Registration Dossier

Administrative data

Description of key information

In a GLP 28-day repeated dose toxicity study (similarly to OECD Guideline 407) with read-across substance coriander oil, NOAEL rats = 160 mg/kg bw/d (males and females)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
12 July to 11 August 1988
Justification for type of information:
See read-across justification in section 13
Reason / purpose:
read-across source
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Isolated incidences of alopecia and sores were noted in both males and females of several groups. In vehicle control group, one male had a small movable head mass at Week 1, but this observation was not present thereafter.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One high-dose female was found dead on Day 2 of the study and was replaced on study with another animal which was dosed for the required period of time. One high-dose male was found dead on Day 9 of the study. However the death was attributed to be handling accident.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No statistically significant changes in body weight was observed.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No statistically significant changes in food consumption was observed.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No treatment related findings were noted in the clinical haematology.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related increases in total protein and serum albumin were observed in the mid- and high-dose males and the high-dose females. Serum calcium was also increased in these same treated groups, apparently as a secondary response to the increase in albumin, its major serum binding protein. The pathogenesis of these increases, however, is unknown.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
A treatment-related increase in absolute and relative kidney weight was observed in the high-dose males and females, and in the mid-dose males and high dose males and females, respectively.
In the liver, a treatment-related increase in both absolute and relative liver weight was observed in the mid and high-dose males and females, While statistical significance was also noted in the absolute liver weight of the low-dose females, the corresponding relative liver weight, while elevated and consistent with a dose-related response, was not statistically significant. Therefore, a relationship to treatment in the low-dose females must be considered as equivocal. A modest increase in both absolute and relative liver weight was observed in the low-dose males. While these increases could be consistent with a dose-related response, the magnitude of the increases and the absence of statistical significance do not appear to attribute these increases to treatment.
While several instances of statistically significant decreases in thyroid/parathyroid weights were observed, these findings were considered incidental to treatment in the absence of a meaningful dose relationship.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related gross pathology findings and treatment-related increases in organ weights were generally observed in the kidney and liver of these same treated groups, and were considered as confirmation of the histopathological findings.
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related periportal hepatocellular cytoplasmic vacuolization was noted in the liver of all treated female groups, with the effect observed in nine of the ten high-dose females. A treatment-related increase in degenerative lesions in the renal cortex was noted in the high-dose males. Treatment related lesions in the non-glandular region of the stomach were observed in the mid- and high-dose females. These lesions consisted of a low incidence of erosion, subacute inflammation and acanthosis, and were somewhat more prevalent in the high-dose females.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
160 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
Remarks on result:
other:
Remarks:
There are no other impact such as an increase in hepatic enzymes (ALP, AST, GGT, GLDH...) or significant changes in other biomarkers indicating a liver dysfunction (Chol, bile acid, TG…) at the low dose both in females and males. Therefore, the effects reported in the females at low dose can be considered as an adaptive response to the test substance and the NOAEL can be established at 160 mg/kg bw/day.
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
400 mg/kg bw/day (actual dose received)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes

None

Conclusions:
Under the test conditions, the NOAEL for test substance was determined to be 160 mg/kg bw/day in males and females.
Executive summary:

In a repeated dose toxicity study performed similarly to OECD test guideline No. 407 and in compliance with GLP, test substance was administered to Crl:CD(SD) rats (10/sex/dose) via oral (gavage) at 160, 400 and 1000 mg/kg bw/day for 28 days. Control animals received 1% methyl cellulose. During the study, clinical signs, mortality, body weight, food consumption, hematology, clinical chemistry, organ weight, gross and histopathology investigations were undertaken.

 

No treatment-related effects on survival, clinical observations, body weights, food consumption and hematology were observed.

Treatment-related increases in total protein and serum albumin were observed at 400 and 1000 mg/kg bw/day in males and at 1000 mg/kg bw/day in females. Serum calcium was also increased in these same treated groups, apparently as a secondary response to the increase in albumin, its major serum binding protein. The pathogenesis of these increases, however, is unknown.

