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EC number: 268-610-1 | CAS number: 68131-13-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
The commercial naphthenic acid was investigated for its repeated dose toxicity according to the OECD Guideline 422. The applied doses were 0, 100, 300 and 900 mg/kg bw.
All animals survived to scheduled termination except two females of 900 mg/kg bw group. The terminal body weight of males and females of 900 mg/kg bw were reduced. Reduced red blood cell count for males of 900 mg/kg bw and increased white blood cell count for females of 900 and 300 mg/kg bw were observed. Liver weight was increased for animals of 900 mg/kg bw and kidney weight was increased for males only in this group. The histopathological findings comprised hepatocellular hypertrophy, hyaline-droplet nephropathy, cortial lymphoid depletion in thymus, epithelial hypertrophy and cytoplasmic vacuolation of the thyroid gland and cytoplasmic vacuolation in the adrenal cortex. The NOAEL was 100 mg/kg bw for parental animals.
With respect to the reproductive/developmental toxicity investigation, reduced live pubs at birth and reduced survival rate from birth to PND 4 was found at doses of 300 and 900 mg/kg bw and reduced pub weights at dose of 900 mg/kg bw. The NOAEL for reproductive/developmental toxicity was 100 mg/kg bw.
The introduced study is proposed to be used to derive the reproduction toxicity of NA-DETA by read-across.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental 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
- Study period:
- 2012
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Rationale for read-across: naphthenic acid is presumed to be the toxic metabolite of NA-DETA Rationale for assigning reliability of 2: read-across, scientifically well performed study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes (incl. QA statement)
- 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:
- Male dosing was for 28-29 days
Females were dosed for 39-53 days - Frequency of treatment:
- daily
- Remarks:
- Doses / Concentrations:
0, 100, 300, 900 mg/kg bw
Basis:
actual ingested - No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent vehicle
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- unspecific toxic signs in females of 900 mg/kg bw
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- no statistically significant effect
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- no statistically significant effect
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- alterations found in liver, kidney, thyroid, thymus and adrenal
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- reduced survival of pubs from birth to lactation day 4
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- reduced at 900 mg/kg bw
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- reduced for pubs of 900 mg/kg bw
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Number of pubs born; Percentage of pups surviving from birth to termination PND 4
- Reproductive effects observed:
- not specified
- Conclusions:
- The commercial naphthenic acid was investigated for its reproduction toxicity according to the OECD Guideliine 422. The NOAEL was 100 mg/kg bw both for parental and offsprings. The introduced study is proposed to be used to derive the reproduction toxicity of NA-DETA by read-across.
- Executive summary:
The commercial naphthenic acid was investigated for its repeated dose toxicity according to the OECD Guideline 422. The applied doses were 0, 100, 300 and 900 mg/kg bw.
All animals survived to scheduled termination except two females of 900 mg/kg bw group. The terminal body weight of males and females of 900 mg/kg bw were reduced. Reduced red blood cell count for males of 900 mg/kg bw and increased white blood cell count for females of 900 and 300 mg/kg bw were observed. Liver weight was increased for animals of 900 mg/kg bw and kidney weight was increased for males only in this group. The histopathological findings comprised hepatocellular hypertrophy, hyaline-droplet nephropathy, cortial lymphoid depletion in thymus, epithelial hypertrophy and cytoplasmic vacuolation of the thyroid gland and cytoplasmic vacuolation in the adrenal cortex. The NOAEL was 100 mg/kg bw for parental animals.
With respect to the reproductive/developmental toxicity investigation, reduced live pubs at birth and reduced survival rate from birth to PND 4 was found at doses of 300 and 900 mg/kg bw and reduced pub weights at dose of 900 mg/kg bw. The NOAEL for reproductive/developmental toxicity was 100 mg/kg bw.
The introduced study is proposed to be used to derive the reproduction toxicity of NA-DETA by read-across.
