4-hydroxy-3-methoxycinnamic acid

Endpoint summary

Description of key information

Two studies are available to evaluate the repeated doses toxicity of ferulic acid by oral route.

In a study (Hirose et al 1987), the effects of naturally occurring antioxidants including ferulic acid on rat forestomach epithelium were compared with those of synthetic antioxidants, butylatedhydroxyanisole (BHA) and butylated hydroxytoluene (BHT), of which the former is a known forestomach carcinogen. Groups of five F344 male rats were given diet containing BHA, BHT, gallic acid, syringic acid, sesamol, caffeic acid, chlorogenic acid, ferulic acid, eugenol or esculin for 4 weeks at a level of 0.7% for BHT or 2% for the other compounds.

Thus following an exposure of 4 weeks of 2% ferulic acid in diet, no effect was observed. The NOAEL was therefore determined to be 2000 mg/kg bw/day or higher for effect on forestomach (corresponding to the 2% ferulic acid in diet).

 

The second study (Tanaka et al 1993), was initially performed to investigate the protective effect of the plant phenolic antioxidants caffeic acid , ellagic acid ,chlorogenic acid and ferulic acid on the induction of tongue carcinogenesis induced by 4-NQO (4-nitroquinoline-l-oxide). However, this study was useful to assessment the repeated dose toxicity since Ferulic acid was administrated alone during 7 weeks at 500 ppm in diet. After these7 weeks, Ferulic acid did not show change in body, liver and relative livers weight. In addition, no tongue neoplasms and no pre-neoplastic lesions of the tongue were observed.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1987

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

The effects of naturally occurring antioxidants including ferulic acid on rat forestomach epithelium were compared with those of synthetic antioxidants, butylatedhydroxyanisole (BHA) and butylated hydroxytoluene (BHT), of which the former is a known forestomach carcinogen. Groups of five F344 male rats were given diet containing BHA, BHT, gallic acid, syringic acid, sesamol, caffeic acid, chlorogenic acid, ferulic acid, eugenol or esculin for 4 weeks at a level of 0.7% for BHT or 2% for other compounds.

GLP compliance:

no

Species:

rat

Strain:

Fischer 344

Details on species / strain selection:

male F344 rats

Sex:

male

Details on test animals or test system and environmental conditions:

6-week-old male F344 rats.

Route of administration:

oral: feed

Details on route of administration:

Oriental M powdered basal diet

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

The rats had free access to food and water. They were kept in an air-conditionedroom at 22-24°C with a 12 hr-12 hr light-dark cycle.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

Each day over a 4 week period.

Frequency of treatment:

The rats had free access to food (2% in diet)

Dose / conc.:

2 000 mg/kg bw/day (nominal)

Remarks:

corresponding to 2% in the diet

No. of animals per sex per dose:

For ferulic acid one Group of five male.

Control animals:

yes

Observations and examinations performed and frequency:

The rats were weighed weekly.
The liver was weighed, and buffered formalin solution was injected into the stomach. Then the anterior and posterior walls of the forestomach were each cut into 6 to 7 strips for histological examination.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

The body weights of rats given 2% of ferulic acid were not modified.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

no effect on the liver weight.

Gross pathological findings:

no effects observed

Description (incidence and severity):

Ferulic acid did not induce any abnormal lesion of the stomach.
Histological examinations of the forestomach showed no lesions in rats.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Organ observed: forestomach

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

Organ observed: forestomach

Other effects:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: induction of forestomach lesions

Critical effects observed:

no

Ferulic acid did not induce any abnormal lesion of the stomach.

Histological examinations of the forestomach showed no lesions in rats treated with 2% ferulic acid.

Conclusions:

In this study, the induction of forestomach lesions in rats for four weeks by the Ferulic acid was evaluated. The limit dose tested 2000 mg/kg bw/day of Ferulic acid produced no adverse effects.
The NOAEL is therefore determined to be 2000 mg/kg bw/day or higher.

