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Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

NOAEL (fertility, rat, oral) = 795 mg/kg bw/day (reported in study report)

Determined on the basis of the reproductive performace of male rats upon administration of the substance for 14 -18 days.

However, the substance caused changes likely affecting reproductive performance of male rats dosed 795 mg a.i./kg bw/day (corrected from 900 mg/kg bw/day) which did not impact early mating period but became apparent at the end of the study.

Based on such findings, the following effect levels may be identified:

NOAEL (male, rat, oral) = 265 mg/kg bw/day

NOAEL (female, rat, oral) = 795 mg/kg bw/day

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
265 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In the reproduction/developmental toxicity screening test with adminstration of the test item for 14 to 18 days prior to pairing there were no test item related differences between the control and all test item treated groups in the examined parameters of reproductive performance of male and female animals.

However, at the end of the study, histological investigations revealed degenerative and necrotic changes in the testes of all high dose males resulting in lack of mature spermatozoa in the epididymides after 48 days of administration of 795 mg/kg bw/day.

During necropsy, blue colouration of various organs and tissues of high dose males and females was observed, i.e. kidneys, adrenal glands, liver, urinary bladder, walls of small and large intestines, subcutaneous connective tissue. In high dose males, in addition testes and epididymides were blue coloured. In high dose males and females, also congestion between the cortex and medulla of kidneys was observed.

During the weekly clinical observations, in all high dose males in the last two weeks (Day 41 and 48 of dosing) blue coloured skin of eyes, scrotum, forelimbs and hindlimbs was observed.

From the observations of blue coloured skin in high dose males towards the end of the dosing period and the blue coloured visceral organs and tissues, it has to be concluded that the test item and / or its metabolite(s) accumulated in the animal body after repeated exposure to high concentrations. Adverse effects on male reproductive organs only occurred after a longer exposure period during which in high dose animals the test item and/or its metabolite(s) accumulated to unknown concentrations in the reproductive organs. Accordingly, this adverse effect cannot be considered as primary toxic effect on

reproductive organs because it could as well be a secondary effect following accumulation of the test substance that does not have lipophilic properties.

For further information, please see the attached report " Evaluation of reported effects on male reproductive organs in a reproduction/developmental toxicity screening test with Direct Blue 267.

Effects on developmental toxicity

Description of key information

NOAEL (development, rat, oral) = 795 mg/kg bw/day

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
795 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

OECD guideline 421: no adverse effects were observed among male or female rats at doses 88.5 to 795 mg/kg bw/day (nominal 100 to 900 mg/kg bw/day) compared to controls regarding the following parameters: litter weight (post-natal days 0, 4 and 13), mean body weight gain per litter (post-natal days 0-4, 4-13 and overall post-natal days), number of live births per litter, number of viable pups per litter (post-natal days 0 and 13), survival index of pups (post-natal day 13), sex ratio % (post-natal days 0 and 13), anogenital distance, nipples/areolae in male pups, and thyroid hormone (T4 and TSH) level (post-natal day 13).

Justification for classification or non-classification

The available information is not sufficient to draw a conclusion on a reproduction hazard. The adverse effect observed in the reproduction toxicity screening study cannot be considered as primary toxic effect on reproductive organs because it could as well be a secondary effect following accumulation of the test substance that does not have lipophilic properties.

Further testing is proposed (sub-chronic oral toxicity study, see Section 7.5.1).

Additional information