Reference
Parental toxicity data:
Table 1. Results of Assessments of hematology and clinical chemistry parameters which were statistically different from control values.1 |
||||
Parameter Measured |
Corn Oil Control |
100 mg/kg/day |
300 mg/kg/day |
900 mg/kg/day |
Males, data taken at terminal sacrifice |
||||
Red Blood Cell Count (106/ul)2 |
9.22 ± 0.54 |
9.28 ± 0.28 |
8.91 ± 0.34 |
8.78 ± 0.22* |
Hemoglobin (g/dL)2 |
15.7 ± 0.72 |
15.8 ± 0.48 |
15.2 ± 0.54 |
14.7 ± 0.44* |
Hematocrit (%)2 |
48.1 ± 2.4 |
48.6 ± 1.6 |
46.5 ± 1.5 |
45.0 ± 1.8** |
Platelet (103/ul)2 |
854 ± 151 |
885 ± 84 |
803 ± 144 |
976 ± 87** |
Leukocytes, absolute (103/ul)2 |
0.02 ± 0.02 |
0.03 ± 0.02 |
0.02 ± 0.02 |
0.04 ± 0.03* |
RDW (%)2 |
11.4 ± 0.4 |
11.5 ± 0.4 |
11.6 ± 0.4 |
12.5 ± 0.6** |
HDW (g/dL)2 |
2.58 ± 0.10 |
2.68 ± 0.12 |
2.76 ± 0.16* |
2.77 ± 0.27* |
Females, data taken at termination (lactation day 4) |
||||
White blood cell count2 |
5.15 ± 1.30 |
6.89 ± 1.58 |
7.68 ± 2.24* |
7.59 ± 1.85* |
APTT (seconds)2 |
16.8 ± 1.9 |
15.9 ± 2.3 |
15.8 ± 3.1 |
13.9 ± 1.4 * |
Lymphocytes, absolute (103/ul), |
3.32 ± 0.61 |
4.50 ± 1.42 |
5.11 ± 1.75* |
4.96 ± 1.60* |
Monocytes, absolute (103/ul) |
0.11 ± 0.10 |
0.24 ± 0.21 |
0.21 ± 0.12 |
0.35 ± 0.23* |
1. Parameters not affected by treatment included:
a. Males – white blood cell count, mean corpuscular volume (fL), mean corpuscular hemoglobin (pg), mean corpuscular hemoglobin content (g/dL), prothrombin time (sec), APTT (sec), reticulocytes (%), reticulocytes, absolute (103/ul), MPV (fL), neutrophils (%), lymphocytes (%), monocytes (%), eosinophils (%), basophils (%), leucocytes(%), neutrophils, absolute (103/ul), lymphocytes, absolute (103/ul), monocytes, absolute (103/ul), eosinophils, absolute (103/ul), basophils, absolute (103/ul).
b. Females – red blood cell count (106/ul), Hemoglobin content (g/dL), hematocrit (%), mean corpuscular volume (fL), mean corpuscular hemoglobin (pg), mean corpuscular hemoglobin content (g/dL), platelet count (103/ul), prothrombin time (sec), reticulocytes (%), reticulocytes, absolute (103/ul), ), MPV (fL), neutrophils (%), lymphocytes (%), monocytes (%), eosinophils (%), basophils (%), leucocytes(%), neutrophils, absolute (103/ul), eosinophils, absolute (103/ul), basophils, absolute (103/ul), Leukocytes absolute (103/ul), RDW (%), HDW (g/dL)
2. Data given as mean + SD
* = p < 0.05, ** = p < 0.01
Table 2. Statistically significant changes in terminal body weights and organ weights.The data are given as mean + SD. |
|||||
Parameter |
Sham Control |
Corn Oil Control |
100 mg/kg/day |
300 mg/kg/day |
900 mg/kg/day |
Males |
|||||
Final Body Weight |
467 ± 27 |
454 ± 45 |
448 ± 45 |
439 ± 34 |
412 ± 28 |
Liver |
15.61 ± 1.43 |
13.46 ± 2.01 |
13.98 ± 2.04 |
15.69 ± 1.83* |
19.94 ± 2.08** |
Kidney |
3.51 ± 0.25 |
3.21 ± 0.20* |
3.38 ± 0.39 |
3.53 ± 0.33 |
3.77 ± 0.46** |
