Tributyl phosphate - Registration Dossier

Registration Dossier

Life Cycle description
Uses advised against

Toxicological information

Toxicological Summary

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 3.13 mg/m³

Acute/short term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 12.52 mg/m³

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 3.13 mg/m³

Acute/short term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 12.52 mg/m³

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 0.44 mg/kg bw/day

Acute/short term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 1.78 mg/kg bw/day

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 0.44 mg/cm²

Acute/short term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 1.78 mg/cm²

Workers - Hazard for the eyes

Additional information - workers

Basis for delineation of the DNEL:

Study: Cancerogenicity study

Rat, male, female,

Cancerogenicity study over 2 years

rat: 0 (control), 200, 700 or 3000 ppm

(ca. 0,8.9, 32.5 or 143.2 mg/kg bw/d - male rats;

ca. 0, 11.6, 42 or 181.5 mg/kg bw/d - female rats) via diet.

NOAEL = 8.9 mg/kg bw/day (male rats), NOAEL = 11.6 mg/kg bw/day (female rats)

Effects: 200 ppm : based on the urinary bladder hyperplasia and neoplasms

Reference: Auletta CS, Richter WR (1994)

An oncogenicty study of tributyl phosphate in the rat via dietary

Bericht-Nr.: 89-3533

Pharmaco LSR Inc.

At the request of SOCMA (Synthetic Organic Chemical Manufacturers Association)

1.) Long-term toxicity – systemic effects (workers)

Long-term oral or dermal route-systemic effects (worker) using extrapolation factors:

NOAEL(rat) from a cancerogenicity study: 8.9 mg/kg bw/day

Penetration oral compared to dermal (both assumed 100%) 1

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1 (experimental data in rats, mice and rabbits available)

For intraspecies differences in workers: 5

For extrapolation of exposure duration: 1

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 20

Worker DNEL long-term for oral or dermal route-systemic: 0.445 mg/kg bw/day

Long-term inhalation route-systemic effects (worker):

NOAEL(rat) from a cancerogenicity study: 8.9 mg/kg bw/day

Correction of the starting point according TGD Figure R.8-3:

Corrected inhalatory NOAEC = Oral NOAEL (8.9 mg/kg) x 1/0.38 m³/kg x 6.7 m³/10m³ x 1

=> NOAEC worker = 15.69 mg/m³

For interspecies differences rat vs. human: 1 (according TGD Table

R.8-4. already covered by correction of starting point)

For remaining interspecies differences: 1 (experimental data in rats, mice and rabbits available)

For intraspecies differences in workers: 5

For extrapolation of exposure duration: 1

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 5

Worker DNEL long-term for inhalation exposure: 3.13 mg/m³

2.) Short-term toxicity – systemic effects (workers)

Concerning the systemic effects an exceeding factor of 4 based on the DNEL for long term exposure seems justified.

Therefore the

Worker DNELshort-term for oral or dermal route-systemic: 1.78 mg/kg bw/day

Worker DNEL short-term for inhalation exposure: 12.52 mg/m³

3.) Reproductive Toxicity – systemic effects (workers)

In a 2-generation toxicity study (EPA OTS 798.4700) with 700 and 3000 ppm reductions of body weights, weight gain and food consumption during F0 and F1 prebreed dosing periods , no signs of toxicity, no treatment related mortality; with 200 ppm only transient effects on body weight and food consumption. No NOAEL for adult toxicity. No evidence of reproductive organ histopathology at any dose, no effect on pre- and postnatal mortality. NOAEL for reproductive toxicity (reduced pup body weights) was at or below 200 ppm.

(NOAEL = approx.15 mg/kg bw/day (rats, male + female)

Tributyl phosphate was also investigated in a developmental toxicity feeding study in rats and rabbits:

Tributyl phosphate was administered by gastric intubation to rats during the day 6-15 gestation interval. Dose levels were 188, 375 and 750 mg/kg/day. Each study group was comprised of 24 mated female CD rats. Animals were sacrificed on day 20 of gestation and given a gross postmortem evaluation.

No embryotoxic effects were seen at any of the dose levels evaluated and only at the 750 mg/kg/day dose level was a reduction in mean fetal weight seen.

In groups treated at the 188 and 375 mg/kg/day dose levels, only mild developmental delays were seen in regard to both concurrent control data and historical control data.

No embryotoxic effects were seen at any of the dose levels evaluated and only at the 750 mg/kg/day dose level was a reduction in mean fetal weight seen.

External, visceral and skeletal examination of the fetuses recovered from females in the treatment groups at day 20 of gestation revealed no teratogenic response at any of the dose levels evaluated.

The NOAEL = 750 mg/kg bw for teratogenicity and embryotoxicity.

Tributyl phosphate was administrated by gastric intubation to mated New Zealand White rabbits (18 mated females/group) at dose levels of 50, 150 and 400 mg/kg/day during the day 6-18 gestation period. The 400 mg/kg/day dose level was not considered to be fetotoxic or teratogenic. At the 50 and 150 mg/kg/day dose levels was not considered to be maternally toxic, embryotoxic, fetotoxic or teratogenic in the rabbit. Thus, the no-observable-adverse-effect level (NOAEL)for developmental toxicity of tributyl phosphate in the rabbit for this study was 150 mg/kg bw/day.

