Sodium 4-oxovalerate

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

The NOAEL (No Observed Adverse Effect Level) for the test item 4-oxovaleric acid for TOXICITY in pregnant females was established as 500 mg/kg bw/day.

 

The NOAEL (No Observed Adverse Effect Level) for the test item 4-oxovaleric acid for PRENATAL DEVELOPMENT was established as 1000 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:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
For details please refer to Read Across Justification Document, Section 13.2

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
For details please refer to Read Across Justification Document, Section 13.2

3. ANALOGUE APPROACH JUSTIFICATION
For details please refer to Read Across Justification Document, Section 13.2

4. DATA MATRIX
For details please refer to Read Across Justification Document, Section 13.2

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Description (incidence and severity):

No unscheduled death of females was recorded during the study

Mortality:

no mortality observed

Description (incidence):

No unscheduled death of females was recorded during the study

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Only females who were found pregnant on the 20th day of gravidity (females with live foetuses) were used for calculation of mean body weights. The statistical evaluation was performed from the 5th to 20th day of pregnancy.
The body weights were decreased at the dose level 1000 mg/kg bw/day compared to the control group, on the 14th and 20th day of pregnancy statistically significantly. The body weight increments were statistically significantly decreased at the dose levels 100 and 1000 mg/kg bw/day.

Description (incidence and severity):

Although this is not a feeding study food consumption was assessed and results are reported hereafter.
Only females which were found to be pregnant on the 20th day of gestation (females with live foetuses) were used for calculation of mean food consumption. The statistical evaluation was performed from the 5th to 20th day of pregnancy.
Mean food consumptions were decreased from the 8th to 14th day of pregnancy at the dose level 1000 mg/kg bw/day compared to the control group, on the 8th day of the pregnancy with statistical significance

Endocrine findings:

no effects observed

Description (incidence and severity):

Blood samples from the females which were found to be pregnant on the 20th day of gestation were assessed for serum levels of thyroid hormones (T3, T4, TSH).
No statistically significant differences were recorded in serum levels of thyroid hormones T3, T4 and TSH in females from treated groups against control females.

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

The behaviour of treated maternal animals were similar compared to the control animals.

Description (incidence and severity):

The uteri of all females were weighed, but only females which were found to be pregnant on the 20th day of gestation were used for calculation of the mean weight of uterus. The absolute weight of uterus was recorded and the relative weight of uterus was computed. The statistical evaluation of absolute and relative weight of uterus was performed.
The absolute weight of uterus was insignificantly decreased at the dose level 1000 mg/kg/day in comparison with control group. The relative weights of uterus in all dose levels was comparable with control.
The thyroid glands of all females were weighed (after fixation), but only females which were found to be pregnant on the 20th day of gestation were used for calculation of mean weight of thyroid gland. The absolute weight of thyroid gland was recorded and the relative weight of thyroid gland was computed. The statistical evaluation of absolute and relative weight of thyroid glands were performed.
Absolute and relative weights of the thyroid glands were similar in the treated and control females. Statistically significant differences of thyroid weights were not detected in females of any dose level.

Gross pathological findings:

no effects observed

Description (incidence and severity):

Macroscopic examination was performed in all females (including non-pregnant females). No finding was noted at necropsy in treated females.

Neuropathological findings:

not examined

Description (incidence and severity):

The histopathology of the thyroid glands was performed for all treated and control females. No histopathological changes were found in more than half of the females in each groups. The changes found in the remaining animals are few in number, weak in expression and affect all groups of animals studied. Mild hypertrophy found in two control females and in four females at the dose level 1000 mg/kg bw/day indicated increased reversible thyroid activity. The changes are isolated, weakly expressed and do not deviate from natural variability of the thyroid histological picture of clinically healthy animals.

Histopathological findings: neoplastic:

not specified

Description (incidence and severity):

Body weight - corrected
Corrected body weight of females was calculated, but only females which were found to be pregnant on the 20th day of gestation were used for calculation of the mean corrected body weight. The statistical evaluation of corrected body weight was performed.
Mean value of corrected body weight of females was statistically significantly decreased at the dose level 1000 mg/kg bw/day in comparison with control

Number of abortions:

not specified

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

The numbers of implantations and corpora lutea were similar in all treated groups with control group. Preimplantation losses (IUDE) and postimplantation losses (IUDL) were comparable or lower in the treated groups than in the control group. Statistically significant differences were not detected in these parameters.

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Description (incidence and severity):

The numbers resorptions were similar in all treated groups with control group.

Dead fetuses:

no effects observed

Description (incidence and severity):

No dead foetus was found in treated groups and control.

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

not specified

Details on maternal toxic effects:

The reduced fetal weights may be related to the maternal toxicity of the test item (decreased maternal body weight and/or food intake) at the highest dose level, but the maternal toxicity was not evident at the dose level 500 mg/kg bw/day.

