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Administrative data

Description of key information

No mortality was observed in an acute oral toxicity study with the structural surrogate FAT 75´819/A when female rats were administered up to 2000 mg/kg bw. In line, no mortality occurred in rats after oral gavage treatment with 2-ethoxyethyl (2Z)-2-cyano-2-[3-(3-methoxypropylamino)cyclohex-2-en-1-ylidene]acetate (CAS 1419401-88-9) both in a 90-day repeated dose toxicity study at up to 1000 mg/kg bw/day and in a micronucleus test after two-fold adminstration of up to 2000 mg/kg bw. 

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Acute oral toxicity:

 

No acute oral toxicity study is available for 2-ethoxyethyl (2Z)-2-cyano-2-[3-(3-methoxypropylamino)cyclohex-2-en-1-ylidene]acetate (C-1701 B_C_3). However, assessment of this endpoint has been made on acute oral toxicity data of a structural analogue via read-across and the available repeated dose toxicity data for C-1701 B_C_3 in a weight of evidence approach.

 

In a repeated dose rat bone marrow micronucleus test (BioReliance, 2012) the high dose group consisting of 5 male and 5 female Sprague-Dawley rats per sex received two oral gavage treatments with C-1701 B_C_3 suspended in Polyethlene glycol 300 (PEG 300) at the limit dose level of 2000 mg/kg bw. This dosing scheme resulted in no mortality until scheduled necropsy, which was conducted 24 hours after the second last oral test item administration.

 

Repeated dosing with C-1701 B_C_3 for a period of 14 days in 5 Wistar rats/sex/dose level at dose levels up to 1000 mg/kg bw/day similarly resulted in no mortality (Charles River Laboratories; 2013).

 

In an oral (gavage) 90 day repeated dose toxicity study in Wistar rats according to OECD 408, no mortality has been observed in animals treated with C-1701 B_C_3 in Polyethylene glycol 300 (PEG 300) up to the limit dose of 1000 mg/kg bw/day.

A low acute oral toxicity of C-1701 B_C_3 is supported by data from a structural analogue, i.e. C-1523 (CAS 1243654-84-3) via read-across. C-1523 contains the core merocyanine structure but differs in its side chains, namely partly branched alkanes instead of ethers. Certain physicochemical parameters show comparability between C-1523 and C-1701 B_C_3 (molecular weight of 346.51 and 322.41 g/mol; log Pow at 4.7 and 1.7) whereas differences in water solubility (0.13 versus 450 mg/l respectively) might lead to differences in oral bioavailability. Furthermore, possible differences in metabolisation between these structures need to be taken into account, however, the acute oral toxicity data on C-1523 are considered to provide supportive information on acute toxicity of C-1701 B_C_3 in a weight of evidence.

 

C-1523 has been tested in a non-GLP oral toxicity study, conducted according to OECD guideline 423 (Acute Toxic Class Method). Wistar rats (3 females/dose) were administered C-1523 at 300 and 2000 mg/kg bw by single dose (gavage) followed by a 8-day observation period (CIT, 2008). None of the animals died during the study period. The LD50 was >2000 mg/kg bw. No clinical signs were observed at the 300 mg/kg dose-level. Hypoactivity and piloerection were noted in all animals from day 1 until day 2 (1 animal) or day 3 (2 animals). Staggering gait (2 animals) and rhinorrea (all animals) were also observed on day 2 at the 2000 mg/kg dose level. The body weight gain of the animals given 300 or 2000 mg/kg was not affected by treatment with the test item.

 

Acute dermal toxicity:

 

In view of the absence of any mortality after repeated oral dosing up to 2000 mg/kg of C-1701 B_C_3 and with special regard to its low percutaneous absorption determined in human skinin vitrowith a dermal delivery (mean) of 1.63 % or 1.08 µg/cm² after 24 hours (Charles River Laboratories, 2013), acute toxicity via single dermal application is unlikely. Based on the low bioavailability after dermal application and the absence of mortality after oral administration, no acute dermal toxicity is to be expected. Therefore an acute dermal toxicity study in rats is not scientifically required and should not be performed for animal welfare reasons.

 

Acute inhalation toxicity:

 

In light of the present data from oral toxicity studies, and the fact, that inhalative exposure is not considered to be the major route of exposure, an acute toxicity study via the inhalative route is scientifically not required in accordance with column 2 of REACH Annex VIII, and is not in line with animal welfare requirements.

 

 

In conclusion, the data described above demonstrate a low acute toxicity potential of C-1701 B_C_3 in a weight of evidence approach.

Justification for classification or non-classification

The present data do not fulfill the criteria laid down in 67/548/EEC and regulation (EU) 1272/2008, and therefore, a non-classification is warranted.