Heart |
1.46 ± 0.09 |
1.46 ± 0.21 |
1.41 ± 0.14 |
1.43 ± 0.13 |
1.32 ± 0.13 |
Thyroid/parathyroid |
0.019 ± 0.002 |
0.019 ± 0.001 |
0.020 ± 0.002 |
0.020 ± 0.002 |
0.020 ± 0.002 |
Epididymis (LT) |
0.57 ± 0.14 |
0.60 ± 0.05 |
0.60 ± 0.04 |
0.66 ± 0.05* |
0.63 ± 0.06 |
Epididymis (RT) |
0.62 ± 0.04 |
0.62 ± 0.06 |
0.61 ± 0.03 |
0.66 ± 0.04 |
0.65 ± 0.06 |
Females |
|||||
Final body Weight |
335 ± 25 |
313 ± 23 |
301 ± 30 |
294 ± 24 |
289 ± 24 |
Liver |
13.6 ± 2.0 |
11.7 ± 1.5 |
12.1 ± 1.1 |
13.3 ± 1.5 |
17.9 ± 2.4** |
Kidney |
2.39 ± 0.17 |
2.07 ± 0.18* |
2.11 ± 0.15 |
2.05 ± 0.25 |
2.17 ± 0.19 |
Heart |
1.21 ± 0.23 |
1.10 ± 0.10 |
1.08 ± 0.10 |
1.07 ± 0.11 |
1.01 ± 0.13 |
Lungs |
1.36 ± 0.13 |
1.40 ± 0.13 |
1.26 ± 0.12* |
1.20 +± 0.12** |
1.20 ± 0.07** |
Uterus/Vagina |
1.07 ± 0.19 |
1.00 ± 0.14 |
0.86 ± 0.08* |
0.88 ± 0.11* |
0.85 ± 0.12* |
* = p < 0.05, ** = p < 0.01
Table 3. Summary of microscopic findings |
||||||||
Doses, mg/kg/day |
Males |
Females |
||||||
Corn Oil |
100 |
300 |
900 |
Corn Oil |
100 |
300 |
900 |
|
N |
12 |
12 |
12 |
12 |
9 |
12 |
10 |
10 |
Kidney |
||||||||
Hyaline Droplets |
0 |
3 |
10** |
11** |
0 |
0 |
0 |
0 |
Minimal |
0 |
3 |
9** |
9** |
0 |
0 |
0 |
0 |
Mild |
0 |
0 |
1 |
2 |
|
|
|
|
|
|
|
|
|
|
|
|
|
Nephropathy |
0 |
0 |
2 |
9** |
0 |
0 |
0 |
0 |
Minimal |
0 |
0 |
2 |
5* |
0 |
0 |
0 |
0 |
Mild |
0 |
0 |
0 |
4 |
|
|
|
|
|
|
|
|
|
|
|
|
|
Liver |
|
|
|
|
|
|
|
|
Hypertrophy, hepatocellular, centrilobular |
0 |
0 |
0 |
8** |
0 |
0 |
0 |
10** |
Minimal |
0 |
0 |
0 |
8** |
0 |
0 |
0 |
10** |
|
|
|
|
|
|
|
|
|
Vacuolation, hepatocellular |
2 |
1 |
2 |
0 |
0 |
1 |
0 |
2 |
Minimal |
1 |
1 |
2 |
0 |
0 |
1 |
0 |
2 |
Mild |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
|
|
|
|
|
|
|
|
Thymus |
|
|
|
|
|
|
|
|
Depletion, lymphoid, cortex |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
5 |
Minimal |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
4 |
Mild |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
|
|
|
|
|
|
|
|
|
Thyroid |
|
|
|
|
|
|
|
|
Hypertrophy, epithelial |
0 |
6 |
9* |
11** |
0 |
3 |
4 |
8** |
Minimal |
0 |
6 |
9** |
11** |
0 |
3 |
4 |
6* |
Mild |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
2 |
|
|
|
|
|
|
|
|
|
Vacuolation, cytoplasmic |
0 |
6 |
9** |
10** |
0 |
3 |
4 |
8** |
Minimal |
0 |
6 |
9** |
10** |
0 |
3 |
4 |
8** |
|
|
|
|
|
|
|
|
|
Adrenal Cortex |
|
|
|
|
|
|
|
|
Vacuolation, cytoplasmic |
0 |
2 |
3 |
2 |
0 |
0 |
0 |
2 |
Minimal |
0 |
2 |
3 |
2 |
0 |
0 |
0 |
1 |
Mild |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
|
|
|
|
|
|
|
|
|
Heart |
|
|
|
|
|
|
|
|
Cardiomyopathy
|
|
|
|
|
|
|
|
|
Minimal |
4 |
7 |
8* |
8* |
3 |
3 |
2 |
5 |
Mild |
2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
* = p < 0.05, ** = p < 0.01
Data on reproduction performance and offsprings
Table 1. Summary of reproductive parameters assessed in the repeated dose/reproductive toxicity study of naphthenic acids. |