Key result

Dose descriptor:

NOAEL

Effect level:

500 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

Description (incidence and severity):

The mean body weight of foetuses was decreased at the dose levels 500 and 1000 mg/kg/day, statistical significance was not detected. Male foetuses were heavier than females in all groups

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

No statistically significant differences with toxicological significance were recorded in number of litters during the statistical evaluation of skeletal findings.

Anogenital distance of all rodent fetuses:

no effects observed

Description (incidence and severity):

The AGD and corrected AGD of male and female foetuses at all dose levels were comparable with control group

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Description (incidence and severity):

Examination of symmetry of fore and hind limbs, number of fingers, closing or opening of eye fissures and external auditory canal, symmetry of head, integrity of superior palatum, status of umbilicus and genital papilla were performed.
No external changes were recorded in treated groups and control

Description (incidence and severity):

Examination of foetal cranium revealed mainly incomplete ossification of cranial bones. Incompletely ossified were mostly parietal bone, interparietal bone, supraoccipital bone, squamosal part of temporal bone, arcus zygomaticus, less frequently nasal bone, frontal bone, premaxilla, maxila and basisphenoid. High incidence of incomplete ossification of parietal bone, interparietal bone, supraoccipital bone, squamosal part of temporal bone were recorded at all dose levels as well in control group. The proportion of litters with incomplete ossification of premaxilla, maxilla and basisphenoid were comparable or lower at all dose levels in comparison with control group. The increased portion of litters with incomplete ossification of frontal bone was recorded at the dose levels 500 and 1000 mg/kg bw/day (9.52 % – 18.18 % – 45.00 % – 27.27 %), without statistical significance and dose dependence. The portion of litters with incomplete ossification of nasal bone was increased only at the dose level 500 mg/kg bw/day. The statistically insignificantly increased incidence of litters with incomplete ossification of arcus zygomaticus was recorded at the dose levels 500 and 1000 mg/kg bw/day (57.14 % – 50.00 % – 80.00 % – 68.18 %), without dose dependence.
The litters with holes in the supraoccipital bone were detected in high percentage in all treated groups as well in the control group. Other changes of foetal cranium were found only sporadically.

During examination of the foetal skeletons incomplete ossification of ossification sites of sternebra and unossified ossification sites of sternebra were recorded. The incidence of incomplete ossification of ossification sites on sternebra was very common finding in the treated groups and also in the control group. All treated and control litters were affected with incomplete ossification of ossification sites of sternebra. The proportion of litters with unossified ossification sites of sternebra (61.90 % – 72.73 % – 75.00 % – 77.27 %) was comparable in treated groups with control. The incidence of litters with bipartite ossification of ossification sites of sternebra was lower at dose levels in comparison with control (19.05 % – 13.64 % – 5.00 % – 0.00 %).

Examination of vertebrae revealed mainly bipartite and dumbbell ossification of vertebrae thoracic centrum. The proportion of litters with bipartite ossification of vertebrae thoracic centrum was increased at the dose levels 1000 mg/kg bw/day in comparison with control group (23.81 % – 13.64 % – 25.00 % – 40.91 %), without statistical significance. Insignificantly increased incidence of litters with the bipartite ossification of vertebrae thoracic centrum with asymmetric ossification was recorded also at the highest dose level.
The proportions of litters with dumbbell ossification of vertebrae thoracic centrum was high in treated groups as well as in the control group (80.95 % – 81.82 % – 90.00 % – 95.45 %). During the statistical evaluation of findings on the vertebrae the statistically significantly increased number of foetuses with dumbbell ossification of vertebrae thoracic centrum were detected at the dose level 1000 mg/kg bw/day, but in the case of conversion to litter no statistical significance was found. Other changes of foetal vertebrae were found only sporadically.

Anomaly of ribs – supernumerary ribs – lumbar ossification site and wavy ribs were recorded. The proportion of litters with supernumerary ribs – lumbar ossification site and wavy ribs were comparable or lower at all dose levels in comparison with control group.

The incomplete ossification of humerus was recorded in all treated groups and also in the control group. The proportions of litters with incomplete ossification of humerus were 4.76 % – 0.00 % – 10.00 % – 9.09 %, respectively for the four groups 0, 100, 500 and 1000 mg/kg bw/day.

Visceral malformations:

no effects observed

Description (incidence and severity):

Detailed gross dissections of foetuses were performed. Placing and morphology of organs and big vessels were reviewed during examination of internal alterations. No adverse findings were observed in any of the test groups or the control group.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: This NOAEL is based on no altered growth and no significant treatment-related structural abnormalities in foetuses of pregnant rats dosed up to 1000 mg/kg bw/day.

Abnormalities:

effects observed, non-treatment-related

Description (incidence and severity):

Skeletal alterations have been observed, however these effects have not been related to the treatment

Key result

Developmental effects observed:

no

Conclusions:

The NOAEL (No Observed Adverse Effect Level) for the test item acid for TOXICITY in pregnant females was established as 500 mg/kg bw/day.
NOAEL value is based on no mortality of females, no altered growth, no changes in health condition status, no alteration to thyroid parameters, no pathological findings in the dams and no dose related changes in reproduction parameters up to 500 mg/kg bw/day.

