Exo-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl propionate

Endpoint summary

Description of key information

The NOAEL of Isobornyl propionate is >=270 mg/kg bw based on read across from a sub-chronic study carried out with Isobornyl acetate (similar to OECD 408) and supported with information from a sub-chronic study with Cyclacet.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: read-across from a (similar to) guideline study

Justification for type of information:

The repeated dose toxicity is based on information from Isobornyl acetate. The read across rationale is presented in the Repeated dose Endpoint summary. The accompanying files are also attached there.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

270 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

organ weights and organ / body weight ratios

Remarks on result:

other: Result obtained from read-across substance Isobornyl acetate (CAS 125-12-2). No correction for the difference in molecular weight is applied as a conservative approach.

Dose descriptor:

NOAEL

Remarks:

renal effects (rat specific)

Effect level:

15 mg/kg bw/day (actual dose received)

Based on:

test mat. (total fraction)

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

organ weights and organ / body weight ratios

urinalysis

water consumption and compound intake

Remarks on result:

other: Result obtained from read-across substance Isobornyl acetate (CAS 125-12-2). No correction for the difference in molecular weight is applied as a conservative approach.

Dose descriptor:

NOAEL

Effect level:

>= 1 504.6 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No toxicological significant effects observed, except hydrocarbon nephropathy which was not considered in the NOAEL derivation for human health, being a rat specific phenomenon.

Remarks on result:

other: Result obtained from read-across substance Cyclacet (EC 911-396-0). No correction for the difference in molecular weight is applied as a conservative approach.

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

90 mg/kg bw/day (actual dose received)

System:

hepatobiliary

Organ:

liver

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

no

Critical effects observed:

yes

Lowest effective dose / conc.:

90 mg/kg bw/day (actual dose received)

System:

urinary

Organ:

kidney

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

no

Conclusions:

For Isobornyl propionate the NOAEL is considered to be the highest dose tested at 270 mg/kg bw at which some rat specific effects in liver and kidney were observed. This value is used as the NOAEL as it is below 1000 mg/kg bw, the limit dose.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

270 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No studies are available on the substance itself. The information is derived from a sub-chronic study on the close structural analogue Isobornyl acetate. In this study a NOAEL of 270 mg/kg bw was derived (the highest dose tested). The liver effects (slight hypertrophy and sligth biliary effects) were not considered adverse. The hydrocarbon nephropathy is a male rat specific phenomena. The absence of adverse effects is supported with information from Cyclacet, which was tested in a sub-chronic study in which similar non-adverse effects were seen up to 1500 mg/kg bw. In the absence of human-relevant effects the NOAEL for systemic toxicity is established at 270 mg/kg bw/day.

Sub-chronic study with Isobornyl acetate (similar to OECD 408)

In the sub-chronic oral toxicity study, similar to OECD 408, 15 male and female CFE rats were exposed daily to 0 (vehicle control), 15, 90 and 270 mg/kg bw/day by oral gavage for a period of 13 weeks (Gaunt 1971). 5 additional animals/ sex were exposed for 2 to 6 weeks for the 0, 90 and 270 mg/kg bw /day dose groups. Corn oil was used as vehicle. The body weight of the animals and their intake of food and water were measured weekly.

Urine was collected for urinalysis from all rats during the final week of treatment and, additionally, during wk 6 from five rats of each sex of each group of the main study. After receiving their final dose, the animals were fasted for 24 hr and then killed by an overdose of barbiturate. Blood was collected from the aorta for haematological examination and serum analyses. Gross pathology and histopathology/ measurement of organ weights was performed.

No deaths and no abnormalities in behaviour or appearance occurred during the study.

There were no significant differences between test and control animals in the rate of bodyweight gain. No treatment related haematological effects or alterations in serum parameters were observed. Urinalysis revealed increased cell excretion in rats receiving 270 mg/kg/day and at wk 13 this effect was seen also in animals receiving 90 mg/kg/day. The males given 270 mg/kg/day also showed an impairment of urine-concentrating ability. At wk 6 this was seen only after prolonged (16-20 hr) water deprivation but at wk 13 it was also seen after dehydration for 6 hr. Although the absolute kidney weight was increased only in females at wk 13, the kidney weight expressed relative to body weight was increased at wk 6 in males and at wk 13 in both sexes. The relative liver weight was increased in both sexes of rats given 270 mg/kg/day for 13 wk. Both absolute and relative caecal weights were increased at wk 13 at the highest level of treatment. No abnormalities were seen at autopsy but the histological examination revealed focal tubular degeneration and atrophy in the kidneys in the high dose group and, in males only, a vacuolation of the tubular epithelium. Slight vacuolation of the epithelial cells of the intrahepatic bile ducts was also seen in males but not considered adverse. Based on these results a NOAEL of 270 mg/kg bw/day was derived in the absence of human-relevant adverse effects.

