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EC number: 231-633-2 | CAS number: 7664-38-2
Toxicological information
Toxicity to reproduction
Currently viewing:
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 008
- Report date:
- 2008
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Combined Repeated Dose and Reproductive / Developmental Toxicity Screening Test (Precursor Protocol of GL 422)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Orthophosphoric acid
- EC Number:
- 231-633-2
- EC Name:
- Orthophosphoric acid
- Cas Number:
- 7664-38-2
- Molecular formula:
- H3O4P
- IUPAC Name:
- phosphoric acid
- Details on test material:
- - Name of test material (as cited in study report): phosphoric acid
- Analytical purity: no data
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: ORIENTBIO Inc., Korea
- Age at study initiation: male rats: 9 weeks old; female rats: 8 weeks old
- Weight at study initiation: male: 288.6 - 336.7 g; female: 163.5 - 188.9 g
- Fasting period before study:
- Housing: Stainless wire cage, 260 W x 50 D x 10 H (mm3). Polycarbonate cage, 260 W x 20 L x 80 H (mm3): number of animals per cage: 1 animal per cage and during mating period: 1 male and 1 female; during lactation period: 1 female and neonate
- Use of restrainers for preventing ingestion (if dermal): not applicable
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: 1 week
- Cages and fodder tub were replaced once every two weeks, and water bottles were replaced twice a week. Housing materials were washed with cage washer and sterilized by an autoclave.
- During the acclimation period, animals were marked on the tail using a red indelible pen in accordance with the method of identification and marked on the tail using a blue indelible pen during the experimental period. Each cage was compartmentalized by an identification card to enable identification of individual animals.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.2 - 23.4 °C
- Humidity (%): 27.6 - 64.3 %
- Air changes (per hr): 10 - 15 times/hour
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light (lights on at 7 a.m., lights off at 7 p.m.
- Light intensity: 150 - 300 Lux
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- The males were treated once daily during 2 weeks prior to mating, the 2 weeks of mating period, and 2 weeks after mating (total 6 weeks). The females of the main group were treated once daily from 2 weeks before mating to Day 4 post partum (approximately 54 days). The females of recovery group (without mating) were treated for approximately 54 days (applied equally main group females). Also, coitus was confirmed, but females did not show gestational signs, and were administrated until gestation Day 26.
- Frequency of treatment:
- Daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 125, 250 and 500 mg/kg
Basis:
no data
- No. of animals per sex per dose:
- 13 males and females per dose
- Control animals:
- yes, concurrent vehicle
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: No data
- Time schedule: No data
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once a week
BODY WEIGHT: Yes
- Time schedule for examinations: no data
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- No data
OTHER: organ weights - Postmortem examinations (parental animals):
- SACRIFICE
Remaining animals were euthanized under CO2 gas anesthesia
GROSS NECROPSY
- Spleen, kidney, epididymis, gastro-intestinal organs, uterus (horn)
HISTOPATHOLOGY / ORGAN WEIGHTS
- Kidney (tubulus), epididymis, uterus (horn) - Postmortem examinations (offspring):
- SACRIFICE
No data
GROSS NECROPSY
- only external examination
HISTOPATHOLOGY / ORGAN WEIGTHS
No data
OTHER: organ weights - Statistics:
- Statistical analysis of this study was performed by the SAS program (SAS R 9.1.3, SAS Institute Inc., U.S.A.). For the data including body weights, food consumption, urine, hematology, blood biochemistry parameters, organ weights, mating results, birth and survival rates, sensory reflex, and motor function test, the Bartlett test was conducted to test for variance homogeneity at the 5.0% one-tailed probability level. One-way analysis of variance (ANOVA) test was employed on homogeneity, if significant, followed by Dunnett's t-test for multiple comparisons. Kruskal-wallis was employed on heterogeneity, if significant, followed by Mann-whitney u-test for multiple comparisons. Group comparison was performed at the 5.0 and 1.0% two-tailed probability level. For the data of recovery, Folded-F test was conducted to test for variance homogeneity at the 5.0% two-tailed probability level. Student t-test was employed on homogeneity, if overrule, Aspin-Welch t-test was performed at the 5.0 and 1.0% two-tailed probability level. Non pregant animals were excluded.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Details on results (P0)
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
In the main group, death was observed in one female (2403) of the 500 mg/kg treatment group on Day 16 of administration. And in the recovery group, death was observed in one female (2416) of the 500 mg/kg treatment group on Day 52 of administration. In the main group, no clinical signs were observed in males and females of the 125 mg/kg treatment group and in females of the 250 mg/kg treatment group. But, transient salivations which appeared immediately after administration were sporadically observed in four males of the 250 mg/kg treatment group during Day 22 of administration to completion of administration. Also, transient salivations were were observed in all males of the 500 mg/kg treatment group from Day 20 of administration to completion of administration and in four females of the 500 mg/kg treatment group from Day 2 of gestation to completion of administration, sporadically or persistently. In addition, mucous stool, soft stool, and dirty nose were observed in one male (1407) of the 500 mg/kg treatment group on Day 22 and 23. In the recovery group, transient salivations were observed in almost all males of the 500 mg/kg tretment group from Day 16 of administration to completion of administration and in almost all females of the 500 mg/kg treatment group from Day 20 of administration to completion of administration, sporadically or persistently.
