Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

A reproduction/developmental toxicity screening test was performed with the read-across substance methyl-ethylketone peroxide in TXIB and DMP according to OECD 421. In this read-across study, methyl-ethylketone peroxide showed a no-observed-adverse-effect level (NOAEL) of 50 mg/kg/day for parental systemic toxicity. No effects on F0 reproduction were noted in animals administered methyl-ethylketone peroxide at dosage levels of 25, 50 or 100/75 mg/kg/day, therefore the NOAEL for F0 reproductive toxicity was >= 75 mg/kg/day. Furthermore, the NOAEL for F1 neonatal toxicity was 50 mg/kg/day.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
75 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP and OECD Guideline conform study
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No data with the test substance is available. Thus data from the read across substance Methyl-ethylketone peroxide was summarized to cover this endpoint. For further justification see IUCLID section 13.

A reproduction/developmental toxicity screening test was performed with the read across substance methyl-ethylketone peroxide in TXIB and DMP according to OECD guideline 421. This study was conducted to provide preliminary information on the potential adverse effects of methyl-ethylketone peroxide on male and female reproduction. This investigation encompassed gonadal function, mating behavior, conception, parturition and lactation of the F0 generation and the development of offspring from conception through day 4 of postnatal life.Three groups of male and female Crl:CD(SD) rats (12/sex/group) were administered the test article, methyl-ethylketone peroxide, in the vehicle (0.1% polysorbate 80), daily by oral gavage for at least 14 consecutive days prior to mating. Dosage levels for the F0 generation were 25, 50 and 100 mg/kg/day; however, due to the mortality/moribundity of 1 male and 2 females in the 100 mg/kg/day group following 2 days of dose administration, the dosage level was lowered to 75 mg/kg/day.

Based on the results of this study, F0 parental systemic toxicity was observed at 100/75 mg/kg/day as mortality/moribundity, reductions in body weight and food consumption, and macroscopic and microscopic findings in the stomach. No signs of parental systemic toxicity were observed at 25 and 50 mg/kg/day; therefore, the no-observed-adverse-effect level (NOAEL) for parental systemic toxicity was 50 mg/kg/day.

No effects on F0 reproduction were noted in animals administered methyl-ethylketone peroxide at dosage levels of 25, 50 or 100/75 mg/kg/day, therefore the NOAEL for F0 reproductive toxicity was 75 mg/kg/day. F1 growth and survival were unaffected by parental test article administration; however, because mean F1 pup body weights in the 100/75 mg/kg/day group were lower than control values, the NOAEL for F1 neonatal toxicity was 50 mg/kg/day. There were no differences between the vehicle control groups when F0 and F1 parameters were evaluated; therefore, the toxicity observed at the 100/75 mg/kg/day dosage level was due to the methyl-ethylketone peroxide and not to the diluent components.


Effects on developmental toxicity

Description of key information
The No Observed Adverse Effect Level (NOAELs) weres determined as follows:
NOAEL (maternal toxicity): 65 mg/kg bw/day
NOAEL (developmental toxicity): 200 mg/kg bw/day.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Please refer to attached read-across justification document in IUCLID Section 13.
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
65 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Key result
Abnormalities:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No test item-related adverse effects observed up to the highest dose tested.
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
reliable GLP and OECD Guideline conform study
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No data with the test substance is available. Thus data from the read across substance Methyl-ethylketone peroxide was summarized to cover this endpoint. For further justification see IUCLID section 13.

The read across substance was examined for its possible prenatal developmental toxicity. Groups of 24 sperm-positive female Hsd. Brl. Han: Wistar rats were treated with the test substance by oral administration daily at three dose levels of 20, 65 and 200 mg/kg bw/day from day 5 up to and including day 19 post coitum. A control group of 24 sperm positive females was included and the animals were given the vehicle sunflower oil. The treatment volume was 2 mL/kg bw. A sufficient stability and homogeneity in the chosen vehicle were verified over the range of relevant concentrations at the appropriate frequency of preparation. The test substance in sunflower oil was stable at room temperature for 4 hours and in a refrigerator (5 ± 3 °C) for 3 days at the concentrations of 10 and 200 mg/mL. Analytical control of dosing solutions was performed on the first and last week of treatment. Concentrations of the test item in the dosing formulations varied in the acceptable range between 95 and 100 % of nominal concentrations at both analytical occasions confirming proper dosing. During the study, mortality was checked and clinical observations were performed. Body weight and food consumption of the dams were also recorded. The day when sperm was detected in the vaginal smear was regarded as day 0 of gestation. Caesarean section and gross pathology were performed on gestational day 20. The number of implantations, early and late resorptions, live and dead fetuses in each uterine horn and the number of corpora lutea were recorded. Each fetus was weighed and examined for sex and gross external abnormalities. The placentas were weighed and examined externally. About half of each litter was preserved for visceral examination and the other half of the litters were preserved for skeletal evaluation. At visceral examination the bodies were micro dissected by means of a dissecting microscope. The heads were examined by Wilson's free-hand razor blade method. After cartilage-bone staining the skeletons were examined by means of a dissecting microscope. All abnormalities found during the fetal examinations were recorded.

In total, there were 23 evaluated litters each in the control and 20 mg/kg bw/day group, 24 and 21 in the 65 and 200 mg/kg bw/day groups respectively.

The death of one as well as clinical signs of three further pregnant females (squish breath, dyspnoea and breath with open mouth started in all cases immediately after drawing the gavage out of the esophagus) in the 200 mg/kg bw/day group were suspected to be due to an aspiration or inhalation of the test item hence as a consequence of a technical reason probably due to the properties of the test item at this concentration.

The stomach and intestines of the dam which died before scheduled necropsy were empty and filled with gas. The necropsy findings (reddish mottled lungs, dark red liver) of the non-pregnant female in the 200 mg/kg bw/day group that died before scheduled termination might confirm the suspect of aspiration/asphyxia.

There was no mortality and treatment related clinical signs and necropsy findings in the 65 and 20 mg/kg bw/day dose groups.

A slight, but statistically significant reduction in the body weight gain was observed in the food consumption and body weight gain of the dams in the 200 mg/kg bw/day group between gestation days 11 and 17 which was attributed to an effect of the test item. There were no treatment related differences in the food consumption and body weight of the animals in the 65 and 20 mg/kg bw/day groups.

The mean number of implantations, intrauterine mortality and sex distribution of the fetuses was not influenced by the treatment.

There were no test item related differences in the fetal- and placental weight, body weight retardation and other external, visceral and skeletal variations. There were no fetal malformations found at external and skeletal examination. External hydrocephaly was found in one fetus as a malformation at visceral examination in the 200 mg/kg bw/day dose group which was judged to be unrelated from the treatment based on the historical control data.

As a conclusion,based on these observations the No Observed Adverse Effect Level (NOAELs) were determined as follows:

NOAEL (maternal toxicity): 65 mg/kg bw/day

NOAEL (developmental toxicity): 200 mg/kg bw/day

 


Justification for selection of Effect on developmental toxicity: via oral route:
only one study available

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data is reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on the results the substance is not considered to be classified for toxicity to reproduction under Regulation (EC) No 1272/2008.