||||
Dose (mg/kg bw) |
Corn Oil Control |
100 mg/kg/day |
300 mg/kg/day |
900 mg/kg/day |
Number of females paired |
12 |
12 |
12 |
12 |
Number of females mated |
12 |
12 |
10 |
11 |
Number of females pregnanta |
9 |
12 |
10 |
11 |
Number of females with litters |
9 |
12 |
10 |
11 |
Precoital interval (days) |
1.4 ± 0.7 |
2.3 ± 1.1 |
4.2 ± 3.3 *b |
3.8 ± 3.5 |
Gestation length (days) |
21.4 ± 0.6 |
21.9 ± 0.3 |
22.0 ± 0.5 |
22.1 ± 0.5 |
Corpora lutea |
15.6 ± 2.3 |
14.0 ± 1.4 |
15.1 ± 3.0 |
13.8 ± 2.1 |
Implantation sites |
15.0 ± 2.4 |
13.6 ± 1.1 |
13.0 ± 1.2 |
12.2 ± 3.7 |
Number born |
14.1 ± 1.9 |
12.9 ± 1.1 |
12.0 ± 1.6 |
10.8 ± 3.8 * |
Post-implantation loss (%) |
6.0 |
5.1 |
7.7 |
11.5 |
a. Pregnant = uterine implantation sites
b. A single female in the 300 mg/kg bw group had a pre-coital interval of 13 days
* = p < 0.05, ** = p < 0.01
Table 2. Survival, viability and growth of offspring
|
||||
Dose (mg/kg bw) |
Corn Oil Control |
100 mg/kg/day |
300 mg/kg/day |
900 mg/kg/day |
Number of viable litters |
9 |
12 |
10 |
11 |
Number of pubs born alive/litter |
13.9 ± 1.9 |
12.9 ± 1.1 |
10.1 ± 4.0 * |
9.6 ± 4.0 ** |
Percentage of pubs surviving from birth to PND 4 |
98.1 ± 3.8 |
100 ± 0.0 |
88.0 ± 24.5 |
67.7 ± 40.6 |
Pubs (litters) found dead or euthanized in extremis |
1(1) |
0(0) |
12(5) |
38(8) |
Sex ratio (% males / litter) |
58.9 ± 9.6 |
53.9 ± 9.6 |
55.2 ± 19.1 |
58.1 ± 22.7 |
Pub weight PND 1 -males |
7.0 ± 0.5 |
6.7 ± 0.6 |
6.7 ± 0.5 |
5.7 ± 0.8 * |
Pub weight PND 1 -females |
6.6 ± 0.6 |
6.5 ± 0.6 |
6.4 ± 0.4 |
5.6 ± 1.1 |
Pub weight PND 4 -males |
9.7 ± 1.1 |
9.4 ± 1.2 |
9.4 ± 0.9 |
7.2 ± 1.5 ** |
Pub weight PND 4 -females |
9.1 ± 1.0 |
9.0 ± 1.0 |
8.8 ± 0.7 |
7.3 ± 1.5 ** |
* = p < 0.05, ** = p < 0.01
Effect on fertility: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 100 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- One valid OECD 422 study in rats for the purpose of read-across
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 developmental toxicity of NA-DETA was investigated according to the OECD Guideline 414 in SD rats. The animals were treated daily from gestation day 5 to 19 and the cesarean section was performed on gestation day 20. The initial dose levels of 0, 60, 120 and 250 mg/kg/day induced clinical signs indicative of severe toxicity (including mortality) so that the dose levels were reduced to 0, 20, 40 and 80 mg/kg bw.
The NOAEL of maternal toxicity was 60/20 mg/kg/day due to the clinical signs, reduced body weight and reduced food intake in the mid and high dose groups. No effect on the maternal reproductive performance was found in all treated animals.
The NOAEL of developmental toxicity was 120/40 mg/kg/day due to the reduced mean fetal weight in high dose group. No effect on litter size was found in all treated groups.
