Reaction mass of 4-methyl-1-oxaspiro[5.5]undec-3-ene and 4-methyl-1-oxaspiro[5.5]undec-4-ene and 4-methylidene-1-oxaspiro[5.5]undecane

Endpoint summary

Description of key information

The acute oral LD50 is > 5000 mg/kg bw based on read across from Orange Flower ether, which was tested in an OECD TG 401.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

3 October, 1983 - 24 October, 1983

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

The information is used for read across to Oxaspirane-819.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, Massachusetts, USA
- Weight at study initiation: 180 – 280 (after fasting)
- Fasting period before study: 18 hours
- Housing: individually, in stainless steel wire mesh cages,
- Diet: Wayne Lab Blox, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Remarks:

only for 3200 mg/kg bw dosing

Doses:

3200, 4000, 5000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were observed immediately and at 1, 4 and 24 hours after dosing and twice daily for 14 days. Body weights were recorded on the 14th day.
- Necropsy of survivors performed: yes

Preliminary study:

In a dose-range finding study, 4 fasted animals, 2 per sex, were administered the test article at 500, 1600 and 5000 mg/kg bw, orally by gavage. Signs observed were abnormal gait, abnormal stance, decreased body tone, piloerection, decreased activity, lacrimation, semiprostration, salivation, poor grooming and prostration. None of the animals died at the 500 or 1600 mg/kg bw dose levels. 3 of 4 animals died at the 5000 mg/kg bw dose level.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

- 1 out of 5 males and 2 out of 5 females died exposed to 3200 mg/kg bw
- 1 out of 5 males and 2 out of 5 females died exposed to 4000 mg/kg bw
- 1 out of 5 males and 1 out of 5 females died exposed to 5000 mg/kg bw

Clinical signs:

Signs observed included decreased activity, abnormal stance, prostration, hypersensitivity, exophthalmos, tremors, semiprostration and dyspnea. One rat was observed with paralysis of both front pays due to self-traumatization.

Gross pathology:

- Necropsy of the animals that died revealed discoloration of the intestines and bladder. Hemorrhages in the stomach, cecum and bladder were observed. Necrotic livers and congested, edematous lungs were also observed.
- Atrophy of the testes was observed upon necropsy of the sacrificed male animals. No test article related lesions were observed in the females that were sacrificed.

Interpretation of results:

other: Not acute harmful

Remarks:

according toEU CLP (EC No. 1272/2008 and its amendments)

Conclusions:

The acute oral toxicity test showed an LD50 of >5000 mg/kg bw in study according to OECD TG 401.

Executive summary:

In an acute oral toxicity test five Sprague-Dawley rats per sex per dose were exposed to the test substance via oral gavage to 3200, 4000, and 5000 mg/kg bw in a study according to OECDTG 401. Signs observed included: decreases activity, salivation, lacrimation, poor grooming, piloerection, decreased body tone, abnormal gait, abnormal stance, prostration, hypersensitivity, exophthalmos, tremors, semiprostration and dyspnea. One rat was observed with paralysis of both front paws due to self-traumatization. Three of ten animals died at the 3200 and 4000 mg/kg bw dose levels and two out of ten died at 5000 mg/kg bw. Necropsy of the animals that died revealed discoloration of the intestines and bladder. Hemorrhages in the stomach, cecum and bladder were observed. Necrotic livers and congested, edematous lungs were also observed. Atrophy of the testes was observed upon necropsy of the sacrificed male animals. No test article related lesions were observed in the females that were sacrificed. The acute oral LD50 for substance in both males, females and combined was determined to be >5000 mg/kg bw.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read-across information.

Justification for type of information:

The result is based on read across from Orange flower ether. The read across rationale is presented in the Encpoint summary and the accompanying files are also attached there.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Interpretation of results:

other: Not acute harmful.

Remarks:

According to EU CLP (EC No. 1272/2008 and its amendments).

Conclusions:

The acute oral LD50 of the substance was determined to be >5000 mg/kg bw, based on read across from Orange Flower ether, which was tested in an OECD TG 401.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The one acute oral toxicity study available is of sufficient quality for the present dossier.

Additional information

Acute oral toxicity of Oxaspirante-819 is derived from Orange Flower Ether which was tested in an OECD TG 401. The executive summary of the study is presented below and is followed by the read-across rationale.

Orange flower ether acute oral toxicity

In an acute oral toxicity test five Sprague-Dawley rats per sex per dose were exposed to the test substance via oral gavage to 3200, 4000, and 5000 mg/kg bw according to OECD TG 401. Signs observed included: decreases activity, salivation, lacrimation, poor grooming, piloerection, decreased body tone, abnormal gait, abnormal stance, prostration, hypersensitivity, exophthalmos, tremors, semiprostration and dyspnea. One rat was observed with paralysis of both front paws due to self-traumatization. Three of ten animals died at the 3200 and 4000 mg/kg bw dose levels and two out of ten died at 5000 mg/kg bw. Necropsy of the animals that died revealed discoloration of the intestines and bladder. Hemorrhages in the stomach, cecum and bladder were observed. Necrotic livers and congested, edematous lungs were also observed. Atrophy of the testes was observed upon necropsy of the sacrificed male animals. No test article related lesions were observed in the females that were sacrificed. The acute oral LD50 for substance in both males, females and combined was determined to be >5000 mg/kg bw.

