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Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: specific pathogen free (Crl: CD (SD) BR VAF plus)
Sex:
not specified
Details on test animals or test system and environmental conditions:
not specified
Route of administration:
oral: unspecified
Vehicle:
other: 1 % methylcellulose
Details on exposure:
Method of administration or exposure: Intragastric intubation
Details on mating procedure:
Dosing regime (males): 7 days/week
Dosing regime (females): 7 days/week
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
not specified
Frequency of treatment:
not specified
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
62.5 mg/kg bw/day (nominal)
Dose / conc.:
250 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Male: 24 animals at 0 mg/kg or mg/l
Male: 24 animals at 62.5 mg/kg or mg/l
Male: 24 animals at 250 mg/kg or mg/l
Male: 24 animals at 1000 mg/kg or mg/l
Female: 24 animals at 0 mg/kg or mg/l
Female: 24 animals at 62.5 mg/kg or mg/l
Female: 24 animals at 250 mg/kg or mg/l
Female: 24 animals at 1000 mg/kg or mg/l
Positive control:
not specified
There were no treatment related clinical signs observed during the study.
One female receiving 1000 mg/kg/day was found dead during week 11. Post mortem revealed moist red staining of the perioral and perinasal fur and severly congested, uncollapsed lungs but no apearent signs of intubation error. One male receiving 1000 mg/kg/day was sacrificed week 13. Prior to sacrifice this animal appeared uncoordinated and continually rolled over, however there were no macroscopic abnormalities.

One female in the low dose group was found dead week 14: Post mortem findings included enlarged cervical lymph nodes, congested thymus and lungs, gaseous distension of and blood in the stomach, dark contents in the small intestines. Uterus contained recently dead foetuses and placentae; 13 pups had been born.

These mortalities were considered to be coincidental and not related to treatment. A further three animals died from accidental intubation errors.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: not specified
Critical effects observed:
not specified
System:
other: not specified
Organ:
other: not specified
Two females resorbed their single implant. This incidence was considered not to be treatment related. Among dams rearing young to weaning, mean values for implantation rates, pup survival, pup growth and associated sex ratio at birth and day 21 post partum were similar for all groups. The macroscopic examination performed at terminal autopsy of surviving adults and offspring revealed no treatment-related changes.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: not specified
Reproductive effects observed:
not specified
Conclusions:
The dosage at which no signs of toxicity were recorded is therefore considered to be 1000 mg/kg/day.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Information from migrated NONS file, as per inquiry number 06-2120846835-43-0000.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In a one-generation reproduction study (87/302/EWG, S.43; OECD 415 (1981)/GLP) the test substance was administered to rats (specific pathogen free (Crl:CD (SD) BR VAF (Plus); 24/sex/dose) by gavage in 1% methylcellulose at dose levels of 0, 62.5, 250, or 1000 mg/kg. The numbers of litters per dose were: 23 (0 mg/kg), 22 (62.5 mg/kg ), 23 (250 mg/kg), or 22 (1000 mg/kg).

 

Parental animals: There were no treatment-related clinical signs observed during the study. Three deaths (1 male and 1 female at 1000 mg/kg and 1 female at 62.5 mg/kg) were considered coincidental and not related to treatment. A further three animals died due to laboratory technical error.

 

Effects on F1 generation: Mean values for implantation rates, pup survival, pup growth and associated sex ratio at birth and Day 21 post-partum were similar for all groups. Macroscopic examination performed at terminal necropsy of surviving adults and offspring revealed no treatment-related changes. The study indicated that all dosages were without adverse effects on the growth and reproductive capacity of male and female rats or the development of their offspring. The NOAEL (parental and F1 generation) is 1000 mg/kg bw/day.

 

Short description of key information:

Toxicity to reproduction (screening study):

NOAEL (parental): 1000 mg/kg bw/day  (87/302/EWG, S.43; OECD 415 (1981), GLP)

NOAEL (F1 generation): 1000 mg/kg bw/day  (87/302/EWG, S.43; OECD 415 (1981), GLP)

 

Justification for selection of Effect on fertility via oral route:

Only 1 key study was available.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the available information in the dossier, the substance 6'-(dibutylamino)-3'-methyl-2'-(phenylamino)spiro[isobenzofuran-1(3H),9-(9H)-xanthen]-3-one (CAS No. 89331-94-2) does not need to be classified for germ cell mutagenicity when the criteria outlined in CLP Regulation (Annex I of 1272/2008/EC) are applied.

Additional information