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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report Date:
2018

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
87 % pure. Dose levels were corrected for purity (ie reported figures are for nominal 100% purity).

Test animals

Species:
rat
Strain:
other: HannRcc WIST
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Dosing began 14 days before mating and continued for 28 days for males and for day four of lactation for females
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
43 mg/kg bw/day (actual dose received)
Dose / conc.:
160 mg/kg bw/day (actual dose received)
Dose / conc.:
600 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10 males and 10 females
Control animals:
not specified

Examinations

Observations and examinations performed and frequency:
Clinical signs daily (including maternal behaviour)
Functional observation battery (FOB)
Food consumption
Body weights
Blood sampling
Body temperature (during FOB)

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Mild signs of local irritation / taste in top group. Food consumption during the pre-mating period was decreased in males and females (19% and 16% below control value, respectively) at 600 mg/kg/day. No other treatment-related effects on food consumption, body weight or body weight gain were observed during the post-mating, gestation and lactation periods. Locomotor activity was not affected by treatment. The reproduction parameters were unaffected by treatment.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight gain was decreased at 160 and 600 mg/kg/day in males (23% and 51% below control value, respectively) and in females (37% and 56% below control value, respectively).
Haematological findings:
effects observed, non-treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
In males at 600 mg/kg/day, urea and potassium concentrations were statistically significantly increased (24% and 15% above control value, respectively). The changes correlated with the histopathological findings in the kidney. No treatment-related effects on clinical chemistry parameters were observed in females.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Mean absolute liver weight was slightly increased (12% above control value) and mean relative liver and kidney weights were statistically significantly increased in males at 600 mg/kg/day (18% and 11% above control value, respectively). Mean absolute and relative liver weights were significantly increased in females at 600 mg/kg/day (19% and 24% above control value, respectively).
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
No treatment-related macroscopic findings in treated males were observed, except possibly enlarged liver in one male at 600 mg/kg/day. At 600 mg/kg/day, dark red foci in the stomach of a female were observed. Since changes in the stomach were noted on histopathological examination, this finding could be treatment-related. On microscopic examination, the incidence of the following findings was increased in the high-dose group: diffuse hypertrophy of the liver in males and females; tubular degeneration/regeneration and hyaline droplets/granulation of the kidneys in males; follicular hypertrophy of the thyroid in males and females; acanthosis of the non-glandular stomach in males and females; inflammation of the non-glandular stomach in males; and congestion, thrombosis and inflammation of the glandular stomach in females. The severity of hyaline droplets/granulation in males and thyroid follicular cell hypertrophy in males and females was also increased. The increased thyroid follicular cell hypertrophy may have been secondary to the enhanced liver cell metabolism. The incidence of splenic congestion was increased in males at 600 mg/kg/day. In females, hematopoiesis was reported in all animals, including the control; the severity was slightly increased in females at 600 mg/kg/day. In females, the incidence of thymus atrophy was slightly increased (3/5 vs. 2/5 in control group), but there was no effect in severity. At 160 mg/kg/day, the incidence of the following was increased: hypertrophy in the liver in males, tubular degeneration/ regeneration and hyaline droplets/granulation of the kidneys in males, and congestion and inflammation of the glandular plus non-glandular stomachs in females. The changes in the liver of males and females at the mid and high doses are considered adaptive in nature and not toxicologically significant.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
43 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: effects reported
Remarks on result:
other: 160 mg/kg bw/day used for calculation of DNELs because effects considered to be adaptive
Dose descriptor:
LOEL
Effect level:
160 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: effects reported
Remarks on result:
other: Based on decreased body weight and adaptive changes in the liver
Dose descriptor:
LOAEL
Effect level:
ca. 600 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology
histopathology: non-neoplastic

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL concludes to be 43 mg/kg/day for purposes of US EPA reporting. The figure of 160 mg/kg/day ihas been used to estimate the DNEL on the basis that the effects are likely to be adaptive and reversible.
Executive summary:

The parental systemic LOAEL for Sodium coco β-iminodipropionate in rats is 160 mg/kg bw/day, based on decreased body weight gain in males and females during the pre-mating period, and an increased incidence of microscopic lesions in the kidneys of males and glandular and acanthosis of the non-glandular stomach of females. The parental systemic NOAEL is 43 mg/kg bw/day.