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Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
OECD study but only extended summary available. Reliable as performed for the Japanese government by Hatano Research Institute, Food and Drug Safety Center (Japan). Additionally, the study was included in the official OECD SIDS document for docosanoic acid.
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
OECD study but only extended summary available. Reliable as performed for the Japanese government by Hatano Research Institute, Food and Drug Safety Center (Japan). Additionally, the study was included in the official OECD SIDS document for docosanoic acid.
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
/
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
Source: NOF CORPORATION, Lot No. 60805X, Purity: 85.9 %, Impurities: (C14-C 20) fatty acids (10.9 %) and C 24 fatty acid
(2.3%)
Kept at room temperature until use.
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
/
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
/
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
/
Duration of treatment / exposure:
Males: 42 days;
Females: from 14 days prior to mating to day 3 of lactation
Frequency of treatment:
daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
13 animals per sex per dose group
Control animals:
yes, concurrent vehicle
Details on study design:
· Vehicle: Corn oil
· Satellite groups and reasons they were added : none
· Clinical observations performed and frequency: Clinical signs were observed at least
once a day, body weights were basically determined once a week. Also, food consumption was measured nearly once a week except for mating period.
Hematologicalexaminations (only for males): Red blood cell count (RBC), white blood cell count (WBC), platlet count, hemoglobin (Hb), hematocrit
(Ht), mean corpuscular volume (MCV),mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin conc entration (MCHC),differentiation of leukocytes
Blood chemical examinations (only for males): total protein, albumin, A/G, blood urea nitrogen (BUN), creatinine, glucose, total cholesterol, total bilirubin, triglyceride, sodium (Na), potassium (K), chloride (Cl), calcium (Ca), inorganic phosphorus (IP), alkaline phosphatase (ALP), GPT, GOT, ?-GTP.
Organs examined at necropsy:organ weights: heart, liver, kidneys, thymus, testes, epididymides histopathological examinations: all animals in control and 1,000 mg/kg, and any organs which have histopathological changes at the higher doses: brain, heart, liver, spleen, thymus, kidney, adrenal, testis, epididymis, urinary bladder, ovary (only for females which were non pregnant or not copulated).
General remarks: This study was conducted to examine both repeated dose toxicity and reproductive/developmental toxicity as an OECD screening combined study. Therefore, haematological and blood chemical examinations, and urinalysis for females were not performed. Functional observation, estrous cycle length and pattern, and sperm examination were not performed because the test was conducted by the TG adopted in 1990.
Positive control:
/
Observations and examinations performed and frequency:
Haematological, biochemical, gross findings, organ weights and histopathological examinations
Sacrifice and pathology:
/
Other examinations:
/
Statistics:
/
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Males: Decrease of MCHC at 300 and 1,000 mg/kg (p<0.01). However, this change in both groups was concluded as a casual one, because the degree of the change in both groups was very slight (the same 2.3 % decrease) and no other haematological changes were noted.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Males: Decrease of serum ALP in treated groups (p<0.05) and decrease of glucose at 1,000 mg/kg (p <0.05). However, these changes were considered to be toxicologically meaningless ones since they were slight and related histopathological findings were not observed.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Males: No treatment-related abnormalities in heart, liver, spleen, kidneys, adrenals and epididymides. In testes, atrophy of seminiferous tube was recognized in two of thirteen at 1,000 mg/kg group, but they were considered not to be treatment related specific findings, because they were slight and sometimes observed in historical control data in the laboratory conducting this study. No abnormalities detected in brain, thymus and urinary bladder.
Female s: No treatment-related abnormalities in brain, liver, spleen, thymus, kidneys and adrenals. No abnormalities detected in heart, urinary bladder and ovaries.
Histopathological findings: neoplastic:
no effects observed
Details on results:
Male: no deaths or abnormalities in clinical signs were observed in any of the treated groups. Also, there were no changes related to the dosing of compound in body weight gain and food consuption. No adverse effects werefound for haematological, biochemical, gross findings, organ weights and histopathological examinations.
Female: No deaths were observed in any of the treated groups. Also, there were no changes related to the dosing of compound in clinical signs, body weight gain and food consumption. No abnormal gross findings, changes of organ weights and histopathology were recognized at autopsy performed on postpartum day 4.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified
Conclusions:
No treatment related adverse effects were found in either dose group up to 1,000 mg/kg. NOAEL is estimated to be 1,000 mg/kg/day for this repeated dose toxicity study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report date:
1998

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
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Docosanoic acid
EC Number:
204-010-8
EC Name:
Docosanoic acid
Cas Number:
112-85-6
Molecular formula:
C22H44O2
IUPAC Name:
docosanoic acid
Test material form:
other: solid
Details on test material:
- Name of test material (as cited in study report): Docosanoic acid
- Molecular formula (if other than submission substance): C22H44O2
- Molecular weight: 340,58g/mol
- Substance type:Not applicable
- Physical state:solid
- Analytical purity:85.9%
- Impurities (identity and concentrations):c14-C20 fatty acids: ca. 11%; C24 fatty acid: ca. 2%
Specific details on test material used for the study:
Source: NOF CORPORATION, Lot No. 60805X, Purity: 85.9 %, Impurities: (C14-C 20) fatty acids (10.9 %) and C 24 fatty acid
(2.3%)
Kept at room temperature until use.

