Allyl 3-cyclohexylpropionate

Endpoint summary

Description of key information

The NOAEL for oral repeated dose toxicity was >214 mg/kg bw/day in a chronic study in the rat.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Remarks:

Pre-GLP, pre-OECD TG study with sufficient detail in documentation

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Deviations:

not specified

Principles of method if other than guideline:

The study was conducted prior to the publication of OECD TGs. The compound was fed in the diet. Fresh diets were made and distributed weekly for a period of 1 year.

GLP compliance:

no

Limit test:

yes

Species:

rat

Strain:

Osborne-Mendel

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: not reported
- Age at study initiation: weaning
- Weight at study initiation: not reported
- Fasting period before study: not reported
- Housing: individually in wire cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS
- not reported

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): not reported
- Storage temperature of food: not reported

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

1 year

Frequency of treatment:

continuous

Dose / conc.:

2 000 ppm

Remarks:

Basis:
nominal in diet

No. of animals per sex per dose:

5

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: not reported

Positive control:

No

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 3, 6, 12 and 22 months
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- The following parameters were examined: white cell counts, red cell counts, haemoglobins and haematocrits

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

No data

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY: no effects

BODY WEIGHT AND WEIGHT GAIN: no effects

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): no effects

FOOD EFFICIENCY: no data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): no data

OPHTHALMOSCOPIC EXAMINATION: no data

HAEMATOLOGY: no effects

CLINICAL CHEMISTRY: no data

URINALYSIS: no data

NEUROBEHAVIOUR: no data

ORGAN WEIGHTS: no effects

GROSS PATHOLOGY: no effects

HISTOPATHOLOGY: NON-NEOPLASTIC: no effects

Dose descriptor:

NOEL

Effect level:

> 2 500 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: based on 30 g/day food consumption and 350 g/rat body weight

Key result

Dose descriptor:

NOEL

Effect level:

> 214 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: based on 30 g/day food consumption and 350 g/rat body weight

Key result

Critical effects observed:

no

Conclusions:

In 1-year feeding study no effects on the test item was observed up to 2500 ppm (mg/kg diet) or > 214 mg/kg bw/day.

Executive summary:

Groups of 5 weanling Osborne-Mendel rats per sex were housed individually in wire cages, and were allowed food and water ad libitum. The animals were administered the test material at 2500 ppm in the diet for 1 year, and the diet was prepared weekly. Weight, food intake and general condition were recorded weekly. Hematological examinations included white cell counts, red cell counts, hemoglobin and hematocrits and these were conducted at the termination of the study. On completion of the study, all surviving animals were sacrificed and examined macroscopically. Organ weights were recorded and tissues were preserved for histopathologic examination. Detailed microscopic examinations were done on 6 or 8 animals evenly divided by sex. No effects on the test item were observed up to 2500 ppm (mg/kg diet) or > 214 mg/kg bw/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

214 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Pre-GLP, pre-OECD TG study, but with sufficient detail in documentation.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The following animal data on repeated dose toxicity of allyl 3-cyclohexylpropionate and allyl heptanoate are available

 

Identifier of the study	Klimisch score and relevance	Test method and animal species	Result	Effect
Leuschner 2010	K1, supporting, conducted with allyl heptanoate (read across)	Repeated dose toxicity:	NOAEL:	Changes in liver (yellow-stained discolouration, chronic inflammation, oval cell hyperplasia, pigment deposition
		oral (gavage)	35 mg/kg bw/day
		28 days, rat
Hagan 1967a	K2, key	Repeated dose toxicity:	NOEL:	No effect
		oral (feeding),	> 2500 ppm (mg/kg diet)
		1 year, rat
Hagan 1967b	K2, supporting	Repeated dose toxicity:	NOEL:	No effect
		oral (feeding),	> 1000 ppm (mg/kg diet)
		27-28 weeks, rat

 

Repeat dose toxicity, oral:

Allyl heptanoate produced adverse effects in a 28-day oral repeated dose toxicity study in the rat at a dose of 100 mg/kg bw/day, corresponding to an oral dose of allyl 3-cyclohexylpropionate of 116.7 mg/kg bw/day. The NOAEL in the key study was 30 mg/kg bw/day (35 mg/kg bw/day for allyl 3-cyclohexylpropionate).

In a reliable key feeding study (Hagan 1967a) allyl 3-cyclohexylpropionate was administered orally via feed to Osborne-Mendel rats (5/gender/dose) for 1 year, at concentrations of 0 (control) and 2500 ppm. No adverse effects were observed in this study.

In the supporting study (Hagan 1967b) rats were exposed orally via feed at a dose level of 1000 ppm allyl 3-cyclohexylpropionate during 27-28 weeks. No adverse effects were observed.

The NOAEL from the chronic feeding study assigned as key study (Hagan 1967a) is chosen as the starting point for DNEL derivation since it reflects most accurately the real exposure scenario in the occupational and general population. Administration of the allyl esters by gavage leads to toxic effects because glutathione (GHS) pathway is saturated rapidly and the presence of acrolein excess causes adverse effects to liver via macromolecular adduct formation, etc. From the available data we assume, that administration of the allyl esters by feeding allows slow acrolein formation and elimination via GHS pathway without this saturation and without causing toxic effects to liver.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The oral repeated dose toxicity of the substance was characeterised from a valid chronic oral toxicity study conducted with allyl 3-cyclohexylpropionate. The NOAEL in the study was >214 mg/kg bw/day.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available studies are considered reliable for this assessment.

 

Repeated dose toxicity, oral:

Based on the above stated assessment of the specific target organ toxicity potential after repeated oral exposure of allyl 3-cyclohexylpropionate, the compound does not need to be classified according to Regulation (EC) No 1272/2008 of the European Parliament and of the Council No 1272/2008 (CLP), as amended for the 17th time in Regulation (EU) 2021/849) as implementation of UN-GHS in the EU.