Silver docosanoate

Toxicity to reproduction

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

Test material information

Constituent 1

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 / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

100 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

300 mg/kg bw/day (nominal)

Doses / concentrations 4

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.