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Description of key information

The data reported here are for the structural analogues DNNSA and CaDNNSA.

A GLP OECD 422 study indicated clinical biochemistry effects at 298 mg/kg/day and established a NOAEL at 95 mg/kg/day. The effects seen on the GI tract (hyperkeratosis of the forestomach epithelium, mucosal hyperplasia and increased severity of lymphogranulocytic inflammation in the caecum and increased amounts of mucus in the large intestines) are most probably related to acidic nature of DNNSA. In addition effects on spleen. liver and bone marrow were reported.

In a study that is performed according to OECD 408 with the calcium salt of the substance, 6/10 females in the highest dose group died, showing alterations in the gastro-intestinal tract, a small thymus and bone marrow atrophy. The surviving females at 1000 mg/kg bw showed similar effects and a reduced body weight (gain). The effects on the gastro-intestinal tract also became apparent in males at 300 and 1000 mg/kg bw. These animals also had a reduced body weight (gain). Other effects included changes in numbers of white blood cells, lymphocytes, platelets as well as effects on several biochemical parameters. Macroscopy and histopathology indicated that next to the GI-tract mainly the thymus and bone marrow could be considered as potentially affected in males at 300 mg/kg bw and above and in females at 1000 mg/kg bw. The NOAEL as derived from this study is 100 mg/kg bw.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
High Quality GLP study following current guidelines.
System:
gastrointestinal tract
Organ:
bone
thymus

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

Treatment of male and female Wistar rats with DNNSA by oral gavage in a study according to OECD 422 at dose levels of 95, 298 and 893 mg/kg bw revealed parental toxicity at 298 and 893 mg/kg bw. At 95 mg/kg, no toxicologically relevant effects were noted in any of the parameters examined. In a 90 -day study on the calcium salt of the substance 6/10 females at 1000 mg/kg bwdied, showing alterations in the gastro-intestinal tract, a small thymus and bone marrow atrophy. The surviving females at 1000 mg/kg bw showed similar effects and a reduced body weight (gain). The effects on the gastro-intestinal tract also became apparent in males at 300 and 1000 mg/kg bw. These animals also had a reduced body weight (gain). Other effects included changes in numbers of white blood cells, lymphocytes, platelets as well as effects on several biochemical parameters. Macroscopy and histopathology indicated that next to the GI-tract mainly the thymus and bone marrow could be considered as potentially affected in males at 300 mg/kg bw and above and in females at 1000 mg/kg bw.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
A well-conducted GLP OECD 408 study without significant deficiencies that established a dose-response relationship and a NOAEL.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Due to low vapor pressure (3.3E-5 Pa at 20 °C) and high boiling point (> 50 °C), the inhalation route is not considered to be a relevant exposure route to human. In addition, the data of acute toxicity by oral is available and sufficient for assessment of acute toxicity of test substance. Thus, the acute inhalation toxicity study can be waived.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Due to low vapor pressure (3.3E-5 Pa at 20 °C) and high boiling point (> 50 °C), the inhalation route is not considered to be a relevant exposure route to human. In addition, the data of acute toxicity by oral is available and sufficient for assessment of acute toxicity of test substance. Thus, the acute inhalation toxicity study can be waived.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
It is considered that exposure via the oral route is considered a worst case exposure whereby the systemic availability of the substance is considered to be maximised. Exposure via the dermal route is expected to be considerably less than via the oral route due to lack of absorption under expected exposure conditions. In addition, the acute dermal study shows that no adverse effects were observed. The data of acute toxicity by oral is available and sufficient for assessment of acute toxicity of test substance. Thus, the acute dermal toxicity study can be waived.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
It is considered that exposure via the oral route is considered a worst case exposure whereby the systemic availability of the substance is considered to be maximised. Exposure via the dermal route is expected to be considerably less than via the oral route due to lack of absorption under expected exposure conditions. In addition, the acute dermal study shows that no adverse effects were observed. The data of acute toxicity by oral is available and sufficient for assessment of acute toxicity of test substance. Thus, the acute dermal toxicity study can be waived.

Justification for classification or non-classification

In the OECD 422 study, side effects were seen at 298 mg/kg bw/d (mid dose group) whereas no effects occurred at 95 mg/kg bw/d (low dose group). The most prominent effects were the mortalities at 893 mg/kg/day (4 males and 1 female) and at 298 mg/kg/day (1 female). Surviving animals in both treatments showed some of the same clinical signs as those in the animals sacrificed. Thus, the NOAEL was set to 95 mg/kg bw/d. In the 90 day oral repeated dose toxicity study with the calcium salt mortality was observed at 1000 mg/kg bw in females. At 300 and 1000 mg/kg in males and at 1000 mg/kg bw in females effects on body weight, GI-tract alterations and histopathlogical changes in the thymus and bonemarrow became apparent. These effects are not considered leading to a classification for specific target organ systemic toxicity, repeat exposure according to CLP (Regulation EC No 1272/2008).

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