The NOAEL for reproductive toxicity in rats is therefore approx. 15 mg/kg bw/day as the lower limit.

Additional or higher assessment factors than those used for the delineation of the DNEL from the cancerogenicity study are not necessary. As the NOAEL for reproductive toxicity (15 mg/kg bw/day) is higher than the NOAEL for cancerogenicity (8.9 mg/kg bw/day), the derivation of a separate DNEL for reproductive toxicity is not necessary, because the DNEL for cancerogenicity covers both endpoints.

The formal DNELs derived for reproductive toxicity are as follows:

Worker DNEL long-term for oral or dermal route-systemic: 0.75 mg/kg bw/day

Worker DNEL long-term for inhalation exposure-systemic: 5.27 mg/m³/day

Conclusion (systemic effects):

Worker DNEL long-term for oral or dermal route-systemic: 0.44 mg/kg bw/day

Worker DNEL long-term for inhalation exposure: 3.13 mg/m³

Worker DNELshort-term for oral or dermal route-systemic: 1.78 mg/kg bw/day

Worker DNEL short-term for inhalation exposure: 12.52 mg/m³

4. Long-term and short-term dermal or inhalation route - local effects (worker)

In rabbits, tributyl phosphate was slightly irritating to the skin (OECD TG 404), and slightly irritating to the eyes (OECD TG 405). The findings were not sufficient for classification.

In a guinea pig maximisation test (EPA OTS 798.4100) tributyl phosphate was negative.

Therefore the DNELs for systemic effects also applies to local effects:

Conclusion (local effects):

Worker DNEL long-term for oral or dermal route-local: 0.44 mg/kg bw/day

Worker DNEL long-term for inhalation exposure: 3.13 mg/m³

Worker DNELshort-term for oral or dermal route-local: 1.78 mg/kg bw/day

Worker DNEL short-term for inhalation exposure: 12.52 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 0.77 mg/m³

Acute/short term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 3.08 mg/m³

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 0.77 mg/m³

Acute/short term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 3.08 mg/m³

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 0.22 mg/kg bw/day

Acute/short term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 0.88 mg/kg bw/day

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 0.22 mg/cm²

Acute/short term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 0.88 mg/cm²

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 0.22 mg/kg bw/day

Acute/short term exposure

Hazard assessment conclusion:: DNEL (Derived No Effect Level)
Value:: 0.88 mg/kg bw/day

DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Basis for delineation of the DNEL:

Study:

Cancerogenicity study

Rat, male, female,

Cancerogenicity study over 2 years

rat: 0 (control), 200, 700 or 3000 ppm

(ca. 0,8.9, 32.5 or 143.2 mg/kg bw/d - male rats;

ca. 0, 11.6, 42 or 181.5 mg/kg bw/d - female rats) via diet.

Effects, NOAEL

NOAEL = 8.9 mg/kg bw/day (male rats), NOAEL = 11.6 mg/kg bw/day (female rats)

Effects: 200 ppm : based on the urinary bladder hyperplasia and neoplasms

Reference: Auletta CS, Richter WR (1994)

An oncogenicty study of tributyl phosphate in the rat via dietary

Bericht-Nr.: 89-3533

Pharmaco LSR Inc.

At the request of SOCMA (Synthetic Organic Chemical Manufacturers Association)

1.) Long-term toxicity – systemic effects (general population)

Long-term oral or dermal route-systemic effects (general population) using extrapolation factors:

NOAEL(rat) from a subchronic toxicity study: 8.9 mg/kg bw/day

Penetration oral compared to dermal (both assumed 100%) 1

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1 (experimental data in rats, mice and rabbits available)

For intraspecies differences in general population: 10

For extrapolation of exposure duration: 1

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 40

General population DNEL long-term for oral or dermal route-systemic: 0.22 mg/kg bw/day

Long-term inhalation route-systemic effects (general population):

NOAEL(rat) from a cancerogenicity study: 8.9 mg/kg bw/day

Correction of the starting point according TGD Figure R.8-3:

Corrected inhalatory NOAEC = Oral NOAEL (8.9 mg/kg) x 1/1.15 m³/kg x 1.0

=> NOAEC general population = 7.73 mg/m³

For interspecies differences rat vs. human: 1 (according TGD Table

R.8-4. already covered by correction of starting point)

For remaining interspecies differences: 1 (experimental data in rats, mice and rabbits available)

For intraspecies differences in general population: 10

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 10

General population DNEL long-term for inhalation exposure: 0.77 mg/m³

2.) Short-term toxicity – systemic effects (general population)

Concerning the systemic effects an exceeding factor of 4 based on the DNEL for long term exposure seems justified.

Therefore the

General population DNELshort-term for oral or dermal route-systemic: 0.88 mg/kg bw/day

General population DNEL short-term for inhalation exposure: 3.08 mg/m³

3.) Reproductive Toxicity – systemic effects (workers)

In a 2-generation toxicity study (EPA OTS 798.4700) with 700 and 3000 ppm reductions of body weights, weight gain and food consumption during F0 and F1 prebreed dosing periods , no signs of toxicity, no treatment related mortality; with 200 ppm only transient effects on body weight and food consumption. No NOAEL for adult toxicity. No ecidence of reproductive organ histopathology at any dose, no effect on pre- and postnatal nortality. NOAEL for reproductive toxicity (reduced pup body weights) was at or below 200 ppm.