Registration Dossier

Administrative data

additional toxicological information
Type of information:
Adequacy of study:
key study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Report based on results from GLP studies according to OECD and/or EU guidelines

Data source

Reference Type:
study report
Report date:

Materials and methods

Type of study / information:
not applicable
Principles of method if other than guideline:
Summary and evaluation fo the toxicity data for AE 141158 gained from several base set studies.
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
potassium 2-carboxy-5-iodobenzene-1-sulfonate
Details on test material:
The test substance which is a light apricot colored powder was tested in all toxicological experiments at a purity of 99.2 % except in the acute
oral study where a technical substance of 96.7 % was administered.

Results and discussion

Any other information on results incl. tables

Acute oral toxicity

AE F 141 158 was applied by gavage at a dose level of 2000 mg/kg bw to five male

Wistar rats. Five female rats per group received dose levels of 1600; 2000 or 2500

mg/kg b w. There were no deaths in males. Mortalities in females were 0/5; 3/5 and 3/5

from 1600 up to 2500 mg/kg bw. Clinical symptoms at 2000 mg/kg bw and 2500

mg/kg bw were comprised of stilted gait, squatting posture, swollen abdomen and

irregular respiration. Some of the females showed decreased spontaneous activity,

stupor, bristled coat, sunken flanks, uncoordinated gait, prone position and trembling.

Clinical symptoms were seen during the first two days after application.

During macroscopic examination of the deceased females light discoloration of the

liver, petechial bleedings and detachment of the stomach mucosa, yellowish or reddish

mucous and detachment of the mucosa in the intestine, light discoloration of the

kidneys and red discoloration of lungs was recorded. Body weight development was

not affected by treatment and the animals did not show macroscopically visible

changes when they were killed and examined at the end of the 14 day observation

period. The LDso for females was calculated 2179 mg/kg bw. Males were less sensitive.


Acute dermal toxicity

AE F 141 158 moistened with deionized water was applied to the shaved dorsal skin of

five male and five female Wistar rats at a dose of 2000 mg/kg b w. There were no

mortalities or symptoms of intoxication. The LD^ dermal was considered to be above

2000 mg/kg bw. No indications for local irritating effects could be found. Treatment

did not affect body weight gain and there were no macroscopical changes when

animals were killed at the end of the post-treatment observation period after 14 days


Primary skin irritation in the rabbit

Primary skin irritation of AE F 141 158 was tested in 3 female New Zealand White

rabbits in a test protocol according to EEC Guideline B.4. of Directive 92/69/EEC. The

test substance was moistened with 0.3 ml deionized water. There were no signs of

irritation or systemic intoxication at any evaluation time (Kreiling 1997a).

Primary eye irritation in the rabbit

Primary eye irritating properties of AE F 141 158 were tested in three female New

Zealand White rabbits in a test protocol according to EEC Guideline B.5. of Directive

92/69/EEC. One hour up to three days after administration the treated eyes of the first

animal showed intense erythema (grade 3) and chemosis (grade 3). The iris was

reddened. Diffuse corneal areas were recorded on day one and two and clear colorless

discharge was noted. Effects were reversible within 7 days.

The other two animals showed intense erythema (grade 3) and chemosis (grade 3).

Also in this case the iris was reddened, diffuse corneal areas were recorded and clear

colorless discharge was noted. The bottom of the treated eyes showed cloudy white

crystalline discolorations. Due to the nature of the irritation findings, especially of the

discoloration at the bottom of the eye, the effects were considered irreversible and the

two rabbits were killed for animal welfare reasons one day after application.

Based on the severe eye irritating properties as observed in the second and third animal

the substance should be classified as Xi: Irritant and labelled with R 41: Risk of serious

damage to the eyes (Kreiling 1997b).

Sensitization testing in the guinea pig

AE F141 158 was tested for sensitizing properties in a Magnusson & Kligman test in a

group of 10 female Pirbright White guinea pigs. Five animals were used as solvent

controls. Intradermal induction was carried out with a concentration of 5 %

AE F141 158 dissolved in deionized water, whereas a 25 % preparation was used for

dermal induction and challenge.

During treatment no indications of systemic toxicity or effects on body weight

development were found.No signs of irritation were seen after challenge treatment.

Based on the results of this assay, AE F 141 158 has no dermally sensitizing potential

under the conditions of the maximization test (Bury 1997).


AE F 141 158 was not mutagenic in a test according to Ames on Samonella

typhimurium TA 100, TA 1535, TA 1537, TA 98 and on E. coli WP 2uvrA in the

presence or absence of a metabolizing system (rat liver S-9 mix, Aroclor 1254

induced). Test concentrations ranged from 4 ug up to 5000 ug per plate. No indication

of cytotoxicity was seen (Miiller 1998a).

The substance did not induce chromosomal aberration in an V 79 Chinese Hamster

Cell system in vitro with or without S-9 mix. Test concentrations in DMSO ranged from

375 ug/ml up to 3200 ug/ml (without S-9 mix) and from 750 ug/ml up to 3661.7 ug/ml

(with S-9 mix). Evaluation was done at 20 and 28 hrs after exposure. Cytotoxicity was

seen only without S-9 mix at 2500 ug/ml and at 3200 ug/ml. AE F 141 158 did not

induce significant increases in chromosome aberration in the presence or absence of a

metabolic activation system (Miiller 1998b).

Oral 28 day study

AE F141 158 dissolved in deionized water was applied via gavage to groups of five

male and five female Wistar rats at dose levels of 0 (solvent control), 62.5; 250 or 1000

mg/kg bw for a period of 28 days in a protocol according to EEC guideline B.7 of

Directive 96/54. In addition to regular health checks, clinical examinations, recording

of body weight, food and water consumption detailed clinical observations under open

field conditions were performed weekly. At the end of the administration period

assessment of sensory function, motor activity, grip strength and landing food spread

tests were carried out. Urinalysis was performed towards the end of the treatment

period. Blood samples for hematology and clinical chemistry were taken immediately

prior to necropsy. Major organs were processed and checked for microscopically

visible changes.

There were no mortalities, clincal symptoms or substance-related findings during

hematology, clinical chemistry, urinalysis or neurotoxicological screening program. No

compound-related macroscopical findings were seen during necropsy. The only doserelated

finding in the histopathological investigation was hypertrophy of mucous neck

cells of the fundic mucous membrane of the stomach at 250 and 1000 mg/kg bw. No

such effect could be seen at 62.5 mg/kg bw. This phenomenon was not interpreted as

adverse effect, since it did not involve cell damage or necrosis and no cell hyperplasia

could be found. It was therefore regarded as a protective effect for the mucous


Based on the above the NOAEL for the 28 day administration of AE F141 158 to male

and female Wistar rats was 1000 mg/kg bw.

Applicant's summary and conclusion

AE F 141 158 was slightly toxic to female rats in acute oral experiments. Males were

less sensitive. No systemic or local hazard potential was identified during testing of the

dermal LDgo. This corresponds well to the skin tests where the compound proved

neither irritating to the rabbit skin nor dermally sensitizing to guinea pigs. A particular

hazard potential was identified in the eye irritation test. The substance caused severe

irritations and irreversible discolorations and should be classified as Xi: Irritant and

labelled with R 41: Risk of serious damage to the eyes. Safety measures and advices to

avoid eye contact are considered necessary.

AE F 141 158 did not show genotoxic properties during in vitro testing for mutagenic

properties in bacterial cells and for chromosomal aberration in V 79 cells. No adverse

effects were found in a 28 day study in rats at the high dose of 1000 mg/kg body