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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
Toxicity to reproduction
Administrative data
- 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
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 012
Materials and methods
Test guideline
- 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
Test material
- Reference substance name:
- Naphthenic acids
- EC Number:
- 215-662-8
- EC Name:
- Naphthenic acids
- Cas Number:
- 1338-24-5
- Molecular formula:
- "CnH2n+zO2, where n = carbon number and z = homologous group series number: z = 0 when no ring structures are present, z = -2 when 1 ring is present, z = -4 when 2 rings are present etc Result of high resolution mass spectroscopy of 4 naphthenic acids samples from different suppliers/sources: Ring distribution of aliphatic fraction: Z = 0 15-30% Z = -2 35-50% Z = -4 10-25% Z = -6 1-7% Z = -8 0-2% Z <= -6 1-5% (unsaturated compounds) Z >= -8 0-2% (unsaturated compounds) C<= 18 8-15% (N-containing compounds) C > 18 0-2% (N-containing compounds) Unknown 0-2% Distribution of carbon number (n) of 4 naphthenic acids samples from different suppliers/sources (n):C4-C27 (main: C8-C20)
- IUPAC Name:
- Naphthenic acids
- Test material form:
- other: oily liquid
- Details on test material:
- Blend of naphthenic acids from three sources.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
Administration / exposure
- 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
Doses / concentrations
- 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
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- 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 / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
Results: F1 generation
General toxicity (F1)
- 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
Effect levels (F1)
- 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
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
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
Applicant's summary and conclusion
- 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.
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