Supporting study with Cyclacet (according to OECD 408)

In a sub-chronic repeated dose toxicity study performed according to OECD 408 and under GLP conditions, rats were orally exposed for 90 days via the food (Harlan 2012). The dose levels were 0, 200, 2000, 6000, and 20000 ppm, corresponding to 0, 15.3, 154.9, 464.1, and 1504.6 mg/kg bw/day, respectively. Clinical signs, functional observations, body weight change, dietary intake, and water consumption were monitored during the study. During week 7 and at the end of the study, haematology, blood chemistry and urinalysis were evaluated. Furthermore, oestrus cycle assessment was performed on female animals between week 6 and 7 and week 12 and 13.Opthalmoscopic examination was performed at the start and end of the study in control and high-dose animals. At the end of the study, all animals were subjected to gross necropsy examination and histopathological examination of tissues was performed on animals from control and high-dose. Furthermore, sperm assessment was performed on males at necropsy. Reduced overall body weight was observed in male and female animals in the highest dose group, correlated with reduced food consumption and adverse effects on food efficiency, indicating decreased food palatability. At the highest dose level, reduced chloride concentration, sodium concentration, aspartate aminotransferase levels, alanine aminotransferase levels, bile acid levels, and increased cholesterol levels were observed in male animals. The observed changes in aminotransferases, bile acid and cholesterol can be explained by the reduced food consumption. Changes in chloride and sodium concentrations may be explained by the observed kidney effects in males. Increased kidney weights were also observed in males, as well as hyalin droplet nephropathy, which is a rat-specific effect that is not relevant for humans. In females, no toxicologically significant effects were observed in clinical chemistry, organ weights or histopathology. Therefore the NOAEL could be established as the highest dose tested, 20000 ppm or 1500 mg/kg bw/day, under the conditions of this test.

Repeated dose toxicity of Isobornyl propionate (Cas no. 2756-56-1using read across from Isobornyl acetate (125-12-2) and Cyclacet (Generic Cas no. 54830-99-8)

Introduction and hypothesis for the analogue approach

Isobornyl propionate consists of an exo-1,7,7-Trimethylbicyclo[2.2.1]heptane) structure to which a propionic ester is attached. For this substance no repeated dose toxicity information is available. 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. The analogue approach is selected since for the structurally related analogues Isobornyl acetate and Cyclacet reliable repeated dose toxicity information is available that can be used for read across. Cyclacet is added to support that all parameters assessed in an OECDTG 408 up to the current standard also no effects are seen.

Hypothesis: Isobornyl propionate has the same repeated dose toxicity as Isobornyl acetate and Cyclacet.

Available information: For Isobornyl acetateand Cyclacet sub-chronic toxicity studies are available. For Isobornyl acetate a published study similar to OECD TG 408 is available (Rel. 2). In this study a human relevant NOAEL is derived of 270 mg/kg bw. For Cyclacet a sub-chronic study is performed according to OECD TG 408, in which a human relevant NOAEL of >=1500 mg/kg bw was derived. In both studies alpha-hydrocarbon nephropathy was seen, which is specifically for male rats and not relevant for humans.

Target chemical and source chemical(s)

Chemical structures of the target chemical and the source chemical(s) are shown in the data matrix, including relevant physico-chemical properties.

Purity / Impurities

Isobornyl propionate is a mono-constituent >=88%, with impurities similar to the parent substance and < 10%.

Analogue approach justification

According to REACH 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 Isobornyl propionate the one methyl shorter Isobornyl acetate was selected as an analogue being the closest analogue for which repeated dose toxicity information is available. E.g. for Isobornyl butyrate no such information was found on the ECHA site or in the RIFM database. Cyclacet is added as an analogue to support the findings in Isobornyl acetate study and show that parameters requested in current guidelines and not tested in the older study can be covered with the Cyclacet test results. 

Structural similarities and differences:Isobornyl propionate and Isobornyl acetate have the same backbone and functional ester group. The only difference between the two is the propionate and acetate group, respectively, which will result in a higher molecular weight of the first one.

