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EC number: 249-060-1 | CAS number: 28510-23-8
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- Ecotoxicological Summary
- Aquatic toxicity
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- Short-term toxicity to fish
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- Long-term toxicity to aquatic invertebrates
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Toxicity to reproduction
Administrative data
- Endpoint:
- one-generation reproductive toxicity
- Remarks:
- based on generations indicated in Effect levels (migrated information)
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Non-GLP, non-guideline study, published in peer reviewed literature, minor restrictions in design and/or reporting but otherwise adequate for assessment.
Data source
Reference
- Reference Type:
- publication
- Title:
- Effects of 2-Ethylhexanoic Acid on Reproduction and Postnatal Development in Wistar Rats.
- Author:
- Pennanen S et al.
- Year:
- 1 993
- Bibliographic source:
- Fundamental and Applied Toxicology 21, 204-212
Materials and methods
- Principles of method if other than guideline:
- Groups of male and female Wistar rats received 0, 100, 300 or 600 mg/kg/day of test material in their drinking water. Males were exposed for 10 weeks and females for 2 weeks prior to mating, both sexes during mating and females during gestation and lactation, and toxicity to reproduction was studied.
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- 2-ethylhexanoic acid
- EC Number:
- 205-743-6
- EC Name:
- 2-ethylhexanoic acid
- Cas Number:
- 149-57-5
- IUPAC Name:
- 2-ethylhexanoic acid
- Details on test material:
- - Name of test material (as cited in study report): 2-ethylhexanoic acid- Analytical purity: 99.5%
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS- Source: National Laboratory Animal Center, University of Kuopio, Finland- Age at study initiation: males: 5-6 weeks; females: 9-10 weeks)- Weight at study initiation: males: 125 ± 25 g; females: 200 ± 20 g- Housing: wire mesh cages, 3 animals/cage; 1 male and 1 female per cage during mating; 1 female/litter per cage during gestation/lactation.- Diet: commercial rat chow (R3-EWOS, Sodertalje, Sweden), ad libitum except during 2-EHA exposure- Water: ad libitum except during 2-EHA exposure- Acclimation period: 1 weekENVIRONMENTAL CONDITIONS- Temperature (°C): 21 ± 1ºC- Humidity (%): 55-65%- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: drinking water
- Vehicle:
- other: drinking water supplemented with NaOH (equal amounts as 2-EHA)
- Details on exposure:
- Rats were given the test substance in their drinking water as a sodium salt by mixing equivalent amounts of 2-EHA and NaOH. Concentrations of 2-EHA solution were adjusted on the basis of water consumption and body weight.
- Details on mating procedure:
- - M/F ratio per cage: 1/1- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy- After successful mating each pregnant female was caged individually
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- Exposure period: Males were exposed for 10 weeks and females for 2 weeks prior to mating, both sexes during mating and females during gestation and lactation.
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:100, 300, 600 mg/kg bwBasis:nominal in water
- No. of animals per sex per dose:
- 24
- Control animals:
- yes, concurrent no treatment
- Positive control:
- None
Examinations
- Parental animals: Observations and examinations:
- CLINICAL OBSERVATIONS: Yes, dailyBODY WEIGHT: Yes, weeklyFOOD CONSUMPTION: Yes, weeklyWATER CONSUMPTION AND COMPOUND INTAKE: Yes, water consumption was recorded for each cage for the whole exposure period and doses were corrected by adjusting the concentration of the 2-EHA solution acccording to the most recent body weights and water consumption. When more than one animals was housed per cage, a mean body weight was used.
- Oestrous cyclicity (parental animals):
- Yes, vaginal smears were evaluated microscopically
- Sperm parameters (parental animals):
- Parameters examined in all male parental animals: testis weight, right epididymis weight, left epididymis: sperm density, motility and morphology.
- Litter observations:
- STANDARDISATION OF LITTERS- Performed on day 4 postpartum: yes- Maximum of 8 pups/litter using equal sex distribution whenever possible; excess pups were examined externally, killed and discarded. PARAMETERS EXAMINEDThe following parameters were examined in offspring:number of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain (postnatal days 0, 4, 7, 14, 21). Pups were examined every other day from postnatal day 1 onwards and the appearance of the following developmental parameters was recorded: pinna reflex, placing reaction, righting reflex in 5 sec, cliff avoidance in 5 sec, approach/avoidance, ipsilateral flexor reflex (hind toe), grip reflex in 5 sec, air righting, opening of eyes, teeth eruption, and hair growth.
- Postmortem examinations (parental animals):
- SACRIFICE- Male animals and non-gravid females: All surviving animals at the end of the mating period (maximum 21 days).- Maternal animals: All surviving animals on postnatal day 21GROSS NECROPSY- Gross necropsy consisted of examination of any pathological changesHISTOPATHOLOGY / ORGAN WEIGHTS- Males: organ weight: testis, right epididymis. Histopathology (5 randomly selected animals/group): testes, right epididymis, seminal vesicle, prostate, and coagulating gland- Non-gravid females and maternal animals: organ weight: ovaries. Histopathology (all non-gravid females and 5 randomly selected maternal animals per group): ovaries, uterus, cervix uteri, vagina
- Postmortem examinations (offspring):
- On postnatal day 21, all pups were examined externally and euthanized without further examination.
