Allyl isothiocyanate

Endpoint summary

Description of key information

The main effects observed in short-term toxicity studies in rats and mice, dosed by gavage, were a thickened mucosal surface of the stomach, adhesion of the stomach to the peritoneum and a thickened urinary bladder wall (the latter change being mainly observed in the males of both species). This indicates that AITC has irritant effects on these tissues. The No-Observed-Adverse-Effect-Levels (NOAELs) from short-term and subchronic toxicity studies in rats and mice which received AITC by gavage were in the range of 10 to 25 mg/kg bw/day. The NOAELs identified in subchronic toxicity studies were mainly based on the effects on kidney, stomach and urinary bladder observed at higher doses.

(EFSA, 2010)

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:

key study

Study period:

1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

Thirteen-week studies were conducted to evaluate the cumulative toxicity of allyl isothiocyanate and to determine the doses to be used in the chronic studies.
Groups of 10 rats and mice of each sex received 1.5, 3, 6, 12, or 25 mg/ kg allyl isothiocyanate by gavage 5 days per week for 13 weeks. Vehicle controls received corn oil alone.

GLP compliance:

not specified

Species:

other: rat and mouse

Strain:

other: F344/N rats and B6C3F1 mice

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration of treatment / exposure:

13 weeks

Dose / conc.:

1.5 mg/kg bw/day (nominal)

Remarks:

5 days per week

Dose / conc.:

3 mg/kg bw/day (nominal)

Remarks:

5 days per week

Dose / conc.:

6 mg/kg bw/day (nominal)

Remarks:

5 days per week

Dose / conc.:

12 mg/kg bw/day (nominal)

Remarks:

5 days per week

Dose / conc.:

25 mg/kg bw/day (nominal)

Remarks:

5 days per week

No. of animals per sex per dose:

Groups of F344/N rats: 10 animals/sex/group
Groups of B6C3F1 mice: 10 animals/sex/group

Control animals:

yes, concurrent vehicle

Observations and examinations performed and frequency:

Animals were observed twice daily for mortality, morbidity and clinical signs of toxicity.

Sacrifice and pathology:

On days 92 to 96, all animals were killed and a necroscopy carried out.

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Key result

Dose descriptor:

NOAEL

Remarks:

rats

Effect level:

25 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

gross pathology

Key result

Dose descriptor:

NOAEL

Remarks:

mice

Effect level:

25 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

gross pathology

Critical effects observed:

no

Conclusions:

No gross or microscopic lesions were seen at the highest dose level (25 mg/kg) in the 13-week study.

Reference 2

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

Groups of 50 rats and 50 mice of each sex received 12 or 25 mg/kg allyl isothiocyanate in corn oil by gavage 5 times per week (Monday through Friday) for 103 weeks. Groups of 50 rats and 50 mice of each sex received corn oil on the same schedule and served as vehicle controls.

GLP compliance:

not specified

Species:

other: rat and mouse

Strain:

other: F344/N rats and B6C3F1 mice

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration of treatment / exposure:

103 weeks

Dose / conc.:

12 mg/kg bw/day (nominal)

Remarks:

5 days per week

Dose / conc.:

25 mg/kg bw/day (nominal)

Remarks:

5 days per week

No. of animals per sex per dose:

Groups of 50 male and 50 female B6C3F1 mice received 0 (vehicle control), 12, 25 mg AITC/kg bw day.
Groups of 50 male and 50 female F344 rats received 0 (vehicle control), 12, 25 mg AITC/kg bw day.

Control animals:

yes, concurrent vehicle

Observations and examinations performed and frequency:

All animals were observed twice daily for signs of morbidity and mortality. Clinical signs and body weights were recorded every 4 weeks. The mean body weight of each group was calculated by dividing the total weight of all animals in the group by the number of surviving animals in the group.

Sacrifice and pathology:

During weeks 104 to 106, surviving animals were killed and a necroscopy carried out.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Rats: One low-dose (12 mg/kg bw/day) male, 2 low-dose females and 1 high-dose male died as a result of gavage error.
Mice: One control male, 6 low-dose males, 7 high-dose males and 1 high-dose female died as a result of gavage error. Many of the female mice that died prior to week 104 (control, 13/34; low-dose, 6/25; high-dose, 12/30) had suppurative inflammation of the peritoneum, uterus, or multiple organs, which was suggestive of generalised infection.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Rats:Throughout the study, the mean body weights of high-dose male rats were lower than those of the controls, and during the last half of the study the mean body weights of both low-and highdose female rats were higher than those of the controls.
Mice: Throughout most of the study, mean body weights of high-dose male and female mice were higher than those of the vehicle controls.

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Rats: The incidence of undifferentiated leukaemia was increased with a significantly positive trend (p<0.05) in treated male rats and at the high dose, the incidence was significantly (p<0.05) greater than controls (control, 2/50; low-dose 6/50; high-dose, 8/50).No significant increases were observed for leukaemia in female rats (control, 7/50; low-dose, 9/50; highdose, 12/50).

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Rats: There was a significant increase in the incidence of non-neoplastic lesions of the eye (i.e., retinopathy and cataract) in high-dose males and low-dose females; however, the increased incidence correlated with cage placement. There was an increase in the incidence of subcutaneous tissue fibrosarcomas in high-dose females with a significantly positive trend tests (p<0.05); however, when compared with controls, the increased incidence in the high-dose group was not statistically significant (control, 0/50; low-dose, 0/50; high-dose, 3/50).
Mice: Male mice showed a statistically significant (p<0.01) dose-related increase in cytoplasmic vacuolization in the liver (control, 2/49; low-dose, 8/49; high-dose, 13/50). The severity of this lesion was similar in all three groups. Most of the hepatocytes with vacuoles were situated in the centrilobular region and all contained fat.

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Rats: In male rats, the incidence of transitional cell papillomas of the urinary bladder occurred with a significant positive trend (p<0.05; control, 0/49; low-dose, 2/49; high-dose, 4/49), but the incidence at the low dose was not statistically significant. One female in the high-dose group also had this lesion, but the incidence was not statistically significant. Epithelial hyperplasia of the urinary bladder also occurred in males with a significant (p<0.05) overall trend and at the high dose, was significantly increased (control, 0/49; low-dose, 1/49; high-dose, 6/49). This hyperplasia did not occur in animals with papillomas.

Dose descriptor:

NOAEL

Remarks:

mice

Effect level:

25 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

histopathology: non-neoplastic

Dose descriptor:

LOAEL

Remarks:

rats

Effect level:

12 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

histopathology: neoplastic

Critical effects observed:

yes

Lowest effective dose / conc.:

12 mg/kg bw/day (nominal)

System:

urinary

Organ:

kidney

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

Results showed hyperplasia in the urinary bladder epithelium and an increased incidence of transitional cell papillomas in male rats (O%, 4%, and 8% for the control, low dose (25 mg/kg/d) and high dose (50 mg/kg/d), respectively). The historical incidence of this tumor in male rats from the NTP and National Cancer Institute (NCI) Laboratories is 0.1 % and the occurrence of this tumor in treated animals was clearly much greater than the historical control incidence. Female rats in this study showed only a single incidence of hyperplasia and papillomas at the high dose and an equivocal increase in subcutaneous fibrosarcomas were observed in females only. The mice showed no increase in any tumor type at the same exposure levels (NTP 1982). The rat bioassay provides the only evidence of in vivo carcinogenicity of AIT.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

10 mg/kg bw/day

Study duration:

subchronic

Species:

rat

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

Justification for classification or non-classification

AITC is not classified for Specific Target Organ Toxicity, according to Regulation (EC) n. 1272/2008.