyl Isobutyraldehyde and Floralozonehave similar absorption characteristics based on similarities in chemical structure and physico-chemical properties: MW, appearance, VP, WS and log Kow are all in the range of good oral absorption. The metabolic processes of Pinyl Isobutyraldehyde and Floralozone are similar.The aldehyde groups likely oxidise into an acid (but reduction to an alcohol can also occur) and therefore are expected to be excreted similarly.

Toxico-dynamics: The reactivity of both substances is similar due to the similar aldehyde, respective acid group.

Experimental data indication reactivity: Pinyl Isobutyraldehyde and Floralozone are both skin sensitisers with similar EC values with the note that the skin sensitisation results from Floralozone were derived from Cyclamen aldehyde (103-95-7). Both substances are not eye irritants and are negative in the Ames test. The absence of skin irritation of Pinyl Isobutyraldehyde may be due to its higher log Kow indicating slower skin absorption compared to Floralozone.

Remaining uncertainties:There are no remaining uncertainties as presented above. A conversion based on the difference in molecular weight is not needed because Floralozone has the lower molecular weight and is therefore a conservative value.

Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in the data matrix in Table 1.

Conclusionsfor acute toxicity

For Pinyl Isobutyraldehyde no information is available regarding acute oral and dermal toxicity. To cover both acute toxicity endpoints, information from Floralozone is used to fill this data gap. For Floralozone acute oral and dermal toxicity test is available with LD50 values of >5000 mg/kg bw. This information can also be used for Pinyl Isobutyraldehyde based on the similarity in structure, toxico-kinetic and reactive (toxicity-dynamic) features. A conversion for molecular weight is not needed because Floralozone has the lower molecular weight (190 versus 206) and therefore its acute values are conservative for Pinyl Isobutyraldehyde (> 5000 versus > 5421 mg/kg bw, respectively).

Final conclusion on hazard and application in the risk assessment:

Pinyl Isobutyraldehyde has an oral and dermal LD50 of >5000 mg/kg bw.

 

Data matrix: Information on Substance target and analogues important for assessment of acute oral and acute dermal toxicity properties

 

Common names	Pinyl Isobutyraldehyde	Floralozone
Chemical structure
CAS no.	33885-52-8	67635-15-5 and 67634-14-4, main and minor constituent, respectively
Molecular formula	C14H22O	C13H180
Molecular weight	206.29	190
Tanimoto*	1	0.53
REACH	To be registered as Annex VIII for 2018	To be registered as Annex VIII for 2018
Phys-chem data
Vapour pressure (Pa) at 25 °C	3.4 (IFF, 2015)	0.43 (IFF, 1999)
Water solubility (mg/l)	10.8 (IFF, 2015 )	40 (IFF)
Log Kow	5.4 (IFF, 2014)	4.0 and 4.2 (IFF, 2015)
pKa of the respective propyl acids of the aldehydes	4.69 (SPARC calculation)	4.62 (SPARC calculation)
Human health
Acute oral toxicity	Read across	LD50 >5000 mg/kg bw (similar to OECD TG 401)
Acute dermal	Read across	LD50 >5000 mg/kg bw (similar to OECD TG 402)
Skin irritation	Not irritating (OECD TG 439)	Irritating (OECD TG 439)
Eye Irritation	Not an eye irritant (OECD TG 438)	Not an eye irritant (OECD TG 438)
Sensitisation	EC3 19.2% (LLNA, OECD TG 429)	EC3 22.3% (read across from Cyclamen aldehyde , Cas no 103-95-7, tested in an LLNA, OECD TG 429)
Ames test	Negative (OECD TG 471)	Negative (OECD TG 471)

*Tanimoto calculation:http://chemmine.ucr.edu/similarity/

Justification for classification or non-classification

Based on the available data, the substance does not need to be classified for acute oral, dermal and inhalation toxicity in accordance with the criteria outlined in EU CLP (EC no 1272/2008 and its amendments).