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Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
125 mg/kg bw/day
Study duration:
subacute
Species:
rat

Additional information

This substance is of complex composition by-process that meets the criteria of a UVCB substance. It contains (1) multiple phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc species (neutral dimeric, trimeric, and tetrameric dithiophosphate forms), (2) their basic salt compliments, (3)Tetrapropenyl phenol (residual starting material), and (4) base oil (solvent) necessary for the successful manufacture of these various constituents.This substance does not have repeat dose test data. However, conducting a repeat dose study with this substance is not required to assess the potential chronic toxicity or to calculate the long-term DNELs. Any toxic effects potentially observed during a toxicology study (e.g. OECD 422) with this substance are likely to be caused primarily by the presence of the impurity tetrapropenyl phenol (TPP). TPP is classified as a reproductive hazard (CLP category 1B; DSD R60 category 2). Further, adequate test data exists on an analog material to assess the repeat dose toxicity potential of phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc.

 

The DNELs for this substance are calculated for each component present. The more protective long-term DNEL calculated from either Phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc or tetrapropenyl phenol is then applied to the risk assessment.

 

This approach is justified by the following:

 

1.      An assessment ofphenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc indicates that low toxicity is expected based on read across and low bioavailability

 

Phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc is part of the zinc dialkyldithiophosphate (ZDDP) category of chemicals found in the US EPA HPV Risk Based Prioritization Assessment(1). Members of this category are manufactured by first reacting phosphorous pentasulfide with an alcohol followed by reaction with excess zinc oxide. Based on their structural similarities, read across among category members to fill missing data requirements is appropriate. The closest ZDDP category member with data to satisfy the missing repeat dose toxicity endpoint for Phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc is the 2-ethyl-1-hexyl derivative; zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) resulted in a NOAEL of 125 mg/kg/day in an OECD 407 28-day repeat dose study in rats (see CASRN: 4259-15-8, EINECS: 224-235-5).

 

The following comparison of physical and chemical properties and toxicology data confirms the suitability of read across from the 2-ethyl-1-hexyl derived ZDDP to the tetrapropenyl phenol (TPP) derived ZDDP. 

 

Endpoint

Phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc

Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate)

Alcohol starting material

Tetrapropenyl phenol (TPP)

2-ethyl-1-hexanol

Water solubility

< 1 mg/L

8.5 mg/L

Log Kow

> 7

3.6

Molecular weight

1303.3

775

Acute oral toxicity

1.      LD50 (rat) > 15,000 mg/kg

2.      LD50 (rat) > 20,500 mg/kg

LD50 (rat) = 3100 mg/kg

Acute dermal toxicity

1.      LD50 (rabbit) > 15,000 mg/kg

2.      LD50 (rabbit) > 25,600 mg/kg

LD50 (rabbit) > 5000 mg/kg

Skin irritation

Not classified as an irritant

Not classified as an irritant

Eye irritation

Not classified as an irritant

Causes irreversible eye damage

 

Based on the large molecular geometry, low water solubility, and high Kow, it is expected that the absorption of thePhenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc from either oral or dermal exposure would be low. This is consistent with the low acute toxicity observed in animal studies, also indicating that this material is hydrolytically stable and is not expected to liberate free TPP in vivo. Further, when compared to zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate), the expected bioavailability and observed toxicity of Phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc are both less. Therefore, reading across the repeat dose data from the analog substance to Phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc is not only appropriate but also provides a conservative estimation of toxicity for this material. 

 

2.      Tetrapropenyl phenol has a robust data set that indicates it will be responsible for any toxicity observed in a repeat dose study

 

Multiple toxicity studies have been conducted both with tetrapropenyl phenol (TPP) alone as well as with materials that contain TPP as an impurity. This robust data set has led to establishing a specific concentration limit (SCL) for materials containing TPP as an impurity(2). The SCL is based on a NOAEL of 15 mg/kg/day TPP in an OECD 416 two generation reproductive toxicity study in rats. Levels of TPP below this NOAEL are not expected to cause reproductive toxicity in an animal model.Phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinccontains 9.1% TPP as an impurity. As such, a dose of 165 mg/kg/day (15 mg/kg/day divided by 0.091) of this UVCB substance is not expected to cause any reproductive effects in a multi-generation animal study.  

 

The 165 mg/kg/day NOAEL is also used to calculate the DNEL of this substance for reproductive toxicity. The calculation of the DNEL uses assessment factors specific for TPP as the goal is to determine a level of TPP that will not cause adverse effects.

 

3.      The alternative is to conduct a repeat dose study with EC 234-277-6, which has the following issues:

a.      Unnecessary use of animals

b.     Purifying the Phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc (removing the TPP) is difficult and may irreversibly alter the chemical structures and toxicological properties of the material as manufacture normally.

 

References

1.      Zinc Dialkyldithiophosphates (ZDDP) Category Risk-Based Prioritization. U.S. Environmental Protection Agency. September, 2008.

2.      Threshold for Reproductive Toxicity of Tetrapropenyl Phenol (TPP) for Purposes of Hazard Classification. Chevron. October 26, 2010 – see attachment in IUCLID dossier for entire document

Justification for classification or non-classification