Treatment-related lesions were noted histopathologically in the kidney at 1000 mg/kg bw/day in males, in the non-glandular region of the stomach at 400 and 1000 mg/kg bw/day in females, and in the liver at 1000 mg/kg bw/day in females. Similar lesions of the liver were also noted at 160 and 400 mg/kg bw/day in the females, but at a lower incidence. Treatment-related gross pathology findings and treatment-related increases in organ weights were generally observed in the kidney and liver of these same treated groups, and were considered as confirmation of the histopathological findings. There were no other impact such as an increase in hepatic enzymes (ALP, AST, GGT, GLDH...) or significant changes in other biomarkers indicating a liver dysfunction (Chol, bile acid, TG…) at the low dose both in females and males. Therefore, the effects reported in the females at low dose can be considered as an adaptive response to the test substance and the NOAEL can be established at 160 mg/kg bw/day.

 

Under the test conditions, the NOAEL for test substance was determined to be 160 mg/kg bw/day in males and females.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
160 mg/kg bw/day
Study duration:
subacute
Species:
rat
System:
hepatobiliary
Organ:
liver

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

Mode of Action Analysis / Human Relevance Framework

Treatment-related periportal hepatocellular cytoplasmic vacuolization was noted in the liver of all treated female groups, considered as adverse from 400 mg/kg bw/day.

A treatment-related increase in degenerative lesions in the renal cortex was noted in the high-dose males. Without further details, it is difficult to evaluate if these lesions are due to the species- and sex- specific alpha-2-microglobulin phathology or not. However, as these effects were observed only in males, they may be related to this species- and sex-specific physiopathologic phenomenon that has no relevance to humans.

Treatment related lesions in the non-glandular region of the stomach were observed in the mid- and high-dose females. These lesions consisted of a low incidence of erosion, subacute inflammation and acanthosis, and were somewhat more prevalent in the high-dose females. These effects are probably due to the strong irritating properties of the test item and the mode of administration (gavage)/concentration of the test item in the formulation. Indeed, coriander oil is classified as Skin Irritant Category 2 (H315: Causes skin irritation) and Serious eye damage category 1 (H318) according to the criteria of the Regulation (EC) No. 1272/2008 (CLP) whereas the registered substance is only classified as category 2 (H319) for eye irritation and it is not classified for skin irritation. Therefore, these effects are probably not relevant for the registered substance and may not occur in real exposure conditions in humans.

Additional information

In a repeated dose toxicity study performed similarly to OECD test guideline No. 407 and in compliance with GLP, test substance was administered to Crl:CD(SD) rats (10/sex/dose) via oral (gavage) at 160, 400 and 1000 mg/kg bw/day for 28 days. Control animals received 1% methyl cellulose.During the study,clinical signs, mortality,body weight, food consumption, hematology, clinical chemistry, organ weight, gross and histopathology investigations were undertaken.

 

No treatment-related effects on survival, clinical observations, body weights, food consumption and hematology were observed.

Treatment-related increases in total protein and serum albumin were observed at 400 and 1000 mg/kg bw/day in males and at 1000 mg/kg bw/day in females. Serum calcium was also increased in these same treated groups, apparently as a secondary response to the increase in albumin, its major serum bindingprotein. The pathogenesis of these increases, however, is unknown.

Treatment-related lesions were noted histopathologically in the kidney at 1000 mg/kg bw/day in males, in the non-glandular region of the stomach at 400 and 1000 mg/kg bw/day in females, and in the liver at 1000 mg/kg bw/day in females. Similar lesions of the liver were also noted at 160 and 400 mg/kg bw/day in the females, but at a lower incidence. Treatment-related gross pathology findings and treatment-related increases in organ weights were generally observed in the kidney and liver of these same treated groups, and were considered as confirmation of the histopathological findings.There were no other impact such as an increase in hepatic enzymes (ALP, AST, GGT, GLDH...) or significant changes in other biomarkers indicating a liver dysfunction (Chol, bile acid, TG…) at the low dose both in females and males. Therefore, the effects reported in the females at low dose can be considered as an adaptive response to the test substance and the NOAEL can be established at 160 mg/kg bw/day.

 

Under the test conditions, the NOAEL for test substance was determined to be 160 mg/kg bw/day in males and females.

Justification for classification or non-classification

Adverse effects potentially relevant for humans were observed in the liver of females from 400 mg/kg bw/day. As this dose level exceeds the threshold limit of 300 mg/kg bw/day for a subsacute study, the registered substance does not need to be classified according to the Regulation (EC) No. 1272/2008.