Isobornyl propionate is also very similar to Cyclacet. These substances have a very similar hydrocarbon backbone and the same functional ester group. The double bond in Cyclacet backbone is not near the ester bond and will not present additional electrophilicity and thus reactivity. The propionate versus the acetate will not affect the electrophilicity of the substance or its metabolites.

Toxico-kinetic, Absorptionvia all routes will be similar in view of similar appearance, molecular weights and physico-chemical parameters.Metabolism:Isobornyl propionate, Isobornyl acetate and Cyclacet will hydrolyse to a similar extent based on the close pKa’s of both propyl and ethyl acid: 4.88 and 4.54, respectively. In addition the ester will be cleaved by carboxyl esters to a similar extent: the ester bond is not hindered to any extent. This is also true for Cyclacet: the acetic ester will be easily cleaved. After the ester cleavage the substance and its analogues are all three secondary alcohols. These alcohols will be conjugated and excreted via the kidneys (EFSA, 2008). There is also a metabolic pathway that will bind the alcohol to alpha-2u globulins and as such transported to the kidneys, where the alcohols are excreted and the alpha-2u globulins sediment when overloaded. Propyl and ethyl (acetic) acid are normal body constituents and are metabolised in the Krebs cycle.

Toxico-dynamic aspects: Isobornyl propionate and its related esters demand significant metabolism in the liver resulting in increased liver weights, which is seen in all repeated dose studies. This is considered adaptive in absence of functional liver changes. The transport of the metabolites with alpha-2u globulins results in sedimentation of the alpha-2u globulin in the male rat kidneys when the sedimentation is higher than the removal rate. This results in alpha-hydrocarbon nephropathy in the male rat and is not considered relevant for humans. Overall Isobornyl propionate will not present adverse effects similar to other similar esters which hydrolyse into secondary alcohols such as Isobornyl acetate and Cyclacet.

Uncertainty of the prediction:There are no remaining uncertainties other than those addressed above.

Data matrix

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

Conclusions on hazard and risk assessment

For Isobornyl propionate no repeated dose toxicity information is available. Information from two analogues can be used for read across. When using read across the result should be applicable for classification and labelling and risk assessment as well as presented with reliable and adequate documentation. This documentation is presented in the current document. Isobornyl acetate does not show adverse effects in a sub-chronic study up to 270 mg/kg bw (OECD TG 408), which is supported with the Cyclacet study in which a NOAEL >=1500 mg/kg bw was found to show that for all current OECD TG 408 parameters also no effects are seen. For conservative reasons the NOAEL of Isobornyl acetate will be used to derive a NOAEL of 270 mg/kg bw

Final conclusion: Isobornyl propionate has a sub-chronic NOAEL of 270 mg/kg bw.

Data matrix to support the read across to Isobornyl propionate from Isobornyl acetate and Cyclacet on repeated dose toxicity

Common names	Isobornyl propionate	Isobornyl acetate	Cyclacet
Chemical structures
	Target	Source	Source
CAS no.	2756-56-1	125-12-2	2500-83-6 (5-yl) and 54830-99-8 (generic)
EINECS	220-410-5	204-727-6	911-369-0
REACH registration	2018	Registered	Registered
Empirical formula	C13H22O2	C12H20O2	C12H16O2
Molecular weight	210.32	196.29	192.25
Phys-chem properties
Physical state	Liquid	Liquid	Liquid
Log Kow (measured)	5.0 (IFF measured)	4.3 (Simonich EpiSuite)	3.9 (IFF measured)
Human health
Acute Toxicity Oral LD50 mg/kg bw	5000 (OECD TG 401)	10000 (OECD TG 401)	2750 (OECD TG 401)
Sub-chronic Repeated dose toxicity mg/kg bw	270 (Read across)	270 (OECD TG 408)	>=1500 (OECD TG 408)

References

EFSA, Flavouring Group Evaluation 87, (FGE.87)1, Consideration of bicyclic secondary alcohols, ketones and related esters evaluated by JECFA (63rd meeting) structurally related to bicyclic

secondary alcohols, ketones and related esters evaluated by EFSA in FGE.47 (2008)

Scientific Opinion of the Panel on Food Additives,Flavourings, Processing Aids and Materials in Contact with Food, site visited May, 2018;

http://www.efsa.europa.eu/sites/default/files/scientific_output/files/main_documents/746.pdf

 

 

Justification for classification or non-classification

Based on the available data the substance does not need to be classified according to EU CLP (EC No. 1272/2008 and its amendments).