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Description of key information

Hazards identified by EU Risk Assessment in May 2008:
- A 13 week feeding study in rats indicated liver and thyroid as the main target organs affected by TCPP. A LOAEL of 52 mg/kg/day is derived for this study.
- In a 2-generation reproductive toxicity study in which rats were fed TCPP in the diet over two successive generations, the low-dose of 99 mg/kg for females is considered to be the LOAEL for parental toxicity.
No data are available on inhalation and dermal repeated dose toxicity.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
52 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Hazards identified by EU Risk Assessment in May 2008:

"A study is available in which male and female rats were fed diets containing TCPP for 13 weeks at concentrations corresponding to mean substance intake values of up to 1349 mg/kg/day and 1745 mg/kg/day for males and females respectively. This study indicated the liver and thyroid to be the main target organs affected by TCPP. Effects observed included statistically significant increases in absolute and relative liver weights in males at all doses and females at the two highest doses, periportal hepatocyte swelling in high dose groups and mild thyroid follicular cell hyperplasia in males at all doses and females at the highest dose. Based on the increase in both absolute and relative liver weights, accompanied by mild thyroid follicular cell hyperplasia observed in males of all dose groups, a LOAEL of 52 mg/kg/day is derived. This LOAEL is taken in preference to the NOAEL which was identified in a 4-week study in which rats were dosed with TCPP at concentrations of 0, 10, 100 and 1000 mg/kg/day, as it was derived from a study of longer duration. The 4-week study also showed the liver as the target organ, with increased liver weight changes observed in the high dose groups, accompanied by hepatocyte hypertrophy in all high–dose males and one mid-dose male and changes in ALAT activity in high-dose animals. A two-week study in which rats were fed diets of TCPP at concentrations corresponding to mean substance intake values of up to 1636 mg/kg/day for males and 1517 mg/kg/day for females showed no major clinical signs of toxicity. There was a significant reduction in weight gain and food consumption in high dose males during week 2, but there were no other significant findings. In a 2-generation reproductive toxicity study in which rats were fed TCPP in the diet over two successive generations, the low-dose of 99 mg/kg for females is considered to be the LOAEL for parental toxicity. This is based on decreased body weight and food consumption seen in mid and high dose parental animals and the effects on uterus weight seen in all dosed animals. For males, a NOAEL of approximately 85 mg/kg is derived for parental toxicity, based on decreased body weights, food consumption and organ weight changes observed at mid and high dose groups. No data are available on inhalation and dermal repeated dose toxicity."

 

Updated relevant information (March 2018):

Tris(chloropropyl)phosphate (M20263) [= TCPP] is currently within the testing procedure of the National Toxicology Program (NTP) with the following repeated dose toxicity tests:

- 13 week repeated dose toxicity study in rats (status: completed; but results not available yet)

- 13 week repeated dose toxicity study in mice (status: completed; limited information on results available, see description below)

- 2 year carcinogenicity studies on rats (status: histopathology in progress; results not available yet)

- 2 year carcinogenicity studies on mice (status: histopathology in progress; results not available yet)

http://ntp.niehs.nih.gov/testing/status/agents/ts-m20263.html

As soon as the entire new information is publically available it should be integrated in the data base for TCPP and the toxicolgical assessment should be updated.

A 13 week feeding study was performed by NTP with male and female B6C3F1 mice. Only limited data on study results are available up to now on the NTP webpage. No assessment report is available and the results have to be estimated by tables and figures. No information is given on organ weights, hematology and clinical chemistry. Doses of 1250 up to 20000 ppm, according to actual ingested doses of about 220, 500, 1000, 2400, and 4500 mg/kg bw/day for males and 200, 450, 900, 1800, and 3500 mg/kg bw/day for females can be roughly calculated from the tables. No mortality was observed.

In male mice the body weight at termination decreased dose dependently by about 4, 11, 16, 21, and 25% compared to control, although food consumption increased by about 4, 7, 14, and 31%, and 10%. No information is available yet on organ weights, hematology, clinical chemistry, and sperm morphology. In the liver of males hepatocyte hypertrophy occurred starting at a dose of about 500 mg/kg bw/day. In the kidney renal tubule cytoplasmic alterations were seen also starting at a dose of about 500 mg/kg bw/day. From the available data the dose of about 220 mg/kg bw/day in males showed no relevant adverse effects on body weight and organ integrity.

In female mice the body weight at termination decreased slightly at doses of 900 mg/kg bw/day and higher by about 5, 10, and 19% compared to control. Food consumption increased slightly to 115% at 900 mg/kg bw/day and again decreased at higher doses to about 104% at the highest dose level. No information is available yet on organ weights, hematology, clinical chemistry, and vaginal cytology evaluations.In the liver of females hepatocyte hypertrophy occurred starting at a dose of about 900 mg/kg bw/day.From the available data the dose of about 450 mg/kg bw/day in females showed no relevant adverse effects on body weight and organ integrity.

 

In conclusion:

As discussed in the EU Risk Assessment in May 2008 the results of a 13 week feeding study in rats indicate the liver and thyroid to be the main target organs affected by TCPP in rats. A LOAEL of 52 mg/kg bw/day was derived in this study. In a 2-generation reproductive toxicity feeding study a LOAEL of 99 mg/kg bw/day was considered for maternal toxicity. This was based on decreased body weight and food consumption seen in mid and high dose parental animals and effects on uterus weight seen in dosed females without histopathological correlate. For males, a NOAEL of approximately 85 mg/kg bw/day was derived.

Preliminary results obtained from the NTP webpage for a 13 week feeding study on male mice indicate a dose-dependently reduced body weight at termination and that liver and kidney are the main target organs affected by TCPP. Female mice seem to be less susceptible than male mice with a reduction in body weight and adverse liver effects at higher doses. On the basis of the available results a dose of 220 mg/kg bw/day for male mice and 450 mg/kg bw/day for female mice showed no relevant adverse effects on body weight and organ integrity.

The LOAEL of 52 mg/kg bw/day taken from the rat 13-week study is thus taken forward for DNEL derivation.

As soon as the full testing results are publically available for the newly performed NTP studies the assessment of repeated dose toxicity for TCPP has to be amended and revised.

Justification for classification or non-classification

EU Risk Assessment in May 2008: Based on the available studies, TCPP needs no classification for repeated dose toxicity according to EU guidelines.

Update March 2018: The conclusion of non-classification for repeated dose toxicity is confirmed and compliant with EU Regulation 1272/2008.