Phosphoric acid, butyl ester, sodium salt

Endpoint summary

Description of key information

In a combined repeated dose oral gavage toxicity study with the reproduction/developmental toxicity screening with the structural analogue dibutyl phosphate the No-Observed-Adverse-Effect Level (NOAEL) for general toxicity was considered to be 30 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:

short-term repeated dose toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

ANALOGUE APPROACH JUSTIFICATION
Please refer to the attached read across justification in section 13.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

1996

Deviations:

no

GLP compliance:

yes

Limit test:

no

Key result

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: damgae to digestive tract mucosa, bladder mucosa and effects in liver

Key result

Critical effects observed:

no

Conclusions:

The NOAEL for systemic toxicity was determined to be 30 mg/kg bw/day.

Executive summary:

In order to investigate the toxicity of the read across substance (CAS 107-66-4) after repeated administration a combined repeated dose toxicity and reproductive toxicity study was undertaken using SD (Crj:CD(SD)) rats. There were 10 male and 10 female rats per group, and the test item doses were 0 (control: solvent administered), 30, 100, 300 and 1000 mg/kg bw/day, administered by forced oral administration every day from 14 days prior to the start of mating, until day 3 of lactation after delivery for the females (40-51 days), and for 44 days for the males. The results obtained were as follows: For the parental males, no effects of test item administration were observed in the 30 mg/kg bw/day group. In the 100 mg/kg bw/day and higher dose groups, epithelial hyperplasia with degeneration and ulceration were observed in the bladder mucosa, and red urine excretion and urine-stained lower abdominal fur were also observed. Food consumption decreased in the early stage of dosing. In the 300 mg/kg bw/day and higher dose groups, thickening of the mucosa due to epithelial hyperkeratosis and hyperplasia were observed in the forestomach, and there were also cases of erosion and ulceration of the glandular stomach mucosa and of the thickened forestomach mucosa. In the 1000 mg/kg bw/day group, distended caecum with epithelial degeneration was observed, bodyweight increase was inhibited, and there were deaths.In the parental females (in the 100, 300 mg/kg bw/day and higher dose groups) there was damage to the bladder and gastric mucosa as seen in the parental males; in the 1000 mg/kg bw/day group there were also deaths, and in addition, in the 1000 mg/kg bw/day group there was hepatocyte enlargement and increased liver weight. Also, in the 100 mg/kg bw/day and higher dose groups there were parental females whose pups all died during or after delivery. These parental females also exhibited erosion and ulceration of the gastric mucosa, and fatty hepatocytes, adrenocortical cell vacuolation, etc., were also observed.

From these results it was concluded that the main repeated dose toxicity in the parental animals was damage to the digestive tract, particularly the gastric mucosa and bladder mucosa, and the liver was also affected. The no-effect dose for general toxicological effects was determined to be 30 mg/kg bw/day, for males and females. This value was also determined to be the no-observed-adverse-effect level (NOAEL).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

30 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP and Guideline 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

In order to investigate the toxicity of the read across substance (CAS 107-66-4) after repeated administration a combined repeated dose toxicity and reproductive toxicity study was undertaken using SD (Crj:CD(SD)) rats. There were 10 male and 10 female rats per group, and the test item doses were 0 (control: solvent administered), 30, 100, 300 and 1000 mg/kg bw/day, administered by forced oral administration every day from 14 days prior to the start of mating, until day 3 of lactation after delivery for the females (40-51 days), and for 44 days for the males. The results obtained were as follows: For the parental males, no effects of test item administration were observed in the 30 mg/kg bw/day group. In the 100 mg/kg bw/day and higher dose groups, epithelial hyperplasia with degeneration and ulceration were observed in the bladder mucosa, and red urine excretion and urine-stained lower abdominal fur were also observed. Food consumption decreased in the early stage of dosing. In the 300 mg/kg bw/day and higher dose groups, thickening of the mucosa due to epithelial hyperkeratosis and hyperplasia were observed in the forestomach, and there were also cases of erosion and ulceration of the glandular stomach mucosa and of the thickened forestomach mucosa. In the 1000 mg/kg bw/day group, distended caecum with epithelial degeneration was observed, bodyweight increase was inhibited, and there were deaths. In the parental females (in the 100, 300 mg/kg bw/day and higher dose groups) there was damage to the bladder and gastric mucosa as seen in the parental males; in the 1000 mg/kg bw/day group there were also deaths, and in addition, in the 1000 mg/kg bw/day group there was hepatocyte enlargement and increased liver weight. Also, in the 100 mg/kg bw/day and higher dose groups there were parental females whose pups all died during or after delivery. These parental females also exhibited erosion and ulceration of the gastric mucosa, and fatty hepatocytes, adrenocortical cell vacuolation, etc., were also observed.

From these results it was concluded that the main repeated dose toxicity in the parental animals was damage to the digestive tract, particularly the gastric mucosa and bladder mucosa, and the liver was also affected. The no-effect dose for general toxicological effects was determined to be 30 mg/kg bw/day, for males and females. This value was also determined to be the no-observed-adverse-effect level (NOAEL).

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on repeated dose toxicity, the test item is not classified according to Regulation (EC) No 1272/2008 (CLP), as amended for the twelth time in Regulation (EU) No 2019/521.