No detailed clinical signs were observed in all animals of the control and treatment groups.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Body weight:
In the main group, no treatment-realted abnormalities in body weight gain were noted in all animals of the control and treatment groups. In females of the recovery group, body weights on Day 55 of administration were significantly decreased (p<0.05) compared with the control group in the 500 mg/kg treatment group. Besides, no treatment-related abnormalities in body weight gain were noted in all males.
Food consumption:
In the main group, no treatment-related abnormalities in food consumption were noted in all animals of the control and treatment groups. In females of the recovery group, food consumption was significantly decreased (p< 0.05) compared with the control group on Day 13 and 34 of administration in the 500 mg/kg treatment group. Besides, no treatment-related abnormalities in food consumption were noted in all males.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
Not applicable (administration by gavage)
MATING RESULT
Mating rate in the control, 125, 250, and 500 mg/kg treatment groups were 100%. Fertility rate in the control, 125, 250 and 500 mg/kg treatment groups were 76.9, 100.0, 92.3, and 100% in the males; and were 76.9, 100.0, 92.3 and 100% in the females. Parturition rate in the control, 125, 250 and 500 mg/kg treatment groups were 2.9, 2.5, 3.5 and 3.0 days and 21.7, 21.7, 21.9 and 21.8 days, respectively. No statistically significant difference was observed in all animals. Pre- and post-implantation loss rate in the control, 125, 250 and 500 mg/kg treatment groups were 4.0, 1.4, 2.2 and 3.4% and 5.2, 10.8, 3.2, and 7.1%, respectively. No statistically significant difference was observed in all animals
ORGAN WEIGHTS (PARENTAL ANIMALS)
In the main group, no treatment-related abnormalities in absolute and relative organ weigths of the males were noted compared with the control group. However, in females, absolute organ weights of kidney were significantly decreased (p<0.05, p<0.01) in all treatment groups compared with the control group, and relative organ weights of uterus were significantly decreased (p< 0.05) in the 500 mg/kg treatment group compared with the control group.
GROSS PATHOLOGY (PARENTAL ANIMALS)
In the necropsy findings of the main group, agenesis of spleen was observed in one male (1302) of the 250 mg/kg treatment group, and yellow spot of epididymis was observed in one male (1408) of the 500 mg/kg treatment group. The other abdominal signs were not observed, and the necropsy finding of recovery group was not noted. In the necropsy findings for dead animals, gaseous distension was observed in one female (2403) of the 500 mg/kg treatment group (main group) on Day 16 of administration. In the recovery group, gaseous distension, severe hydronephrosis of left kidney and dilation of left uterine horn were observed in one female (2416) of the 500 mg/kg treatment group on Day 52 of administration.
HISTOPATHOLOGY (PARENTAL ANIMALS)
In the main group, cast of kidney was observed in one male (1104) of the control group, and sperm granuloma of epididymis was observed in one male (1408) of the 500 mg/kg treatment group. The other abnormal findings were not observed. In the recovery group, basophilic tubules of kidney was observed in one female (2119) of the control group.The other abnormal findings were not observed. In the 500 mg/kg treatment group of the main group, no histopathological change in one dead female animal (2403) was observed. In the 500 mg/kg treatment group of the recovery group, renal tissue in one dead female animal (2416) was not observed by severe hydronephrosis of gross findings, and left urine horn was dilated; however no histopathological change was observed.
In the main group, death was observed in one female (2403) of the 500 mg/kg treatment group on Day 16 of administration. And in the recovery group, death was observed in one female (2416) of the 500 mg/kg treatment group on Day 52 of administration. In the main group, no clinical signs were observed in males and females of the 125 mg/kg treatment group and in females of the 250 mg/kg treatment group. But, transient salivations which appeared immediately after administration were sporadically observed in four males of the 250 mg/kg treatment group during Day 22 of administration to completion of administration. Also, transient salivations were were observed in all males of the 500 mg/kg treatment group from Day 20 of administration to completion of administration and in four females of the 500 mg/kg treatment group from Day 2 of gestation to completion of administration, sporadically or persistently. In addition, mucous stool, soft stool, and dirty nose were observed in one male (1407) of the 500 mg/kg treatment group on Day 22 and 23. In the recovery group, transient salivations were observed in almost all males of the 500 mg/kg tretment group from Day 16 of administration to completion of administration and in almost all females of the 500 mg/kg treatment group from Day 20 of administration to completion of administration, sporadically or persistently.
No detailed clinical signs were observed in all animals of the control and treatment groups.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Body weight:
In the main group, no treatment-realted abnormalities in body weight gain were noted in all animals of the control and treatment groups. In females of the recovery group, body weights on Day 55 of administration were significantly decreased (p<0.05) compared with the control group in the 500 mg/kg treatment group. Besides, no treatment-related abnormalities in body weight gain were noted in all males.