The acute oral toxicity of Oxaspirane-819 using read across from Orange flower ether (CAS 14576-08-0)

 

Introduction and hypothesis for the analogue approach

Oxaspirane-819 consists of 3 main constituents. All three have a 2 hexyl rings touching each other at one spot. One ring contains an ether bond. All constituents have a double bond and a methyl group opposite the ether bond. The two major constituents have an internal double bond conjugated with the methyl group, while the minor one has an external double bond. For Oxaspirane-819 there are no experimental acute oral toxicity data. 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. For assessing the acute oral toxicity of Oxaspirane-819 the analogue approach is selected because for a related analogue, Orang flower ether acute oral toxicity information is available which can be used for read across.

Hypothesis: The acute oral toxicity of Oxaspirane-819 can be predicted with the acute oral toxicity of Orange flower ether.

Available information: Orange flower ether has been tested in an acute oral toxicity test up to 5000 mg/kg bw according to OECDTG 401 and in compliance with GLP (Klimisch 1). The LD50 was observed to be >5000 mg/kg bw.

Target chemical and source chemical(s)

Chemical structures of the target chemical and the source chemicals are shown in the data matrix, including physico-chemical properties and toxicological information, thought relevant for acute oral toxicity, of all substances.

Purity / Impurities

The purity and impurities of the Oxaspirane-819 target chemical do not indicate acute oral toxicity potential other than indicated by the parent substance.

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 C&L and/or risk assessment and it should be presented with adequate and reliable documentation, which is presented below.

Analogue selection:For Oxaspirane-819 Orange flower ether was selected as an analogue based on structural similarities and for which acute oral toxicity was available.

Structural similarities and differences: Oxaspirane-819‘s constituents and Orange flower ether contain a hydrocarbon backbone with at least one hexyl ring. This ring contains a double bond to which a methyl group (allylic methyl) is attached. Both substances have an ether bond too. The difference is that in Oxaspirane-819 part of the hydrocarbon backbone is an additional hexyl ring, while Orange flower ether has the other carbons external of the hexyl ring. Another difference is that Oxaspirane-819 has the ether bond in the ring, while Orange flower ether has it outside the ring. These differences are not considered to influence the acute oral toxicity.

Toxico-kinetic, Absorption: Both Oxaspirane-819 and Orange flower ether will be fully absorbed based on their molecular weight and log Kow (< 500 and < log Kow 7).Metabolism:For both substances the metabolic pathways are expected to be similar. The allylic methyl can oxidise into an acid and/or reduction of the double bond can occur in both substances. The ether in the hexyl ring of Oxasprirane-819 is expected to be fairly stable but demethylation likely occurs of the Orange flower ether bond, resulting in an alcohol. All metabolites will become more water soluble and easily excreted via the kidneys with or without conjugation. Overall the toxico-kinetics between the two substances is considered sufficiently similar.

Toxico-dynamics:The potential acidic metabolites of Oxaspirane-819 and Orange flower ether are expected to be similar reactive resulting in pKas of 4.47 and 4.76, respectively, and will be fully dissociated in the systemic circulation.

Uncertainty of the prediction: There are no other uncertainties than already discussed above.

Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in Table 2.

Conclusion on hazard and risk assessment

For Oxaspirane-819 no acute oral toxicity information is available. When using read across the result derived should be applicable for C&L and/or risk assessment and be presented with adequate and reliable documentation, which is presented in the current document.For Orange flower ethera well conducted acute oral toxicity test is available (Reliability 1) with a LD50 of >5000 mg/kg bw, which can be used for Oxaspirane-819.

Final conclusion on hazard and risk assessment:Oxaspirane-819 has an LD50 of > 5000 mg/kg bw. 

 

Table 1. Data matrix for the constituents of Oxaspirane-819 and Orange flower ether

Common names	Oxaspirane-819		Orange flower ether
	Target		Source
Constituent	1 and 2	3
Constituents	4-methyl-1-oxaspiro[5.5]undec-4-ene	4-methylidene-1- oxaspiro[5.5]undecane	4-(1-methoxy-1-methylethyl)-1-methylcyclohexene
Chemical structures
Typical concentration (%)	30-50 and 25-45	15-35
Likely reactive metabolite
CAS no	62062-89-9	62062-84-4	14576-08-0
Smiles:	CC2=CC1(CCCCC1)OCC2	C=C2CC1(CCCCC1)OCC2	COC©©C1CCC©=CC1
EC no	944-753-1		238-620-0
REACH registration	2018		Registered
Empirical formula	C11H18O	C11H18O	C11H20O
Molecular weight	166	166	168
Physico-chemical data
Water solubility, mg/l	24.95* (6300, measured)	21.38*	22.61*(83, measured)
Log Kow	3.99* (4.3, measured)	4.07* (4.4, measured)	4.03* (4.5, measured)
pKa	4.47	4.47	4.76
Human health
Acute oral toxicity in mg/kg bw	>5000 Based on read across		>5000 (OECD TG 401)

* Episuite v4.11

 

Justification for classification or non-classification

Based on the results, the substance does not need to be classified and labelled for acute oral toxicity in accordance with EU CLP (EC No. 1272/2008 and its amendments).