Allyl hexanoate

Endpoint summary

Description of key information

The NOAEL for oral (feeding) 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:

other: Pre-GLP, pre-OECD TG study with sufficient detail in documentation, but volatilisation of test substance from food was not considered

Principles of method if other than guideline:

The study was conducted prior to the publication of OECD TGs. Rats received the test substance via for a period of 52 weeks.

GLP compliance:

no

Limit test:

no

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: weanling
- 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 reporte

ENVIRONMENTAL CONDITIONS
- not reported

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): fresh diets were prepared 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:

52 weeks

Frequency of treatment:

Continuously (animals had free access to food)

Remarks:

Doses / Concentrations:
2500 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

5 males and 5 females

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: not reported

Positive control:

No

Observations and examinations performed and frequency:

Body weight, food intake and general conditions: every week
Haematology (white cell count, red cell count, haemoglobins, haematocrits): after 3, 6 12 months
Gross pathology: at termination of study
Histopathology: at termination of study

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

Not reported

Statistics:

Not reported

Clinical signs:

not specified

Mortality:

not specified

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 examined

Behaviour (functional findings):

not examined

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:

no effects observed

Details on results:

No adverse effects were observed/reported.

Dose descriptor:

NOAEL

Effect level:

> 2 500 mg/kg diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects observed/reported

Dose descriptor:

NOAEL

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

Critical effects observed:

not specified

Conclusions:

Oral repeated exposure of rats to allyl hexanoate in food at a concentration of 2500 ppm (mg/kg food) over a period of one year had no adverse effects on male and female rats.

Executive summary:

The repeated oral dose toxicity of allyl hexanoate to male and female Osborne-Mendel rats was studied over a period of 1 year. Five males and five females were fed food containing the test substance at a level of 2500 ppm (mg/kg food). Animals had free access to food over the whole study period. The body weight, food consumption and general condition of animals were recorded regularly. Haematological investigations were performed after 3, 6 and 12 months. At the end of the study all animals were sacrificed. Gross pathology was performed on every rat and organs were weighed. Sections were prepared from relevant organs for histopathological studies, which were performed for a representative fraction of animals in high dose and control groups evenly divided by sex. No adverse effects were observed during or at the end of the study at a dose level of 2500 mg/kg food.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

214 mg/kg bw/day

Study duration:

subchronic

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 data from tests are available:

Identifier of the study	Klimisch score and relevance	Test method and animal species	Result	Effect
Hagan 1967	K2KS	Repeated dose toxicity: oral feed, 52 weeks, rat	NOEL: >2500 mg/kg diet or > 214 mg/kg bw/day	no
Hagan 1967	K2SS	Repeated dose toxicity: oral feed,28 weeks, rat	NOEL: 1000 mg/kg diet	no
Hagan 1967	K2SS	Repeated dose toxicity: oral (gavage), 18 weeks, rat	NOEL: 15 mg/kg bw LOAEL: 65 mg/kg bw	Microscopic and/or macroscopic changes in liver observed at higher doses. Liver: Slight bile-duct proliferation in 2 of 8 rats examined
Clode 1978a	K2SS	Repeated dose toxicity: oral (gavage), 14 weeks, rat	LOAEL: 35 mg/kg bw	Increase in relative liver weights, periportal vacuolation in the liver
Clode 1978b	K2SS	Repeated dose toxicity: oral (gavage), 13 weeks, rat	LOEL: 12 mg/kg bw	Slight to medium vacuolation in the periportal area of the liver
Bär 1967	K3SS	Repeated dose toxicity: oral (feed), 2 years, rat	NOEL: 40-67 mg/kg bw, male 50-100 mg/kg bw, female	Effects on body weight, pathological and histological findings

KS: key study; SS: supporting study; K2: reliable with restrictions, Klimisch 2; K3: not reliable, Klimisch 3.

-Repeated dose toxicity, oral:

In a reliable oral toxicity study (Hagan et al. 1967) allyl hexanoate was administered orally via feed to Osborne-Mendel rats (5/gender/dose) for 1 year, at concentrations of 0 (control) and 2500 ppm, i.e. 214 mg/kg bw/day. No adverse effects were observed in this study and NOAEL was above 2500 ppm. This study is taken as the key study for the chemical safety assessment of allyl hexanoate.

The chronic oral toxicity study by Bär & Griepentrog (1967), in which the substance was administered to rats via feed for a period of 2 years, is considered as less reliable than the key study and therefore is used as supporting study only. Effects in the bile (formation of adenoma in the bile duct) were reported in a group of animals receiving 0.5% of substance in feed (corresponding to a dose of approximately 333 mg/kg/day in males and 500 mg/kg/day in females) over a period of 1.5 years in this study. These findings were considered as not unambiguous due to the low number of incidences and the small size of the test group. The publication mentions that an additional testing group was started. However, no further results from the additional group were reported.

In a supporting study (Clode 1978a) considered as reliable with restrictions allyl hexanoate was administered orally via gavage to Wistar rats (15/gender/dose) for 14 weeks, at concentrations of 0 (control), 35 and 100 mg/kg bw/day. There was an increase in relative liver weights, a dose-related periportal vacuolation in the liver indicating hepatotoxic damage by allyl hexanoate. In the highest dose group a bile-duct proliferation, enlargement of hepatocytes and focal necrosis in the periportal area were observed. The LOAEL of 35 mg/kg bw is based on increase in relative liver weights and periportal vacuolation in the liver.

The NOAEL from the chronic feeding study assigned as key study (Hagan 1967) 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 the glutathione (GSH) pathway is saturated rapidly and the presence of acrolein excess causes adverse effects to the liver via macromolecular adduct formation. From the available reliable data we assume, that administration of the allyl esters by feeding allows slow acrolein formation and elimination via GSH 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 repeated dose toxicity of the substance was characterised from a valid chronic oral (feeding) toxicity study conducted with allyl hexanoate. The NO(A)EL in the study was >214 mg/kg bw/day.

Justification for classification or non-classification

-Repeated dose toxicity, oral:

Based on the above stated assessment of the specific target organ toxicity potential after repeated oral exposure of allyl hexanoate, the compound does not need to be classified according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) or according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.

-Repeated dose toxicity, dermal:

As no data of the specific target organ toxicity potential after repeated dermal exposure of allyl hexanoate is available a classification is not possible according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) or according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.

-Repeated dose toxicity, inhalation:

As no data of the specific target organ toxicity potential after repeated dermal exposure of allyl hexanoate is available a classification is not possible according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) or according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.