A mixture of: propan-2-one-O,O'(methoxyvinylsilandiyl)dioxime; propan-2-one-O-(dimethoxyvinylsilyl)oxime; propan-2-one-O,O',O''-(vinylsilantriyl)trioxime

Toxicity to reproduction

Administrative data

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
According to the column 1 of REACH Annex IX, the extended one generation reproductive toxicity study does not need to be conducted since the available repeated dose toxicity studies (28-day and 90-day studies) does not indicate adverse effects on reproductive organs or tissues or reveal other concerns in relation with reproductive toxicity.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
See attached the rationale for read-across.
See attached the reporting format and data matrix.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across: supporting information

Key result

Dose descriptor:

NOAEL

Effect level:

13.22 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: red blood cell rate of turnover resulting in associated changes in the spleen.

Remarks on result:

other: Based on a read-across from an analogue substance for which the NOAEL was 15 mg/kg-bw/day.

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

44.06 mg/kg bw/day (nominal)

System:

haematopoietic

Organ:

erythrocyte development

spleen

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

Based on the read-across approach from the analogue substance OS2200, the sub-chronic NOAEL for Wasox-VMAC2 was determined to be 13.22 mg/kg bw/day for general systemic toxicity.

Executive summary:

A 13 week repeated dose toxicity test followed by a 4 week recovery period was performed to assess the systemic toxicity of the analogue substance OS 2200 by the oral route in rats. It was concluded that the principal action of OS2200 was to affect the red blood cell rate of turnover occurring mainly among animals receiving 50 mg/kg/day, resulting in associated changes in the spleen. A dosage level of 15 mg/kg/day was considered the NOAEL for OS 2200. Based on the read-across approach from the analogue substance OS2200, the sub-chronic NOAEL for Wasox-VMAC2 was determined to be 13.22 mg/kg bw/day for general systemic toxicity.

Cross-reference 2

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Key study (sub-acute): A Repeated dose 28-Day Oral toxicity Study in Rodents for the test substance was performed in rats. The No-observed-effect-level of the test substance was at 20 mg per kg body weight and day in both sexes.

Key study (sub-chronic): Based on the read-across approach from the analogue substance OS2200, the sub-chronic NOAEL for the test substance was determined to be 13.22 mg/kg bw/day for general systemic toxicity.

Key study (sub-acute): A short term inhalation repeated dose toxicity study is available for the degradation product methanol performed with a method similar to OECD Guideline 412. Rats exposed to up to 5010 ppm (6 hr/d, 5d/wk for 4 weeks) showed no treatment-related histopathological effects. Inhalation exposure only resulted in some slight treatment-related signs.

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

13.22 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Two studies are available: one of 28-days and the other of 90-days duration. Both of them are GLP compliant (Klimisich score = 1). The overall quality of the database was determined to be appropriate for assessment.
The study with the longest duration (90-days) was chosen.

System:

haematopoietic

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

6 677 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

One study available with Klimisch score=2

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Key study: Test substance Wasox-VMAC2 (RDT 28 days, rats):

The test material was administered blended with corn oil, given orally by gavage to 3 groups of 5 male and 5 female rats, once a day for 28 consecutive days. The dose used were 20, 63, and 200 mg/kg/day. A negative control group (treated with the vehicle) was included.In addition, 2 groups of 5 males and 5 females each (i.e. one high dose satellite group and one control satellite group) were treated in the same way as their corresponding groups, but were kept for further 14 days without test substance administration in an attempt to observe the reversibility or persistence of test substance induced lesions.

The effects noted at a dose of 200 mg/kg and below were mainly adaptations to damage to peripheral erythrocytes without an impairment of the blood cell production in the bone marrow. All other effects noted were only borderline ones.

Key study: Read-across from experimental data on the analogue OS2200 (RDT 90 days, rats)

A 13 week repeated dose toxicity test followed by a 4 week recovery period was performed to assess the systemic toxicity of the analogue substance OS 2200 by the oral route in rats. It was concluded that the principal action of OS2200 was to affect the red blood cell rate of turnover occurring mainly among animals receiving 50 mg/kg/day, resulting in associated changes in the spleen. A dosage level of 15 mg/kg/day was considered the NOAEL for OS 2200. Based on the read-across approach from the analogue substance OS2200, the sub-chronic NOAEL for the test substance was determined to be 13.22 mg/kg bw/day for general systemic toxicity. Nevertheless, it is important to note the low severity of the observed effect (reductions of haemoglobin less than 10 % without marked organ disfunction) and the absence of persistence of the observed effects (reversibility within 4 weeks recovery-period).

Key study: Degradation product methanol (RDT, inhalation route, 4 weeks, rats)

A short-term repeated dose toxicity study (inhalation route) was performed on methanol according to a similar method to OECD guideline 412. Groups of 5 male and 5 female rats were exposed to the test item by whole body inhalation at concentrations of 0, 520, 1980 and 5010 ppm, 6 hours per day, 5 days per week for 4 weeks. During the study, clinical observations, bodyweight, organ weight, ophthalmoscopic examination, macropathology and histopathology were undertaken. The only treatment and dose-related effect noted was that of mucoid nasal discharge in rats, which was considered reflective of upper respiratory tract irritation. No consistent treatment-related effects were found for organ or body weights or for histopathologic or ophthalmoscopic examinations. These results suggest that a NOAEL of 5010 ppm equivalent to 6.67 mg/L can be established for the test substance.

Based on the available data on a 28-day study, the substance is not classified for repeated dose toxicity since the effects noted at a dose of 200 mg/kg and below were mainly adaptations to damage to peripheral erythrocytes without an impairment of the blood cell production in the bone marrow. All other effects noted were only borderline ones. Effects seen in mature erythrocytes in the peripheral blood did not result in any damage to the bone marrow production/functionality. An adaptative response was shown by haematopoiesis in spleen. The decrease in haemoblobin was compensated without organ damage. Furthermore the satellite group had shown complete recovery of haematological parameters. Therefore according to the Guidance on the Application of Regulation (EC) nº 1272/2008, annex I: 3.9.2.8.1 the adaptative responses seen in the study are not considered toxicologically relevant to classify the substance.

The 13 weeks-NOAEL (oral, rat) was determined to be 13.22 mg/kg bw/day based on haematologic changes resulting in associated changes in the spleen observed at an estimated dose of 44.06 mg/kg bw/day. Nevertheless, given the low severity of this effect (reductions of haemoglobin less than 10 % without marked organ disfunction) and the absence of persistence of the observed effects (reversibility within 4 weeks recovery-period), the substance is not classified for STOT RE according to CLP Regulation (EC) No. 1272/2008.

Furthermore, methanol was determined not to have treatment related effects in a subacute inhalation toxicity test performed in rats up to concentrations of 5010 ppm (equivalent to 6.67 mg/L). Thus, the test substance also does not need to be classified STOT RE according to CLP Regulation (EC) No. 1272/2008 because of its degradation product methanol.

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:

not specified