Reaction mass of lithium sodium hydrogen 4-amino-6-({5-[(5-chloro-2,6-difluoropyrimidin-4-yl)amino]-2-sulfonatophenyl}diazenyl)-5-hydroxy-3-[(4-{[2-(sulfonatooxy)ethyl]sulfonyl}phenyl)diazenyl]naphthalene-2,7-disulfonate and lithium sodium hydrogen 4-amino-6-({5-[(5-chloro-2,6-difluoropyrimidin-4-yl)amino]-2-sulfonatophenyl}diazenyl)-5-hydroxy-3-{[4-(vinylsulfonyl)phenyl]diazenyl}naphthalene-2,7-disulfonate

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

other: Information from migrated NONS file, as per inquiry number 06-2120053365-59- 0000, permission to refer granted by ECHA

Title:

Unnamed

Year:

2014

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Automatically generated during migration to IUCLID 6, no data available

IUPAC Name:

Automatically generated during migration to IUCLID 6, no data available

Details on test material:

EC number 401-560-2
Notification number 87-04-0062-02
Result Partly provided (some studies submitted less than 12 years previously)

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

other: Deionized water

Details on exposure:

Method of administration or exposure: Schlundsonde (gavage)

Details on study schedule:

Number of litters per dose/conc.: 0 at mg/kg or mg/l

No. of animals per sex per dose:

Male: 28 animals at 0 mg/kg or mg/l
Male: 28 animals at 62.5 mg/kg or mg/l
Male: 28 animals at 250 mg/kg or mg/l
Male: 28 animals at 1000 mg/kg or mg/l
Female: 28 animals at 0 mg/kg or mg/l
Female: 28 animals at 62.5 mg/kg or mg/l
Female: 28 animals at 250 mg/kg or mg/l
Female: 27 animals at 1000 mg/kg or mg/l

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

Results of examinations: parental animals
Details on results (parental animals)
Behaviour and health status was not affected in the
control-, low- and mid-dose group animals with the
exception of males Nos. 66, 79 and 81 (mid dose group)
exhibiting broken off incisors from week 7 onwards. In the
high dose group 1 male and 1 female animal was found dead
(days 19 and 5) with unknown pathogenesis. In addition
further 6/28 males and 4/27 females were found dead or
killed on human grounds form study week 6 - 7 onwards due to
severe broken off- and white discolored incisors; no
compound related clinical signs were observed in the control
and low dose group; blue discolored feces on all
P-generation male and female animals of the 250 mg/kg body
weight group, males from day 22 and females from day 15 up
to the end of the study. Male animal Nos. 66 and 81 had
lover or upper incisors broken off from weeks 12 and 7,
respectively. The latter also showed stilted gait and
quatting posture. In the high dose group all males and
females exhibited bluish discolored feces, a few of them
later on also bluish discolored urine. The lower and
upper incisors were white discolored from week 5 onwards and
generally broke off within a few days. Some of those animals
developed general clinical signs (stilted gait,
hypoactivity, coat bristling, irregular respiration,
respiratory sounds diarrhea, snout encrusted blood colored
or swollen etc.) and some of those ended up in a general
poor condition due to the fact that they could not take up
food properly. 13/27 females in this group did not get
pregnant. Body weight gains were only significantly
influenced (decreased) for high dose males (10 %) due to
dental problems. Mating results: all females of the
control-, low and middle dose group were recorded as being
successfully mated. In the high dose group only 23/27
females were detected sperm positive.
A slight but statistically significant increase in mean
total bilirubin in high dose males and females was
considered to be substance related. Absolute organ weights
were not influenced by administration fo the test compound
in the low-and mid dose groups, no organ toxicity. No
significant changes in organ weights relative to body weight
were recorded for the low-, mid and high dose females, no
changes of statistical significance in the low and mid-dose
group males. No relevant macroscopic changes in male or
female animals of the control and low dose groups. Males
and females of the mid dose group exhibited dicolored
kidneys. Relevant histopathological findings were:
kidneys: appearance of intratubular pigment in 10 males and
5 female animals,
liver: increased number ofnecrotic/apoptotic cells; one
animal showed a peripheral fatty change;
stomach: mixed cellular infiltrations in the submucosal area
in particular for the males. The intracellular storage of
pigment in the kidneys of the high dose animals is caused by
test compound which was not released by the tubular cells
after filtration. The appearance of inflammatory cells in
the submucosal area of the stomach is obiously a sign of
irritation caused by the test compound.
Dental examinations indicate a significantly higher amount
of fluor in particular on the dental surface.

Results: F1 generation

Details on results (F1)

Results of examinations: offspring
Details on results (offspring)
Effects on F1 generation:
At birth the number of pregnancies were 22, 19, 22 and 12
for controls, low, mid- and high dose females. At 1000 mg/kg
body weight 3/11 females delivered normally developed pups.
The mean body weight of live pups during dactation was
significantly decreased in the high dose offspring from days
14 post partum onwards. No behavioral or other physical
abnormalities were redorded for the offspring in any dose
group including the high dose.
Overall remarks,

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

62.5 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

there was no evidence of selective reproductive toxicity in rats