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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Isobornyl propionate has a NOAEL for fertility and developmental toxicity of >=300 mg/kg bw based on read across from Isobornyl acetate which was tested in a one generation toxicity study (OECD TG 415).

Link to relevant study records

Reference

Endpoint:

one-generation reproductive toxicity

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 guideline study

Justification for type of information:

The fertility information is derived from Isobornyl acetate. The read across rationale is presented in the Toxicity to reproduction Endpoint summary. The accompanying files are also attached there.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

Systemic toxicity

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No treatment related adverse effects up to the highest dose tested

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.

Key result

Dose descriptor:

NOAEL

Remarks:

fertility

Effect level:

>= 300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects on fertility up to the highest dose tested

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.

Key result

Critical effects observed:

no

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

>= 300

Based on:

test mat. (total fraction)

Sex:

male/female

Basis for effect level:

other: No effects observed at the highest dose tested

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.

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Study duration:

subchronic

Species:

rat

Additional information

For Isobornyl propionate the fertilty and developmental toxicity information is based on read across from Isobornyl acetate. First the one-generation reproductive toxicity study of this substance will be presented, followed by the read across rationale.

One-generation reproductive toxicity study (OECD 415) with Isobornyl acetate

A one-generation study was performed according to OECD guideline 415 and GLP principles (Charles River 2011). One hundred male and 100 female rats were assigned to four dosage groups, 25 rats persex per group, for treatment with the test substance. Suspensions of the test substance, or the vehicle, corn oil, were administered via gavage to the male rats once daily beginning 84 days before the cohabitation period, through the cohabitation period (maximum of 14 days) and continuing until the day before euthanasia; and to the female rats once daily beginning 14 days before the cohabitation period, through the cohabitation period (maximum of 14 days) and continuing through the day of euthanasia (through Day 25 of presumed gestation [rats that do not deliver] or Day 22 of lactation [rats that deliver a litter]). Dosage levels were 0 (Vehicle), 30, 100 and 300 mg/kg/day, which was based on a dose-range finder study. The dosage volume was 4 mL/kg, which was adjusted weekly on the basis of the individual body weights.The following parameters were evaluated: P generation males: viability, clinicalobservations, body weights, feed consumption; mating and fertility, organ weights, grossand microscopic observations, sperm assessments (motility and concentration);P generation females: viability, clinical observations, body weights, feed consumption,estrous cycling, mating and fertility, natural delivery and litter observations, organweights, gross and microscopic observations, and ovarian follicle counts; F1 generationpups/rats: viability, body weights, anogenital distance (days 1 and 22 postpartum),sexual maturation, nipple eruption (day 12 postpartum), and gross observations.Surviving male rats were euthanized after completion of the cohabitation period (Days114 through 117 of study). Female rats that delivered a litter and pups not selected forcontinued evaluation were euthanized on Day 22 of lactation (DL 22). Female rats thatdid not deliver a litter were euthanized on Day 25 of presumed gestation (DG 25).F1 generation rats selected for continued evaluation were euthanized on Days 57 through63 postpartum.

Results: Analytical verification of dosing solutions

Analytical verification of the dosing solution revealed that all prepared dose formulations were acceptable for use on this study.

Results: P Generation Male Rats

No mortality related to the test substance occurred during this study. Clinical signs in P generation male rats that were attributed to treatment included slight and moderate excess salivation at 300 mg/kg/day. Slight excess salivation was observed as early as DS 27 and occurred in 22 of 25 males in the 300 mg/kg/day dosage group. Moderate excess salivation occurred in 6 of 25 males in the same dosage group. The substance did not affect body weights, body weight gains or feed consumption values (g/day or g/kg/day) at any dosage level, and did not increase the incidence of gross or microscopic findings at dosages as high as 300 mg/kg/day.There were no apparent effects on mating and fertility, reproductive (epididymides, caudal epididymis, testes, seminal vesicles [with and without fluid] and prostate) or non-reproductive (pituitary, brain, paired kidneys and paired adrenals) organ weights or sperm motility and concentration at any dosage level tested.

Results: P Generation Female Rats

No mortality related to the test substance occurred during this study.Similar to male rats, the number of P generation female rats with excess salivation (slight and/or moderate) was significantly increased at 300 mg/kg/day during the premating, gestation and lactation periods, in comparison to the vehicle control group values. At 100 mg/kg/day, the number of P generation female rats with slight excess salivation was significantly increased only during the gestation dosage period, in comparison to the vehicle control group value. In addition, low incidences of urine-stained abdominal fur occurred at 300 mg/kg/day during the gestation period.Body weights, body weight gains and absolute (g/day) and relative (g/kg/day) feedconsumption in P generation female rats were unaffected by dosages as high as 300 mg/kg/day prior to mating and during the gestation and lactation periods. In addition, there were no apparent effects on the estrous cycle, mating and fertilityparameters or natural delivery and there were no treatment-related gross lesions ormicroscopic changes at any dosage level tested. Terminal body weights were comparable among the four dosage groups and did not significantly differ from the vehicle control group value. Reproductive (left and right ovaries and the uterus with cervix) and non-reproductive (i.e., pituitary, brain, liver, paired kidneys and paired adrenals) were unaffected by oral administration at dosages as high as 300 mg/kg/day. In addition, there were no microscopic findings, including ovarian follicle evaluation, that were attributed to the test substance at any dosage level.

