Anthranilamide

Endpoint summary

Description of key information

In a 2 years (feed) oral repated dose toxicity study, effects for clinical pathology at ~6 and 12 months and for anatomic pathology (organ weights, gross and microscopic pathology) at the end of 12 months.
In a 15-day (gavag) and 28-day (feed) oral repeated dose toxicity study, effects were observed on the thyroid.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Information from public copy of a correspondance letter to US EPA, reliability not known but contributing to a weight of evidence assessment.

Qualifier:

no guideline followed

Principles of method if other than guideline:

A 2-year feeding study is being conducted in Crl:CD(SD) rats (SO/sex/concentration) with the test substance at dietary concentrations of 0, 20, 200, 2000, or 20000 ppm. This notification covers effects through the one-year interim sacrifice. The rats have been observed for mortality, clinical signs, body weight effects, and food consumption, and rats received an ophthalmologic examination after ~ 1 year of dosing. Ten rats/sex/concentration were designated for evaluation of chronic toxicity. These rats were evaluated for clinical pathology at ~6 and 12 months and for anatomic pathology (organ weights, gross and microscopic pathology) at the end of 12 months.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

not specified

Duration of treatment / exposure:

12 months

Dose / conc.:

20 ppm

Dose / conc.:

200 ppm

Dose / conc.:

2 000 ppm

Dose / conc.:

20 000 ppm

No. of animals per sex per dose:

10

Control animals:

yes

Observations and examinations performed and frequency:

The rats have been observed for mortality, clinical signs, body weight effects, and food consumption, and rats received an ophthalmologic examination after ~ 1 year of dosing.

Sacrifice and pathology:

These rats were evaluated for clinical pathology at 6 and 12 months and for anatomic pathology (organ weights, gross and microscopic pathology) at the end of 12 months.

Details on results:

Mild reductions in mean body weight, body weight gain, food consumption, and food efficiency were observed in females in the 2000 ppm and 20000 ppm groups compared to control. Mild reductions in food efficiency were observed in the male 2000 ppm and 20000 ppm groups. Clinical observations included subdued behavior, ataxic gait, dragging hindlimbs, and tilted head.These were only observed in isolated cases involving 1 animal in any dose group throughthe one year time point, and did not exhibit a dose-response. The following clinical chemistry changes were observed in males (not all statistically significant or clear dose response and many differences of small magnitude) at 6 and/or 12 months: at 20000 ppm - HGB, MCRC, AST, bilirubin, ALKP, i Ca; at 2000 ppm - ! bilirubin, i hemoglobin distribution width, Ca, cholesterol, triglycerides, Na; At 200 ppm - ! RBC ghosts, i HGB, Na; and at 20 ppm - ! BUN.
The following clinical chemistry changes were observed in females (not all statistically significant) at 6 and/or 12 months: at 20000 ppm - ! prothrombin time (PT), triglycerides, AST,ALT, bilirubin, Cl, i red cell distribution width, cholesterol, Ca: at 2000 ppm - ! HGB, MCHC, RBC ghosts, prothrombin time (PT), AST, bilirubin, ired cell distribution width, activated partial thromboplastin time (APTT), cholesterol, Ca, total protein, globulin, CI; at 200 ppm - ! RBC ghosts, AST; and at 20 ppm i total protein, globulin. None of these differences was considered to be adverse or test substance related except the increased cholesterol in females at 2000 or 20000 ppm. No gross observations at necropsy were attributed to test substance exposure. Test substance-related increases in absolute and/or relative liver weights were observed in males and females at 2000 and 20000 ppm. Non-statistically significant elevations in liver weights were also observed in 20 and 200 ppm female groups. Correlative centrilobular hepatocellular hypertrophy (minimal or mild) was observed in 20000 ppm males and females and in 200 and 2000 ppm females. Minimal or mild vacuolar degeneration of the liver was also observed in 2000 and 20000 ppm males; however, no correlative clinical pathology effects were observed. Other statistically significant organ weight changes were increased relative kidney weight (2000 and 20000 ppm females), increased absoluteheart weight (2000 ppm males), and increased relative heart weigh (2000 ppm females). No microscopic pathology correlates were observed. Other microscopic pathology lesions attributed to test substance exposure were increased adrenal cortical microvesiculation (minimal) in 20000 ppm females and increased thyroid gland follicular cell hypertrophy (minimal) in 2000 and 20000 ppm females. Uterine squamous metaplasia (minimal) was observed in all dose groups, but not in controls. However, the incidence was highest in the 20 ppm group and did not display a doseresponse; therefore, the detennination of whether or not this lesion is test substance related will be made based on overall incidence at the end of the study.

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Information from public copy of a correspondance letter to US EPA, reliability not known but contributing to a weight of evidence assessment.

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

not specified

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
- Concentration in vehicle: dietary concentrations of 0, 300, 1500, or 5000 ppm

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

4 weeks

Remarks:

Doses / Concentrations:
300, 1500, and 5000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

5 - 7

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

Body weights, food consumption, and clinical signs were evaluated weekly.

Sacrifice and pathology:

Clinical pathology endpoints were evaluated during week 4. After 4 weeks of treatment all surviving rats were euthanized and given a gross and microscopic pathological examination.

