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Effects on fertility

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study obtained through inquiry process; SNIF file obtained from ECHA.
Qualifier:
according to guideline
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Deviations:
not specified
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
70 days
Frequency of treatment:
Dosing regime (males): 7 days/week
Dosing regime (females): 7 days/week
Details on study schedule:
Number of litters per dose/conc.: at ≥ 24 mg/kg or mg/L
No. of animals per sex per dose:
Male: 30 animals at 0 mg/kg or mg/L
Male: 30 animals at 10 mg/kg or mg/L
Male: 30 animals at 50 mg/kg or mg/L
Male: 30 animals at 1000 mg/kg or mg/L
Female: 30 animals at 0 mg/kg or mg/L
Female: 30 animals at 10 mg/kg or mg/L
Female: 30 animals at 50 mg/kg or mg/L
Female: 30 animals at 1000 mg/kg or mg/L
One female treated with 1000 mg/kg/day group died owing to difficult parturition (dystocia). No other compound-related deaths or clinical signs were found. No effects on the mean body weight and the mean daily food consumption of treated males were observed at any dosage, while the mean body weight of the females given 50 and 1000 mg/kg day was lower than controls, more so at 1000 mg/kg/day. The same trend was observed regarding the daily food intake. No interferences were found on the F0 reproductive performance and no effects were observed on the weight of the gonads. In fact the testis weight at 1000 mg/kg/day was higher only as absolute weight and not as percentage of the final body weight at sacrifice and no treatment related modifications were seen histologically either in testes or in epididymides of the 1000 mg/kg/day treated group.
Gestation and birth data.
The length of parturition was slightly longer at 1000 mg/day; in addition difficult parturition was found in one 1000 mg/kg/day treated female. An increase in early resorptions and a higher number of still born with a related lower number of live births was found at 1000 mg/kg/day. No other effects were seen at this and a lower doses.
Dose descriptor:
NOEL
Effect level:
10 mg/kg bw/day
Based on:
not specified
Sex:
male/female
No effects were observed on the postnatal survival development of the F1 live pups. The apparent higher frequency of female fetuses was not considered compound-related, since such an effect was not found in the females allowed to litter.
Dose descriptor:
NOEL
Generation:
F1
Effect level:
50 mg/kg bw/day
Based on:
not specified
Sex:
male/female
Reproductive effects observed:
not specified

A lower body weight gain and mean daily food consumption was observed at 50 and 1000 mg/kg/day, more evident at 1000 mg/kg/day.

Effects on fetus (Ft generation): One malformed fetus was observed at 1000 mg/kg/day, and it was considered incidental, since it was a pluri-malformed fetus with malformations that sometimes occur in controls. No other effects were seen at this and at lower doses. The higher number of early resorptions and of still born and, the related decrease in live born observed at 1000 mg/kg/day, was interpreted as a consequence of non specific toxicity in parents (lower body weight gain and mean daily food consumption) rather than a specific effect on reproduction. No specific labelling is therefore required.

Conclusions:
The NOEL for the F0 parents is 10 mg/kg/day and for the F1 generation progeny 50 mg/kg/day. No specific labelling is therefore required.
Executive summary:

The toxicity to reporduction of the structural analogue has been determined in a GLP study with rats according to OECD Guideline No. 415 (one-generation reproduction toxicity study;oral gavage exposure at doses of 0, 10, 50 and 1000 mg/kg bw/d). In this study the effects of the substance on the reproductive performance of male and female rats and on the subsequent development of the F1 generation were assessed

and information on possible teratogenic activity was obtained. A lower body weight gain and mean daily food consumption was observed at 50 and 1000 mg/kg/day, more evident at 1000 mg/kg/day. One malformed fetus was observed at 1000 mg/kg/day, and it was considered incidental, since it was a pluri-malformed fetus with malformations that sometimes occur in controls. No other effects were seen at this and at lower doses. The higher number of early resorptions and of still born and, the related decrease in live born observed at 1000 mg/kg/day, was interpreted as a consequence of non specific toxicity in parents ( lower body weight gain and mean daily food consumption) rather than a specific effect on reproduction. No specific labelling is therefore required. The NOEL for the F0 parents is 10 mg/kg/day and for the F1 generation progeny 50 mg/kg/day.

Since EC 700-397-7 is a near analogue to the test substance (EC 413-750-2), the experimental data from this substance were used in a read-across approach.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The data has been extracted from ECHA databases. The files were first migrated from the SNIF (Structured Notification Interchange Format) format (used under Directive 67/548/EEC) into the IUCLID 5 format (used under the REACH Regulation) and represent all of the information that ECHA currently holds on this endpoint, which were submitted in the framework of a notification at least 12 years previously (as per Article 25(3)) for the substance with the same EC number for which you inquired.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The toxicity to reporduction of the structural analogue has been determined in a GLP study with rats according to OECD Guideline No. 415 (one-generation reproduction toxicity study;oral gavage exposure at doses of 0, 10, 50 and 1000 mg/kg bw/d). In this study the effects of the substance on the reproductive performance of male and female rats and on the subsequent development of the F1 generation were assessed

and information on possible teratogenic activity was obtained. A lower body weight gain and mean daily food consumption was observed at 50 and 1000 mg/kg/day in females, more evident at 1000 mg/kg/day. One malformed fetus was observed at 1000 mg/kg/day, and it was considered incidental, since it was a pluri-malformed fetus with malformations that sometimes occur in controls. No other effects were seen at this and at lower doses. The higher number of early resorptions and of still born and, the related decrease in live born observed at 1000 mg/kg/day, was interpreted as a consequence of non specific toxicity in parents ( lower body weight gain and mean daily food consumption) rather than a specific effect on reproduction. No specific labelling is therefore required. The NOEL for the F0 parents is 10 mg/kg/day and for the F1 generation progeny 50 mg/kg/day.

Since EC 700-397-7 is a near analogue to the test substance (EC 413-750-2), the experimental data from this substance were used in a read-across approach.

No NOAEL was determined within the original file. In females an increase in early resorptions and a higher number of still born with a related lower number of live births was found at 1000 mg/kg/day. No other effects were seen at this and at a lower dose. The higher number of early resorptions and of still born and the related decrease in live born observed at 1000 mg/kg/day, was interpreted as a consequence of non specific toxicity in parents. The mean body weight of the females given 50 and 1000 mg/kg day was lower than controls, more so at 1000 mg/kg/day. The same trend was observed regarding the daily food intake. So it can be concluded that the diminished body weight was a direct results of diminished food intake. This can be considered attributable to the taste of the test item and an associated refusal of food uptake. However, the lower body weight is considered to be directly attributable to the substance itself. So, the NOAEL can be set as 50 mg/kg, as toxic effects were observed at 1000 mg/k bw.


Short description of key information:
One-generation study oral (gavage), rat (Sprague-Dawley) m/f: NOEL (F0) = 10 mg/kg bw/day, NOEL (F1) = 50 mg/kg bw/day [OECD TG 415, GLP; test item: structural analogue with EC 413-750-2]

Justification for selection of Effect on fertility via oral route:
GLP and guideline study

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

The test material is not subject to classification and labelling for toxicity to reproduction in accordance with European Regulation (EC) No. 1272/2008.

Additional information