The NOAEL of teratogenicity was 250/80 mg/kg/day as no effect was found upon skeletal and visceral observation.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2015-2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Duration of treatment / exposure:
- from gestation day 6 to gestation day 19 / per gavage
- Frequency of treatment:
- once per day
- Duration of test:
- until the cesarean section on gestation day 20
- Dose / conc.:
- 80 mg/kg bw/day
- Remarks:
- The treatment at 250 mg/kg/day was reduced to 80 mg/kg/day due to the apparent toxicity. The period of treatment at 250 mg/kg/day was at most four days at the beginning of the treatment.
- Dose / conc.:
- 40 mg/kg bw/day
- Remarks:
- The treatment at 120 mg/kg/day was reduced to 40 mg/kg/day due to the apparent toxicity. The period of treatment at 120 mg/kg/day was at most four days at the beginning of the treatment.
- Dose / conc.:
- 20 mg/kg bw/day
- Remarks:
- The treatment at 60 mg/kg/day was reduced to 20 mg/kg/day due to the apparent toxicity. The period of treatment at 60 mg/kg/day was at most four days at the beginning of the treatment.
- No. of animals per sex per dose:
- 24
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- The dose selection was based on the dose-range-finding study, in which the animals were treated at volume of 10 mL/kg. In the presented main study the animals were treated at volume of 4 mL/kg, so that the test-item concentration of the applied formulation was in creased. In the presented main study, the animals exhibited clinical signs indicative of higher toxicity when compared to the dose-range finding study. After max. four days of exposure, the dose levels were reduced. The increased toxicity observed in the presented main study is likely to be associated with the local effects of the test-material, which in turn is likely to be associated with increased test-item concentration of the applied formulation.
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- effects observed, treatment-related
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- effects observed, non-treatment-related
- Description (incidence and severity):
- one animal out of 21 pregnant animals at mid dose
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed - Changes in number of pregnant:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 20 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- Key result
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined - 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):
- not relevant
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 80 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- fetal/pup body weight changes
- Key result
- Abnormalities:
- no effects observed
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 80 mg/kg bw/day
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects as a secondary non-specific consequence of maternal toxicity effects
- Conclusions:
- NA-DETA is not a developmental toxicant. No classification is warranted.
- Executive summary:
The developmental toxicity of NA-DETA was investigated according to the OECD Guideline 414 in SD rats. The animals were treated daily from gestation day 5 to 19 and the cesarean section was performed on gestation day 20. The initial dose levels of 0, 60, 120 and 250 mg/kg/day induced clinical signs indicative of severe toxicity (including mortality) so that the dose levels were reduced to 0, 20, 40 and 80 mg/kg bw.
The NOAEL of maternal toxicity was 60/20 mg/kg/day due to the clinical signs, reduced body weight and reduced food intake in the mid and high dose groups. No effect on the maternal reproductive performance was found in all treated animals.
