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Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 428 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.08 mg/cm²

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Dose descriptor starting point:

other: LOAEL

Additional information - workers

The following DN(M)EL were not derived:

- Dermal for acute / short-term exposure- systemic effects

- Inhalation for acute / short-term exposure- systemic effects

- Inhalation for acute / short-term exposure- local effects

- Dermal for long-term exposure- systemic effects

- Dermal for long-term exposure- local effects

- Inhalation for long-term exposure- local effects

The available data are sufficient to conclude that C-4000 does not pose an acute toxicity hazard via any anticipated route of exposure.  It is not corrosive to eyes or skin and produced only slight irritation in rabbits in both organs that was below the minimum to be classified in the GHS.  The dermal dose in the appropriate unit is provided as a LOEL for the short-duration erythema and edema noted in the primary dermal irritation study.

C-4000 is a water-insoluble [137 μg/L] liquid of low volatility [VP@100°C = 1.359E-05 hPa)].  This liquid is formulated into pellets 2-5 mm in size to produce the commercial product, ADVAPAK Neo.  The ADVAPAK Neo pellets are shipped and are subsequently compounded directly with PVC plastic at the site producing the plastic article, typically PVC pipe.  The product formulation and pipe production processes use no water;  the cleaning operations use only rinse water that typically goes to a sewage treatment.

The results reported in the toxicology dataset for C-4000 indicate that all treatment-related responses in test animals are threshold effects.  None of the toxicological mechanisms involved in elucidating these are based on an assumption of a non-threshold response.  This further supports the decision that a correction of dose descriptors for route-to-route extrapolation or the derivation of a DNEL are not necessary for C-4000 for acute effects.

The repeated dose results for C-4000 indicate that the NOAEL, 810 mg/kg bw/day basis in rats, is sufficient to prevent a toxic response in any target organ, noting that hypertrophy, an adaptive non-toxic response of the liver and the follicular thyroid, was observed.  The NOEL in the prenatal developmental toxicity study was 1000 mg/kg bw/day.  Thus, the overall NOAEL is 810 mg/kg bw/day which precludes developmental toxicity and any adverse morphological or functional response in the reproductive organs.  Therefore, the NOAEL from the 28-day study for is sufficient to prevent all treatment-related adverse responses in test animals.  It follows that the DNEL’s derived from the 28-day study for oral and inhalation exposure are sufficient to prevent adverse health effects in humans.

The treatment-related responses in test animals are all threshold effects.  This supports the decision to use only a correction of dose descriptors for route-to-route extrapolation in the derivation of a repeated-dose DNEL for C-4000.  No assumption of a non-threshold response is needed in extrapolating the NOAEL dose to possible toxicological responses in humans. 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

704 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.08 mg/cm²

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Dose descriptor starting point:

other: LOAEL

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

203 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - General Population

The following DN(M)EL were not derived:

- Dermal for acute / short-term exposure- systemic effects

- Inahaltion for acute / short-term exposure- systemic effects

- Oral for acute / short-term exposure- systemic effects

- Inhalation for acute / short-term exposure- local effects

- Dermal for long-term exposure- systemic effects

- Dermal for long-term exposure- local effects

- Inahalation for long-term exposure- local effects

Consumers will not be exposed to C-4000 as a pure substance.  The use of C-4000 as a component of heat stabilizers for PVC pipe creates the possibility of some consumer exposure via leaching into potable water.  Estimates for this have been calculated and found to be quite low.  The approval by the Netherlands KIWA / RIVM of C-4000 for use in water pipe supports the industry position that consumer risks via this potential route of exposure are acceptable.

Other potential consumer risks have the same toxicological endpoints of concern as apply to potential risks for workers.  The available data are sufficient to conclude that C-4000 will not pose an acute toxicity hazard via any anticipated route of exposure.  In addition, C-4000 is not toxic after repeated doses, it does not produce any developmental toxicity, and is not likely to produce any reproductive toxicity.  Therefore, the DNEL’s derived from the 28-day study for oral and inhalation exposure are sufficient to prevent adverse health effects in consumers.

The substance, C-4000, does not require special hazard considerations for the general population or special sub-populations, e.g. breast-fed babies, and should carry no classification in the GHS System.