- Statistics:
- Body weights (adult males, adult females, litters, pups), organ weights, food and water consumption, number of live pups in litter, male fertility data, and data on pup development were analyzed by one-way ANOVA. Comparisons of significant group effects were conducted using Fisher PLSD test of Scheffe's test. The observations on pups (litter percentages) were analyzed by Scheffe's test and the dose-response relationship by the Pearson correlation test.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 600 mg/kg bw: 9-12% decrease in bodyweight
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- 600 mg/kg bw: 9-12% decrease in bodyweight
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- mid- and high-dose group, a slight dilatation of the lumen in uterus and epithelial hyperplasia in vagina
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance intake: 600 mg/kg bw: liquid consumption slightly reduced in pregnant animals
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- effects observed, treatment-related
- Description (incidence and severity):
- 100 mg/kg bw: motility reduction
- Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- 100 mg/kg bw: delay in fertilisation
Details on results (P0)
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Delay in fertility.
- Dose descriptor:
- LOEL
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: Non-significant reduction in sperm motility.
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- effects observed, treatment-related
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 600 mg/kg bw: transient decrease during lactation
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not specified
Details on results (F1)
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: lower litter size, lower body weights and delayed physical development
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Table 1: Reproductive indices and sperm morphology parameters.
| 2-ethylhexanoic acid (mg/kg bw/day) | |||
| Control | 100 | 300 | 600 |
Litters | 23 | 21 | 24 | 23 |
Live pups | 251 | 214 | 258 | 208 |
Sex ratioa | 0.53 | 0.53 | 0.57 | 0.58 |
Stillbirths (m/f) | 3/1 | 0/0 | 0/2 | 5/1 |
Mean litter size (PND 0) | 10.9 ± 2.2c | 10.2 ± 1.9 | 10.8± 2.1 | 9.2± 2.4* |
Postnatal deaths (m/f) | 0/2 (0.7)b | 4/7 (5.1)* | 0/5 (1.9) | 5/1 (2.9) |
Lactation indexd | 175/177 (99%) | 152/163 (93%) | 203/208 (98%) | 167/173 (96%) |
|
|
|
|
|
Sperm morphology |
|
|
|
|
Normal | 21e(87.5)f | 22 (91.6) | 16 (66.7) | 17 (70.9) |
Agglutinated sperm | 2 (8.3) | 1 (4.2) | 6 (25.0) | 2 (8.3) |
Abnormal heads | 1 (4.2) | 1 (4.2) | 3 (12.5) | 5 (20.8) |
* p<0.05.
aMales/all pups.
bPercentage of pups (males and females).
cMeans ± SD.
dNumber of pups live on Postnatal Day 21 /Postnatal Day 4.
eNumber of rats with the observation
fPercentage of the examined rats
Table 2: Sperm density and motility parameters.
| 2-ethylhexanoic acid (mg/kg bw/day) | |||
| Control | 100 | 300 | 600 |
Total cells (x106/g cauda epididymis) | 666.0± 347.0 | 683.5± 443.3 | 616.9± 295.5 | 574.5± 302.9 |
Motile cells (x106/g cauda epididymis) | 249.4± 194.6 | 170.2± 168.6 | 197.3± 172.5 | 173.8± 133.9 |
Motility (%) | 34.8± 12.6 | 21.9± 13.1 | 28.0± 13.9 | 27.0± 12.3 |
Rapid (%) | 18.6± 10.8 | 8.6± 8.4 | 13.0± 10.1 | 14.7± 10.7 |
Moderate (%) | 14.7± 9.0 | 12.3± 7.8 | 14.2± 6.6 | 12.0± 4.4 |
Slow (%) | 1.2± 1.9 | 0.8± 0.9 | 0.9± 1.1 | 0.25± 0.5 |
Static (%) | 68.1± 15.2 | 78.1± 13.1 | 71.9± 13.9 | 73.0± 12.3 |
•p<0.05.
The figures are means ± SD of 24 animals per group
Table 3: Observations on pups.
| 2-ethylhexanoic acid (mg/kg bw/day) | |||
| Control | 100 | 300 | 600 |
Kinky tail | 13e(4.86)f | 32 (14.99) | 66 (24.48)* | 54 (25.59)* |
Hematomas | 7 (2.91) | 18 (7.59) | 12 (4.56) | 12 (7.60) |
Hypothermc | 0 | 0 | 1 (0.32) | 9 (4.35) |
Thin hair | 1 (0.4) | 0 | 12 (5.98) | 4 (3.45) |
Diarrhea | 0 | 0 | 2 (0.64) | 2 (0.79) |
Lethargy | 0 | 0 | 65 (26.74)* | 29 (13.04) |
Flabby legs | 0 | 3 (1.30) | 7 (2.71) | 5 (2.69) |
Long, thin legs | 0 | 0 | 8 (3.17) | 2 (1.24) |
Twisted hind legs | 0 | 0 | 2 (0.68) | 0 |
•p<0.05.
eNumber of pups
fGroup mean of litter percentages (affected fetuses in litter)
gSlightly paralyzed
Applicant's summary and conclusion
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