The NOAEL of developmental toxicity was 120/40 mg/kg/day due to the reduced mean fetal weight in high dose group. No effect on litter size was found in all treated groups.
The NOAEL of teratogenicity was 250/80 mg/kg/day as no effect was found upon skeletal and visceral observation.
Reference
Summary of Clinical Signs, Physical examination and Mortality |
|||||
The animals were treated at dose of 0, 60, 120 and 250 mg/kg bw from the gestation day 5. After four days of treatment, the dose levels were reduced to 0, 20, 40, and 80 due to the severe maternal toxicity. |
|||||
|
Group No. |
G1 |
G2 |
G3 |
G4 |
Observations |
Dose (mg/kg/day) |
0 |
60/20 |
120/40 |
250/80 |
|
Total No. of rats found sperm positive |
24 |
24 |
24 |
24 |
Clinical signs and Physical examination |
|
|
|
|
|
Slight/moderate/severe salivation
|
0 |
0 |
7 |
11 |
|
Reddish nasal discharge |
0 |
0 |
2 |
7 |
|
Reddish eye discharge |
0 |
0 |
0 |
5 |
|
Moderate gasping |
0 |
0 |
0 |
1 |
|
Mortality |
0 |
0 |
0 |
1 |
Summary of maternal group mean body weight (g) |
|||||||||||
The animals were treated at dose of 0, 60, 120 and 250 mg/kg bw from the gestation day 5. After four days of treatment, the dose levels were reduced to 0, 20, 40, and 80 due to the severe maternal toxicity. |
|||||||||||
Group No. |
Dose (mg/kg/day) |
No. of Dams |
Group mean body weight (g) on day |
||||||||
|
0 |
3 |
5 |
8 |
11 |
14 |
17 |
20 |
|||
G1 |
0 |
21 |
Mean |
225.49 |
238.50 |
243.67 |
253.85 |
269.83 |
285.16 |
317.43 |
353.16 |
|
|
|
SD |
14.85 |
15.10 |
14.59 |
14.94 |
15.62 |
17.02 |
18.76 |
23.12 |
|
|
|
|
|
|
|
|
|
|
|
|
G2 |
60/20 |
21 |
Mean |
228.50 |
241.63 |
247.57 |
250.37 |
266.63 |
279.29 |
306.02 |
342.75 |
|
|
|
SD |
15.70 |
18.69 |
18.47 |
21.70 |
22.56 |
25.22 |
34.11 |
42.34 |
|
|
|
|
|
|
|
|
|
|
|
|
G3 |
120/40 |
21 |
Mean |
225.64 |
238.91 |
244.96 |
244.03 |
249.79* |
259.49* |
282.75* |
310.79* |
|
|
|
SD |
17.34 |
17.91 |
19.09 |
24.23 |
27.24 |
33.90 |
45.87 |
54.99 |
|
|
|
|
|
|
|
|
|
|
|
|
G4 |
250/80 |
21 |
Mean |
226.53 |
240.94 |
246.50 |
242.10 |
247.44* |
256.26* |
278.65* |
307.31* |
|
|
|
SD |
15.18 |
14.96 |
15.21 |
18.88 |
24.63 |
28.59 |
39.17 |
47.22 |
|
|
|
|
|
|
|
|
|
|
|
|
*: Significantly different from vehicle control group.
Summary of Food Intake (g/rat /day) |
||||||
The animals were treated at dose of 0, 60, 120 and 250 mg/kg bw from the gestation day 5. After four days of treatment, the dose levels were reduced to 0, 20, 40, and 80 due to the severe maternal toxicity. |
||||||
Period of treatment (days of gestation) |
Group No. |
G1 |
G2 |
G3 |
G4 |
|
Dose (mg/kg/day) |
0 |
60/20 |
120/40 |
250/80 |
||
No. of Dams |
21 |
21 |
21 |
21 |
||
Intermittent food intake |
|
|
|
|
|
|
|
|
|
|
|
|
|
0-3 |
|
Mean |
16.64 |
17.24 |
17.34 |
17.45 |
|
|
SD |
1.58 |
2.30 |
1.89 |
1.45 |
|
|
|
|
|
|
|
3-5 |
|
Mean |
18.56 |
18.98 |
19.28 |
19.14 |
|
|
SD |
1.63 |
1.92 |
2.29 |
1.73 |
|
|
|
|
|
|
|
5-8 |
|
Mean |
16.01 |
13.97 |
13.17* |
11.38* |
|
|
SD |
1.66 |
3.75 |
4.43 |
3.80 |
|
|
|
|
|
|
|
8-11 |
|
Mean |
18.46 |
17.13 |
14.62* |
12.66* |
|
|
SD |
1.46 |
3.19 |
4.47 |
5.94 |
|
|
|
|
|
|
|
11-14 |
|
Mean |
19.95 |
18.49 |
16.65* |
14.81* |
|
|
SD |
1.59 |
3.39 |
5.68 |
4.58 |
|
|
|
|
|
|
|
14-17 |
|
Mean |
22.28 |
20.83 |
18.92 |
17.91* |
|
|
SD |
2.58 |
5.11 |
6.64 |
6.19 |
|
|
|
|
|
|
|
17-20 |
|
Mean |
21.64 |
21.89 |
18.16 |
18.06 |
|
|
SD |
2.35 |
4.66 |
6.06 |
5.89 |
|
|
|
|
|
|
|
*: Significantly different from vehicle control group.