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
Weight at study initiation: 312.1-363.7 g for males, 205.3 - 230.8 g for females
Number of animals per dose:13 per sex per dose

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
/
Details on mating procedure:
Male/female per cage; 1/1, length of cohabitation; at the most 14 days, until proof of pregnancy (formation of vaginal closing or sperm detection in vagina)
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
/
Duration of treatment / exposure:
Males, 42 days
Female, from 14 days prior to mating to day 3 of lactation
Frequency of treatment:
Daily
Details on study schedule:
Age at study initiation was 8 week old for both sexes. Males were killed on the day after the administration period. Females were sacrificed on the day 4 of lactation. Females with no delivery were killed 4 days after the delivery expected date. Females with no copulation were sacrificed at the termination of mating period.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
13 per sex per dose
Control animals:
yes, concurrent vehicle
Details on study design:
· Vehicle: Corn oil
· Satellite groups and reasons they were added : none
· Clinical observations performed and frequency: Clinical signs were observed at least
once a day, body weights were basically determined once a week. Also, food consumption was measured nearly once a week except for mating period.
Hematologicalexaminations (only for males): Red blood cell count (RBC), white blood cell count (WBC), platlet count, hemoglobin (Hb), hematocrit
(Ht), mean corpuscular volume (MCV),mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin conc entration (MCHC),differentiation of leukocytes
Blood chemical examinations (only for males): total protein, albumin, A/G, blood urea nitrogen (BUN), creatinine, glucose, total cholesterol, total bilirubin, triglyceride, sodium (Na), potassium (K), chloride (Cl), calcium (Ca), inorganic phosphorus (IP), alkaline phosphatase (ALP), GPT, GOT, ?-GTP.
Organs examined at necropsy:organ weights: heart, liver, kidneys, thymus, testes, epididymides histopathological examinations: all animals in control and 1,000 mg/kg, and any organs which have histopathological changes at the higher doses: brain, heart, liver, spleen, thymus, kidney, adrenal, testis, epididymis, urinary bladder, ovary (only for females which were non pregnant or not copulated).
General remarks: This study was conducted to examine both repeated dose toxicity and reproductive/developmental toxicity as an OECD screening combined study. Therefore, haematological and blood chemical examinations, and urinalysis for females were not performed. Functional observation, estrous cycle length and pattern, and sperm examination were not performed because the test was conducted by the TG adopted in 1990.
Positive control:
/

Examinations

Parental animals: Observations and examinations:
Body wt. (basically once a week), food consumption(basically
once a week), No. of pairs with successful copulation, copulation index (No. of pairs with successful copulation/No. of pairs mated x 100), pairing days until copulation, frequency of vaginal estrus, No. of pregnant females, fertility index = (No. of pregnant animals/No. of pairs with successful copulation x 100), No. of corpora lutea, No. of implantation sites, implantation index (No. of implantation sites/No. of corpora lutea x 100), No. of living pregnant females, No. of pregnant females with parturition, gestation length, No. of pregnant females with live pups on day 0, gestation index (No. of females with live pups/No. of living pregnant females x 100), No. of pregnant females with live pups on day 4, delivery index (No. of pups born/No. of implantation sites x 100),
Oestrous cyclicity (parental animals):
/
Sperm parameters (parental animals):
/
Litter observations:
No. of pups alive on day 0 of lactation, live birth index (No. of live pups on day 0/No. of pups born x 100), sex ratio (Total No. of male pups/Total No. of female pups), No. of pups alive on day 4 of lactation, viability index (No. of live pups on day 4/No. of live pups on day 0 x 100), body wt. of live pups (on day 0 and 4).
Postmortem examinations (parental animals):
Parent: organ weight: heart, liver, kidneys, thymus, testes,
epididymidesHistopathological examinations: all animals in control and 1,000 mg/kg, and any organs which have histopathological changes at the higher doses: brain, heart, liver, spleen, thymus, kidney, adrenal, testis, epididymis, urinary bladder, ovary (only for females which were non pregnant or not copulated).
Postmortem examinations (offspring):
Foetal: full macroscopic examinations on all of pups
Statistics:
Dunnett’s or Scheffe’s test for continuous data, Chi square test for copulated index and fertility index, and Mann-Whitney U
test or Fisher’s test for histopathological examination data.
Reproductive indices:
/
Offspring viability indices:
/

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

No compound related changes were observed in length of gestation period and any parameters during gestation, delivery and lactation. The compound showed no adverse effects on copulation or fertility.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: /

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
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
Sexual maturation:
no effects observed
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
no effects observed

Details on results (F1)

No compound related changes were observed on the sex ratio, body weights or viability of pups.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: /

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
There were no treatment related abnormalities. NOAELs for both maternal and foetal toxicity are 1,000 mg/kg/day.