6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide

Endpoint summary

Description of key information

There was no evidence of significant general or specific tarfget organ toxicity in a 16 week dietary study in rats at doses up to 1094 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non GLP study, pre-dates OECD guidelines and has limitations in design and reporting.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

No FOB

GLP compliance:

no

Remarks:

Pre-dates GLP

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: approx. 6 week old

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 5

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

The substance was added to the feed which consisted of wheat flour, fish meal, soybean cake, salt, trace minerals, vitamins, thertiary calcium phosphate, soynean oil and corn starch. Full details in the attached report

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

16 weeks

Frequency of treatment:

Continuous in feed

Remarks:

Doses / Concentrations:
0, 159, 399, 1023 mg/kg bw/day (males); 0 177, 445, 1094 mg/kg bw/day (females)
Basis:
actual ingested

Remarks:

Doses / Concentrations:
0, 0.24, 0.6 and 1.5%
Basis:
nominal in diet

No. of animals per sex per dose:

20

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: fortnightly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: termination
- Anaesthetic used for blood collection: No data - animals decapitated
- Animals fasted: No data
- How many animals: 10/sex/group
- Parameters examined: red and white cells counts, hemoglobin, hematocrit and differential white cell count.

CLINICAL CHEMISTRY: Yes / No / No data
- Time schedule for collection of blood: termination
- Animals fasted: No data
- How many animals: 10/sex/group
- Parameters examined: GOT, GPT, Al-P, protein, albumin and urea-nitrogen.

URINALYSIS: Yes
- Time schedule for collection of urine: termination
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: Urine protein, sugar and Ph were determined by using urorubstick test paper.

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

Pathological examinations were performed in the heart, liver, kidney, spleen, lung, pancrea, seminal vesicle, ovarine, marrow, stomach, small intestine, large intestine and cecum.

Statistics:

Evaluation of the body weight increase, feed intake, organ weight, the morophohematological test and the biochemical test were made by making statistical treatment of the data in conformity with the randomized block design. The number of the dead animals as well as the results of the pathological test were evaluated by performed the X2-test.

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

effects observed, treatment-related

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

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

Details on results:

Females in the 1.5% HCA group had a lower food utilisation efficiency.

There were no other effects considered to be related to treatment with HCA

Dose descriptor:

NOAEL

Effect level:

1 023 - 1 094 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: No significant adverse effects at highest dose tested

Critical effects observed:

not specified

Mortality: 2 female animals in the control died at 13 and 16 weeks respectively, 1 male in the group exposed to 0.24% of HCA in the feed died at 8 weeks, 3 males exposied to 0.6% of HCA in the feed died; 1 after 14 weeks and 2 after 15 weeks. 1 female exposed to 1.5% of HCA in the feed died at 8 weeks while one male died at 15 weeks.

Body weight: The animals body weight increased across the test period in line with expectations.

Food consumption: There were no differences between the groups in food consumption.

Food utilisation: The feed requirement ratio was significantly increased in females in group 4 i.e. lower food utilisation efficieny. This is shown in Table 4 of the attached report.

Organ weights: There were no treatment related effects. The weight of the spleen of female animals in the group 3 was lower than that in the controls.

Gross pathology: The anatomic findings revealed that no lesion caused by the administration of HCA was observed as shown in Table 7 of the attached report.

Haematology: The results, as shown in Table 8 of the attached report, showed no significant difference between the groups.

Urinalysis: The result revealed, as shown in Table 9 of the attached report, no significant difference between the groups.

Biochemical test: As shown in Table 10 of the attached report, the biochemical test revealed no abnormality caused by the administration of HCA. Histopathology:

1) Liver: Pimelosis of the liver and nest like cellular infiltration in the periportal region were observed in several cases, but as they appeared equaly in all groups, they were not considered to have been caused by the administration of HCA.

2) Kidney: Nephritis was observed in all groups (1, 1, 3,2 in groups 1, 2, 3, 4 respectively). However, considering the fact that nephritis in the control group was more severe than in the treated groups, they were not considered to have been caused by the administration of HCA.

3) Heart, lung: One animal with endopericarditis was observed, which was, however, considered to have been caused by pneumonia.

4) Pancreas: Several cases of vacuole were observed, but they were considered to have been produced after the animals’ death.

5) Seminal vesicle and ovary: Abnormality was observed in the seminal vesicle of one male animal of the group 2, but no other abnormality was observed.

6) No significant abnormality was observed in the spleen, marrow stomach, small intestine, large intestine and caecum.

From these results it was concluded that no abnormality caused by HCA was observed pathologically.

Conclusions:

In the rat, dietary intake of 0.24, 0.6 or 1.5% HCA (159, 399 or 1023 mg/kg bw/day in males; 177, 445 or 1094 mg/kg bw/day in females) for 16 weeks showed no evidence of specific target organ toxicity.

Executive summary:

Groups of 20 rats/sex/group were administered HCA in the diet at 0, 0.24.0.6 or 1.5% for 16 weeks. Body weight and food consumption were measured fortnightly. At termination samples were collected from 10/sex/group for blood and urine clinical chemistry, haematology, organ weight measurement and histopathology.

There were no treatment related effects apart from lower food utilisation efficiency in females at 1.5%. In the absence of any effects on body weight this is considered to be of no toxicological significance.

A dose of 1023 (males) or 1094 (females) mg HCA/kg bw/day for 16 weeks showed no evidence of specific target organ toxicity and was a No Adverse Effect Level (NOAEL).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Only one 16-week dietary study is available. The study pre-dates GLP and OECD regulatory guidelines but includes many standard end-points for a sub-chronic study.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Groups of 20 rats/sex/group were administered HCA in the diet at 0, 0.24.0.6 or 1.5% for 16 weeks. Body weight and food consumption were measured fortnightly. At termination samples were collected from 10/sex/group for blood and urine clinical chemistry, haematology, organ weight measurement and histopathology. There were no treatment related effects apart from lower food utilisation efficiency in females at 1.5%. In the absence of any effects on body weight this is considered to be of no toxicological significance. A dose of 1023 (males) or 1094 (females) mg HCA/kg bw/day for 16 weeks showed no evidence of specific target organ toxicity and was a No Observed Adverse Effect Level (NOAEL).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Only study available

Justification for classification or non-classification

There was no evidence of significant general or specific tarfget organ toxicity in a 16 week dietary study in rats at doses up to 1094 mg/kg bw/day. Therefore, no classification is warranted under DSD (Dir 67/548/EEC) or CL (Reg (EC) 1272/2008).