Summary of Maternal Data |
|||||
The animals were treated at dose of 0, 60, 120 and 250 mg/kg bw from the gestation day 5. After four days of treatment, the dose levels were reduced to 0, 20, 40, and 80 due to the severe maternal toxicity. |
|||||
|
Group No. |
G1 |
G2 |
G3 |
G4 |
Parameters |
Dose (mg/kg/day) |
0 |
60/20 |
120/40 |
250/80 |
|
No. of Dams |
21 |
21 |
21 |
21 |
|
|
|
|
|
|
Gravid uterine weight (g) |
Mean |
79.12 |
66.92 |
64.69 |
70.21 |
|
SD |
19.23 |
18.14 |
25.18 |
20.02 |
|
|
|
|
|
|
Number of Corpora lutea |
Mean |
16.52 |
15.48 |
15.90 |
17.05 |
SD |
2.52 |
2.50 |
2.21 |
2.04 |
|
|
|
|
|
|
|
Number of Implantations |
Mean |
14.43 |
12.86 |
13.86 |
14.81 |
SD |
3.64 |
3.53 |
2.92 |
2.23 |
|
|
|
|
|
|
|
Early Resorptions |
Mean |
0.67 |
0.76 |
1.62 |
0.95 |
SD |
0.80 |
1.04 |
3.20 |
1.63 |
|
|
|
|
|
|
|
Late Resorptions |
Mean |
0.19 |
0.48 |
0.52 |
0.62 |
SD |
0.68 |
0.98 |
1.78 |
1.91 |
|
|
|
|
|
|
|
Pre-implantation Loss |
Mean |
2.10 |
2.62 |
2.05 |
2.24 |
SD |
1.61 |
2.16 |
1.75 |
1.61 |
|
|
|
|
|
|
|
Post-implantation Loss |
Mean |
0.86 |
1.24 |
2.14 |
1.57 |
SD |
1.28 |
1.34 |
3.58 |
2.29 |
|
|
|
|
|
|
|
Dams with any Resorption
|
Total |
10
|
14
|
11
|
11
|
Dams with only implantation site |
Total |
0 |
0 |
1 |
0 |
(complete resorptions) |
|
|
|
|
|
Summary of Litter Data |
|||||
The animals were treated at dose of 0, 60, 120 and 250 mg/kg bw from the gestation day 5. After four days of treatment, the dose levels were reduced to 0, 20, 40, and 80 due to the severe maternal toxicity. |
|||||
|
Group No. |
G1 |
G2 |
G3 |
G4 |
Parameters |
Dose (mg/kg/day) |
0 |
60/20 |
120/40 |
250/80 |
|
No. of Dams |
21 |
21 |
21 |
21 |
|
|
|
|
|
|
No. of litters |
|
21 |
21 |
20 |
21 |
|
|
|
|
|
|
Total no. of fetuses |
|
285 |
244 |
246 |
278 |
|
|
|
|
|
|
Mean litter size |
|
13.6 |
11.6 |
12.1 |
13.2 |
|
|
|
|
|
|
Dead fetuses |
Total |
0 |
0 |
0 |
0 |
|
% |
0 |
0 |
0 |
0 |
|
|
|
|
|
|
Total live fetuses |
|
|
|
|
|
a. Number |
|
285 |
244 |
246 |
278 |
|
|
|
|
|
|
b. Weight (g) |
Mean |
3.83 |
3.72 |
3.38 |
3.13* |
|
SD |
0.33 |
0.56 |
0.74 |
0.79 |
|
|
|
|
|
|
Live male fetuses |
|
|
|
|
|
a. Number |
|
137 |
129 |
121 |
140 |
|
|
|
|
|
|
b. Weight (g) |
Mean |
3.96 |
3.82 |
3.47 |
3.24* |
|
SD |
0.33 |
0.59 |
0.78 |
0.79 |
|
|
|
|
|
|
Live female fetuses |
|
|
|
|
|
a. Number |
|
148 |
115 |
125 |
138 |
|
|
|
|
|
|
b. Weight (g) |
Mean |
3.71 |
3.62 |
3.30 |
3.02* |
|
SD |
0.35 |
0.51 |
0.69 |
0.77 |
|
|
|
|
|
|
Sex Ratio - Male : Female |
|
1:1.08 |
1:0.89 |
1:1.03 |
1:0.99 |
|
|
|
|
|
|
*: Significantly different from vehicle control group.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 40 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- One valid OECD 414 study in rat 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
No classification is warranted.
The commercial naphthenic acid (read-across substance) induced reduced pup survival rate at doses that were associated with apparent parental toxicity. No other effect on the reproduction performance was found.
The registration substance NA-DETA induced reduced fetal weight at dose that was associated with apparent maternal toxicity. No other effect on the maternal reproduction performance was found and no indication of teratogenicity was found.
Additional information
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