Results: F1 Generation Rats

No deaths related to the test substance occurred in the F1 generation rats. One F1 generation male rat in the 100 mg/kg/day dosage group was euthanized on day 63 postpartum because of a broken palate. All other F1 generation rats selected for continued evaluation postweaning survived until scheduled euthanasia. There were no treatment-related clinical signs, gross lesions or changes in body weight, body weight gains, feed consumption (g/day or g/kg/day) or organ weights (reproductive or nonreproductive) in the male and female F1 generation rats at any dosage level tested. Anogenital distance on day 1 or 22 postpartum, nipple eruption on day 12 postpartum and sexual maturation was unaffected in either sex following treatment of the P generation male and female rats with dosages of up to and including 300 mg/kg/day.

Conclusion

Based on the results of this study, the NOAEL for parental systemic toxicity is 300 mg/kg/day. Increased incidences of excess salivation occurred in P generation male and female rats at 100 and/or 300 mg/kg/day throughout the dosage period, and low incidences of urine-stained abdominal fur occurred in females at 300 mg/kg/day during the gestation period. However, these clinical signs were not considered an adverse effect test item.The reproductive NOAEL in the P generation rats and the NOAEL for viability andgrowth of the F1 generation offspring is greater than or equal to 300 mg/kg/day. Therewere no apparent effects on estrous cycling, mating and fertility, reproductive organweights or natural delivery parameters in the P generation, and growth and development(including anogenital distance, nipple eruption or sexual maturation) in the F1 generationrats at the highest dosage level tested (300 mg/kg/day).

Reproductive toxicity of Isobornyl propionate (CAS# 2756-56-1) using read across from Isobornyl acetate (Cas no. 125-12-2)

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 reproductive toxicity 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 analogue Isobornyl acetate a reliable one generation reproduction test is available that can be used for read across.

Hypothesis: Isobornyl propionate has the same reproductive toxicity as Isobornyl acetate.

Available information: For Isobornyl acetate a one generation reproductive toxicity study (OECD TG 415, Rel. 1) is available in which a NOAEL of >= 300 mg/kg bw is derived, absence of adverse effects for fertility and developmental toxicity. To support the absence of reproductive toxicity up to 1000 mg/kg bw the reproductive screening information from Cyclacet is added (OECD TG 421, Rel. 1).

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 analogue Isobornyl acetate is selected being the closest analogue for which reproductive toxicity information is available. Cyclacet is added to reproductive toxicity information up to 1000 mg/kg bw.

Structural similarities and differences:For Isobornyl propionate the one methyl shorter Isobornyl acetate was selected as an analogue being the closest analogue for which reproductive toxicity is available.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 and its acetate as well as Cyclacet will be hydrolysed to a similar extent based on the close pKa’s of both propyl and ethyl acids: 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. After the ester cleavage both substance turn into the same secondary alcohol and will be excreted in the same way (EFSA, 2008). Propyl and ethyl (acetic) acid are normal body constituents and metabolised in the Krebs cycle.

Fertility and developmental toxicity aspects: Isobornyl-propionate and –acetate will present the same exposure to Isobornyl alcohol and therefore have the same fertility and developmental toxic effects. Propyl and ethyl acids being normal constituents of the body and being metabolised in the Krebs cycle will not cause any reproductive toxicity either. For Cyclacet the systemic exposure will be to Cycla-alcohol and this alcohol is structurally well comparable to Isobornyl-alcohol further presenting the structural similarity and therefore reproductive toxicity.

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 reproductive toxicity information is available. Information from two analogues Isobornyl acetate and Cyclacet 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 one generation reproductive toxicity study >= 300 mg/kg bw (OECD TG 415, Rel.1), supported with information from Cyclacet which did not show reproductive effects >=1000 mg/kg bw in a Reproductive screening test (OECD TG 421).

Final conclusion: Isobornyl propionate has a fertility and developmental toxicity NOAEL >=300 mg/kg bw resulting in No adverse effects for this endpoint.

Data matrix to support the read across to Isobornyl propionate from Isobornyl acetate and Cyclacet on reproductive 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
Repeated dose toxicity in mg/kg bw		270 (similar to OECD TG 408)	>=1500 (OECD TG 408)
Reproductive screening test in mg/kg bw	>=1000 (Read across)		>=1000 (OECD TG 421)
One generation test in mg/kg bw	>=300 (Read across)	>=300 (OECD TG 415)

 

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

Effects on developmental toxicity

Description of key information

Isobornyl propionate has no developmental toxicity based on information from Isobornyl acetate, which was tested in a one-generation oral reproductive toxicity study according to OECD415: NOAEL maternal systemic effects = >300 mg/kg bw/day and the NOAEL for developmental toxicity in the F1 generation is ≥300 mg/kg bw/day.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

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 guideline study

Justification for type of information:

The information is retrieved from Isobornyl acetate. The read across rationale is presented in the Toxicity to Reproduction Endpoint summary. The accompanying files are also attached there.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: No treatment related adverse effects up to the highest dose tested

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.

Key result

Abnormalities:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

>= 300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects observed at the highest dose tested

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.

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Study duration:

subchronic

Species:

rat

Additional information

The information on developmental toxicity is included in the fertility section.

Justification for classification or non-classification

Based on the available data the substance does not need to be classified for fertility or developmental toxicity in accordance with criteria in EU CLP (EC No. 1272/2008 and its amendments).