Registration Dossier

Administrative data

Endpoint:
fish early-life stage toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2008-2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: full GLP compliant study

Data source

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

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 210 (Fish, Early-Life Stage Toxicity Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: particulates
Details on test material:
test was performed with the tosylate salt of BAY 43-9006 (sorafenib tosylate=4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)ureido]phenoxy}pyridine 2-carboxylic acid methylamide 4-methylbenzenesulfonate)

Sampling and analysis

Analytical monitoring:
yes

Test solutions

Vehicle:
yes

Test organisms

Test organisms (species):
Pimephales promelas

Study design

Test type:
flow-through
Water media type:
freshwater
Limit test:
no
Total exposure duration:
33 d

Results and discussion

Effect concentrations
Duration:
28 d
Dose descriptor:
EC10
Effect conc.:
0 mg/L
Nominal / measured:
meas. (arithm. mean)
Conc. based on:
test mat.
Basis for effect:
mortality

Any other information on results incl. tables

Fish larvae hatched 4 days after the introduction of the eggs in all test solutions. The hatching success was > 66 % in all test and control solutions. The number of dead fish increased with increasing concentration. From the second highest concentration on, fish growth (weight and length) decreased. The NOEC and LOEC for weight and length was 2.4 ¿g/L and 14.8 ¿g/L, respectively, for survival the NOEC was < 1.0 ¿g/L and the LOEC was ¿ 1.0 ¿g/L and for hatchability NOEC and LOEC were ¿14.8 ¿g/L.

In order to define a threshold for toxic effects, the EC10 for weight and length inhibition was determined with 0.47 ¿g/L and 0.32 ¿g/L, respectively, for survival (28 dph) was 0.17 ¿g/L.

Applicant's summary and conclusion

Validity criteria fulfilled:
yes
Conclusions:
The results of this study showed that sorafenibtosylate has effects on growth and survival of fish
(fathead minnow) at concentrations from 1.0 ¿g/L onwards. Thus, the overall no observed effect concentration (NOEC) was <1.0 ¿g/L, the lowest observable effect concentration (LOEC) was 1.0 ¿g/L. The lowest EC10 for survival was 0.17 ¿g/L.
Executive summary:

The eggs and larvae were exposed to three test solutions of sorafenibtosylate with nominal

concentrations of 6, 17 and 50 ¿g (nominal) per liter tap water and additionally to a vehicle

(dimethylformamide, DMF) and a control for a period of 28 days post hatch (ph). For the

preparation of the stock solution, the test substance was dissolved in DMF.

The stock solution was mixed with tap water and delivered continuously to the tanks.

Mortalities and visible abnormalities were recorded daily over the exposure phase. Hatching

success and survival were recorded during the first phase of embryonic development as well as

growth and survival during the larval stage until the end of the exposure period. The

hydrographic parameters were recorded weekly.

The oxygen concentration in the test vessels was >60 % of air saturation value, the

temperature was maintained at 24 ± 2 ºC and the pH-value between 6.5 and 8.5.

Samples for the concentration analysis in the test solutions were taken at the start of the exposure

and weekly thereafter. The determination of sorafenibtosylate in the test solutions was carried

out by HPLC/MS.

The endpoint survival was statistically evaluated by the computer program

TOXRat Professional XT, length and weight was evaluated by PROVANTIS (NOEC, LOEC)

and TOXRat Professional XT (ECx).

Then analytical results gave mean measured concentrations of 1, 2.4 and 14.8 µg/L.

Hatching and short-term survival (day 5 ph) was not affected by the test substance while

mortality of the larvae (day 28 ph) increased clearly with increasing concentration of

sorafenibtosylate. Additionally, the growth of the treated fish decreased with increasing

concentration of the test substance.

A significant substance-related effect on growth and survival of the treated fish compared to the

control could be observed. The NOEC (survival) was <1.0 ¿g/L and the LOEC (survival) was

¿1.0 ¿g/L, the EC10 for survival was 0.17 ¿g/L. The NOEC for length and weight was 2.4 ¿g/L,

the LOEC was 14.8 ¿g/L. The EC10 was 0.47 ¿g/L for weight and 0.32 ¿g/L for length.

Accordingly, 0.17 ¿g/L was the toxicity threshold for sorafenib tosylate.