The NOAEL (No Observed Adverse Effect Level) for the test item for PRENATAL DEVELOPMENT was established as 1000 mg/kg bw/day.
This NOAEL is based on no altered growth and no significant treatment-related structural abnormalities in foetuses of pregnant rats dosed up to 1000 mg/kg bw/day.

Executive summary:

The test item was tested for prenatal developmental toxicity using the OECD Test Guideline No. 414, Prenatal Developmental Toxicity Study, Adopted by the Council on June 25^th 2018.

 

There were no deaths of females during the study at any dose level. No adverse changes in health condition and no clinical symptoms of intoxication were observed in maternal animals following administration of the test item at any dose. In this prenatal developmental study the negative effect of the test item on the growth of maternal animals was observed at the highest dose level 1000 mg/kg bw/day. The body weight of treated females was decreased at the dose level 1000 mg/kg bw/day compared to the control group, on the 14^th and 20^th day of pregnancy statistically significantly. The body weight increments were significantly decreased at the dose levels 100 and 1000 mg/kg bw/day. Also value of corrected body weight of females was statistically significantly decreased compared to the control group at the highest dose level.

The weight reduction correlated with the decrease of food consumption in treated females at the highest dose. The food consumption of treated mothers was decreased from the 8^th to 14^th day of pregnancy at the dose level 1000 mg/kg bw/day, on the 8^th day of the pregnancy with statistical significance.

 

Evaluation of uterus biometry detected decrease of absolute weights at the dose level 1000 mg/kg bw/day. This decrease in the absolute weight of the uterus was related to the lower necropsy body weight of the treated females whereas the relative uterine weight remains unchanged throughout all the treated as well as control groups.

Macroscopic structure of examined organs of pregnant females and reproduction parameters (number of females with live foetuses, number of live and dead foetuses, early and late resorptions) were unaffected by treatment with the test item.

Examination of the thyroid glands (absolute and relative weight of thyroid gland, histological examination of thyroid gland and serum levels of thyroid hormones) did not reveal any changes associated with the application of the test item.

 

Test item-related foetal mortality was not evident at any dose level. Detailed necropsy of foetuses did not reveal an increase of external and visceral variations and malformations at any dose level.

 

The mean body weights of foetuses were decreased at the dose level 500 and 1000 mg/kg bw/day compared to the control, but without statistical significance and dose dependence.

 

The mean AGD and corrected AGD of male and female foetuses in treated groups was not statistically significantly different from the control group.

 

No statistically significant differences with toxicological significance were recorded in number of litters during the statistical evaluation of skeletal findings.

Increased incidence of delayed ossification of some cranial bones (frontal bone, arcus zygomaticus, nasal bone) was observed at the dose levels 500 and 1000 mg/kg bw/day, without statistical significance and without dose relationship. These changes were not considered to be adverse due to their reversibility in postnatal life.

 

The NOAEL (No Observed Adverse Effect Level) for the test item for TOXICITY in pregnant females was established as 500 mg/kg bw/day.

NOAEL value is based on no mortality of females, no altered growth, no changes in health condition status, no alteration to thyroid parameters, no pathological findings in the dams and no dose related changes in reproduction parameters up to 500 mg/kg bw/day.

 

The NOAEL (No Observed Adverse Effect Level) for the test item for PRENATAL DEVELOPMENT was established as 1000 mg/kg bw/day.

This NOAEL is based on no altered growth and no significant treatment-related structural abnormalities in foetuses of pregnant rats dosed up to 1000 mg/kg bw/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subchronic

Species:

rat

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 developmental toxicity data are available for the target substance. However, data on similar substance was taken into account to fulfill the data-gap. Details on the similarity are reported in section 13.

The test item was tested for prenatal developmental toxicity using the OECD Test Guideline No. 414, Prenatal Developmental Toxicity Study, Adopted by the Council on June 25^th 2018.

The NOAEL (No Observed Adverse Effect Level) for the test item for TOXICITY in pregnant females was established as 500 mg/kg bw/day.

NOAEL value is based on no mortality of females, no altered growth, no changes in health condition status, no alteration to thyroid parameters, no pathological findings in the dams and no dose related changes in reproduction parameters up to 500 mg/kg bw/day.

 

The NOAEL (No Observed Adverse Effect Level) for the test item for PRENATAL DEVELOPMENT was established as 1000 mg/kg bw/day.

This NOAEL is based on no altered growth and no significant treatment-related structural abnormalities in foetuses of pregnant rats dosed up to 1000 mg/kg bw/day.

Justification for classification or non-classification

According to the CLP Regulation (EC 1272/2008), "Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1. If deficiencies in the study make the quality of evidence less convincing, Category 2 could be the more appropriate classification.

Such effects shall have been observed in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of the other toxic effects."

 

The available experimental data are adequate for classification and labelling and the substance is not classified for reproductive and developmental toxicity according to the CLP Regulation (EC 1272/2008).