Details on results:

CLINICAL SIGNS AND MORTALITY
- Test substance-related mortality was observed in 3/7 high dose female rats on the first day of dosing. Following the first day of dosing no adverse clinical signs were observed in any dose group.

BODY WEIGHT AND WEIGHT GAIN
-Body weight gain was approximately 10 and 20% lower in male and female rats fed 5000 ppm, respectively, compared to the controls.

FOOD CONSUMPTION AND COMPOUND INTAKE
- Food consumption was 13 % lower in female rats fed 5000 ppm compared to the control rats.

FOOD EFFICIENCY
- Male and female food efficiency was 6 % lower in rats fed 5000 ppm compared to the control rats.

ORGAN WEIGHTS
- Absolute and relative liver weights were statistically higher in male and female rats fed 1500 and 5000 ppm compared to the control rats.

HAEMATOLOGY
- Prolongation of prothrombin time and activated partial thromboplastin time were observed in male rats fed 5000 ppm (30 and 33% prolongation compared to control group means, respectively). Increased clotting times were not observed in female rats at any dietary concentration.

HISTOPATHOLOGY: NON-NEOPLASTIC
- Hepatocellular hypertrophy was observed in male and female rats fed all dietary concentrations of test substance.
- Thyroid hypertrophy was observed in male and female rats fed 5000 ppm and also in male rats fed 1500 ppm. Colloid depletion was observed in male rats fed 5000 ppm.

Dose descriptor:

NOAEL

Effect level:

300 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Only effect observed at this dose level was hepatocellular hypertrophy, but this effect is considered to be an adaptive physiologic response to exposure to a xenobiotic and not biologically adverse.

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Study duration:

chronic

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

Additional information

A 2-year feeding study is being conducted in Crl:CD(SD) rats (8O/sex/concentration) with the test substance at dietary concentrations of 0, 20, 200, 2000, or 20000 ppm.he rats have been observed for mortality, clinical signs, body weight effects, and food consumption, and rats received an ophthalmologic examination after ~ 1 year of dosing. Ten rats/sex/concentration
were designated for evaluation of chronic toxicity. These rats were evaluated for clinical pathology at ~6 and 12 months and for anatomic pathology (organ weights, gross and microscopic pathology) at the end of 12 months. 

 

In a repeated dose oral toxicity study similarly performed in accordance with OECD guideline 407, the test substance was administered to 4 groups of male and female rats (5-7 rats/sex/dose) at dietary concentrations of 0, 300, 1500, or 5000 ppm for 4 weeks. Body weights, food consumption, and clinical signs were evaluated weekly. Clinical pathology endpoints were evaluated and all surviving rats were euthanized for pathological examination. Mortality was observed in 3/7 high dose female rats on the first day of dosing. No adverse clinical signs were observed in any dose group. A decrease in body weight gain, food consumption, and food efficiency was observed in the 5000 ppm exposure groups. Prolongation of prothrombin time and activated partial thromboplastin time was observed in male rats fed 5000 ppm. Hepatocellular hypertrophy was observed in male and female rats at all concentrations, but this effect is considered to be an adaptive physiologic response to exposure to a xenobiotic and not biologically adverse. Thyroid hypertrophy was observed in male and female rats fed 5000 ppm and also in male rats fed 1500 ppm. Colloid depletion was observed in male rats fed 5000 ppm.

 

In a 15-day repeated dose oral toxicity study the test substance was administered by oral gavage to 3 groups of male rats at concentrations of 0, 50 or 250 mg/kg/day. Rats were dosed daily for 15 days and euthanized on the morning of test day 15. The liver, thyroid gland, adrenals, and reproductive organs were weighed, and the testes, epididymides, and thyroid gland were saved for histopathological evaluation. Blood was collected and serum was prepared for hormonal evaluation. Mortality was observed on the first day of dosing in 4/15 rats dosed with 250 mg/kg/day of the test substance. Throughout the remainder of the study, no adverse clinical signs were observed and there were no effects on final body weights or the incidence of clinical signs. At necropsy, relative liver weights were significantly higher in rats dosed with 50 and 250 mg/kg/day when compared to the control rats. Absolute thyroid weights were significantly higher in rats dosed with 250 mg/kg/day when compared to the control rats, although relative thyroid weights were not significantly higher. Serum thyroid stimulating hormone (TSH) concentrations were significantly higher in rats dosed with 50 and 250 mg/kg/day, compared to the controls. Serum thyroxine (T4) concentrations were significantly lower in rats dosed with 50 and 250 mg/kg/day when compared to the controls.

 

These two studies contradict the results observed in the acute toxicity study considering that the LD50 is 2200 mg/kg and in these two repeated dose toxicty studies animals already died at 250 mg/kg. Since these effects already occured on day 1, it can be excluded that mortality is based on cumulation of the test substance. Considering that the original study report is not available, but only a brief summary, the results of these studies are not considered for the evaluation of the hazardous properties of the test substance.

Justification for classification or non-classification

Based on the effects observed in the studies performed, classification in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, classification and labelling is not warranted.