Food consumption:
In the main group, no treatment-related abnormalities in food consumption were noted in all animals of the control and treatment groups. In females of the recovery group, food consumption was significantly decreased (p< 0.05) compared with the control group on Day 13 and 34 of administration in the 500 mg/kg treatment group. Besides, no treatment-related abnormalities in food consumption were noted in all males.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
Not applicable (administration by gavage)
MATING RESULT
Mating rate in the control, 125, 250, and 500 mg/kg treatment groups were 100%. Fertility rate in the control, 125, 250 and 500 mg/kg treatment groups were 76.9, 100.0, 92.3, and 100% in the males; and were 76.9, 100.0, 92.3 and 100% in the females. Parturition rate in the control, 125, 250 and 500 mg/kg treatment groups were 2.9, 2.5, 3.5 and 3.0 days and 21.7, 21.7, 21.9 and 21.8 days, respectively. No statistically significant difference was observed in all animals. Pre- and post-implantation loss rate in the control, 125, 250 and 500 mg/kg treatment groups were 4.0, 1.4, 2.2 and 3.4% and 5.2, 10.8, 3.2, and 7.1%, respectively. No statistically significant difference was observed in all animals
ORGAN WEIGHTS (PARENTAL ANIMALS)
In the main group, no treatment-related abnormalities in absolute and relative organ weigths of the males were noted compared with the control group. However, in females, absolute organ weights of kidney were significantly decreased (p<0.05, p<0.01) in all treatment groups compared with the control group, and relative organ weights of uterus were significantly decreased (p< 0.05) in the 500 mg/kg treatment group compared with the control group.
GROSS PATHOLOGY (PARENTAL ANIMALS)
In the necropsy findings of the main group, agenesis of spleen was observed in one male (1302) of the 250 mg/kg treatment group, and yellow spot of epididymis was observed in one male (1408) of the 500 mg/kg treatment group. The other abdominal signs were not observed, and the necropsy finding of recovery group was not noted. In the necropsy findings for dead animals, gaseous distension was observed in one female (2403) of the 500 mg/kg treatment group (main group) on Day 16 of administration. In the recovery group, gaseous distension, severe hydronephrosis of left kidney and dilation of left uterine horn were observed in one female (2416) of the 500 mg/kg treatment group on Day 52 of administration.
HISTOPATHOLOGY (PARENTAL ANIMALS)
In the main group, cast of kidney was observed in one male (1104) of the control group, and sperm granuloma of epididymis was observed in one male (1408) of the 500 mg/kg treatment group. The other abnormal findings were not observed. In the recovery group, basophilic tubules of kidney was observed in one female (2119) of the control group.The other abnormal findings were not observed. In the 500 mg/kg treatment group of the main group, no histopathological change in one dead female animal (2403) was observed. In the 500 mg/kg treatment group of the recovery group, renal tissue in one dead female animal (2416) was not observed by severe hydronephrosis of gross findings, and left urine horn was dilated; however no histopathological change was observed.
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 500 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: fertility
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Details on results (F1)
Mean litter size, live birth rate and survival rate:
Mean litter size and live birth rate in the control, 125, 250, and 500 mg/kg treatment groups were 13.3, 14.4, 14.5, and 15.0 animals and 99.4, 99.0, 100.0, and 97.5%, respectively. Day 0 and 4 postpartum survival rates in the control, 125, 250, and 500 mg/kg treatment groups were 100% in all and 99.4, 99.1, 99.3, and 98.4%, respectively. No statistically significant difference was observed in all animals.
Neonate body weights,
On Day 0 and 4postpartum, no treatment-related abnormalities in body weight gain of neonate were noted in all animals of the control and treatment groups.
Sex ratio and external findings of live neonate:
Sex ratio of live nonate in the control, 125, 250, and 500 mg/kg treatment groups were 0.9, 0.8, 0.9, and 1.2, respectively. On Day 0 and 4 postpartum, no treatment-related abnormalities in external findings were noted in all animals.
Mean litter size and live birth rate in the control, 125, 250, and 500 mg/kg treatment groups were 13.3, 14.4, 14.5, and 15.0 animals and 99.4, 99.0, 100.0, and 97.5%, respectively. Day 0 and 4 postpartum survival rates in the control, 125, 250, and 500 mg/kg treatment groups were 100% in all and 99.4, 99.1, 99.3, and 98.4%, respectively. No statistically significant difference was observed in all animals.
Neonate body weights,
On Day 0 and 4postpartum, no treatment-related abnormalities in body weight gain of neonate were noted in all animals of the control and treatment groups.
Sex ratio and external findings of live neonate:
Sex ratio of live nonate in the control, 125, 250, and 500 mg/kg treatment groups were 0.9, 0.8, 0.9, and 1.2, respectively. On Day 0 and 4 postpartum, no treatment-related abnormalities in external findings were noted in all animals.
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 500 mg/kg bw/day
- Based on:
- not specified
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The NOAEL for reproductive and development toxicity was estimated to be 500 mg/kg for phosphoric acid.
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