Executive summary:

The effects of naturally occurring antioxidants including ferulic acid on rat forestomach epithelium were compared with those of synthetic antioxidants, butylatedhydroxyanisole (BHA) and butylated hydroxytoluene (BHT), of which the former is a known forestomach carcinogen. Groups of five F344 male rats were given diet containing BHA, BHT, gallic acid, syringic acid, sesamol, caffeic acid, chlorogenic acid, ferulic acid, eugenol or esculin for 4weeks at a level of 0.7% for BHT or 2% for other compounds.

In this study, no effect was observed following an exposure of 4 week of 2% ferulic acid in diet. The NOAEL is therefore determined to be 2000 mg/kg bw/day (corresponding to the2% ferulic acid in diet).

Reference 2

Endpoint:

repeated dose toxicity: oral, other

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1993

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other:

Remarks:

Study not detailed enough and only few information on effect of ferulic acid alone, as it was not the aim of this study.

Qualifier:

no guideline followed

Principles of method if other than guideline:

The modifying effects of dietary administration of the plant phenolic antioxidants caffeic acid (CA), ellagic acid (EA), chlorogenic acid (CGA) and ferulic acid (FA) during the initiation phase on 4-nitroquinoline-l-ojdde (4-NQO)-induced tongue carcinogenesis and on the number and area of silver stained nucleolar organizer region proteins (AgNORs), a new cell proliferation marker, of the tongue squamous epithelium were investigated in male F344 rats. Rats were fed the diet containing 500 ppm CA, 400 ppm EA, 250 ppm CGA or 500 ppm FA for 7 weeks. One week after the commencement of the diets, 4-NQO (20 ppm) was administered in the drinking water for 5 weeks.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Fischer 344

Details on species / strain selection:

Male F344 rats obtained at 4 weeks of age from Japan SLC Inc., Hamamatsu City, Shizuoka, Japan were used.

Sex:

male

Details on test animals or test system and environmental conditions:

Male F344 rats obtained at 4 weeks of age from Japan SLC Inc., Hamamatsu City, Shizuoka, Japan were used. After being acclimatized for 2 weeks with free access to basal diet CE-2 (Clea Japan Inc., Tokyo), they were transferred to the holding room and randomized into experimental and control groups. Rats were housed three or four to a wire cage. The holding room was maintained at 23 ± 2°C, 50 ± 10% humidity, and a 12 h light/dark cycle.

Route of administration:

oral: feed

Details on oral exposure:

8 rats were fed the diets containaing 500 ppm of Feriulic acid for 7 weeks starting at 6 weeks of age, and were then maintained on the basal diet during the subsequent experimental period.

Dose / conc.:

500 ppm

No. of animals per sex per dose:

8

Dose descriptor:

NOEL

Effect level:

500 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

other: body, liver and relative livers weight

Critical effects observed:

no

For the ferulic acid, no toxic clinical signs were observed during the experiment. Body, liver and relative liver weights (g/100 g body wt) in ferulic acid alone group at the termination of the study were almost the same of the control.

No histopathological findings indicating toxicity due to test chemicals were seen in liver, kidney and lung.

No neoplasms of tongue were found in rats.

Conclusions:

After 7 weeks, rat fed with diet containing 500 ppm of Ferulic acid, did not show change in body, liver and relative livers weight. No tongue neoplasms and no pre-neoplastic lesions of the tongue were observed.

Executive summary:

Initiality, this study was performed in order to determine the protective effect of the plant phenolic antioxidants caffeic acid (CA), ellagic acid (EA), chlorogenic acid (CGA) and ferulic acid (FA) on the induction of tongue carcinogenesis induced by 4-NQO (4-nitroquinoline-l-oxide).

However, in this study Ferulic acid was administrated alone during 7 weeks at 500 ppm in diet. After 7 weeks Ferulic acid, did not show modification in body, liver and relative livers weight. No tongue neoplasms and no pre-neoplastic lesions of the tongue were observed.

Also, the study conclusion is that affeic acid (CA), ellagic acid (EA), chlorogenic acid (CGA) and ferulic acid (FA) inhibited the tongue carcinogenesis induced by 4-NQO when they were administered concurrently with the carcinogen.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Justification for classification or non-classification

Based on this two studies ferulic acid showed low systemic effect even if only some parameters were investigated in these two studies.

Based on these two studies no classification is proposed.