Toxicological Evaluation and Limit Values for Nonylphenol, Nonylphenol Ethoxylates, Tricresyl, Phosphates and Benzoic Acid

7. Evaluation

7. Evaluation
7.1.1 o-TCP
7.1.2 TCP´s containing less than 0,1% o-TCP

As appears from the preceding sections, there are striking differences in the toxicity of different isomers of tricresyl phosphate, the differences being dependent on the occurrence of one or more or, as the second alternative, no o-cresyl moieties in the molecule. Therefore, in this and the following sections, the results involving studies with o-TCP and those with TCP containing less than 0.1% o-TCP will be dealt with separately.

The toxicological data relating to the toxicity of o-TCP is mainly restricted to effects on the nervous system, as this organ for long has been considered the target organ for o-TCP toxicity. The studies include both human case stories and animal studies.

The human data base consists of a number of studies, where poisoning and or development of organophosphorous induced delayed neurotoxicity (OPIDN) have occurred. However, only few of them have assessed the actual dose of o-TPC ingested. Neurotoxicity and especially organophosphorous induced delayed neurotoxicity (OPIDN) is the critical effect of o-TCP in man.

A single dose of 0.15 g o-TCP (2 mg/kg b.w.) is stated to produce toxic symptoms (type not specified) in man and severe neurological disturbance (OPIDN) developed after a single dose of 0.5-0.7 g o-TCP (7-10 mg/kg b.w.).

After repeated intake of TCP with a varying content of o-TCP, a number of cases have been described. In a recent, well described incident, mild nausea and weakness were seen in 85 individuals and OPIDN in 91 individuals who had ingested flour contaminated with TCP (containing 20% of o-TCP); the intake of TCP by the affected individuals has been estimated to 47.5-76 mg/day (equivalent to 0.16 to 0.25 mg o-TCP/kg b.w./ day assuming a body weight of 60 kg and 20% o-TCP in the TCP).

In a variety of animal species, several studies have shown that single gavage dosing of 100 mg o-TPC/kg b.w. causes OPIDN. However, most of the animal studies are not suitable for setting a NOAEL for acute toxicity, as only a single dose was used.

In the hen, which is considered to be the most relevant animal species for extrapolating the results to humans with respect to OPIDN, a NOAEL of 2.5 mg/kg b.w./day in 90-day oral studies applies; at the next dose level (5.0 mg/kg b.w./day), OPIDN developed.

For estimation of a TDI for o-TCP, the LOAEL of 0.16 mg o-TCP/kg b.w./day for OPIDN in humans will be used. This LOAEL is below the dose levels causing neurotoxicity in humans and animals following acute exposure and below the NOAEL for OPIDN in the hen. This LOAEL is also clearly below the LOAEL for reproductive effects in roosters (100 mg/kg b.w./day) and is considered also to safeguard against reproductive effects.

7.1.2 TCP’s containing less than 0.1% o-TCP

There is only one report on human poisoning after ingestion of TCP stated not to contain o-TCP. Here neurotoxic symptoms/OPIDN was observed in women after two weeks ingestion of 5-10 mg TCP/kg b.w./ day. However, in the short original description, no information on the content of mono- or di-o-cresyl phosphates is given. It is considered likely that the neurotoxic symptoms observed could be caused by these substances or by other substances capable of inducing OPIDN. Therefore, this study is not considered adequate for estimating a TDI for TCP containing less than 0.1% o-TCP.

The most comprehensive studies on TCP toxicity have been carried out by NTP. These include a number of short and long term studies in mice and rats as well as a reproductive toxicity study using mice and genotoxicity tests.

In the two year rat study, a NOAEL of 7 mg/kg b.w./day was observed with ovarian interstitial cell hyperplasia occurring at higher dose levels. Ovarian interstitial cell hyperplasia represents one of the first signs of reproductive toxicity and is considered the critical effect in female rats. In male rats, no critical effects were observed. No dose related neurotoxicity, including grip strength change, was observed in this study.

In the two year mouse study, liver changes (clear cell foci, fatty change, and ceroid pigmentation) were observed in male mice with a NOAEL of 7 mg/kg b.w./day. The liver changes seen are generally considered to be the first signs of liver toxicity and are thus considered as being of toxicological significance, i.e. for male mice the critical effect is liver changes. In female mice, no critical effects were observed. No dose related neurotoxicity, including grip strength change, was observed in this study.

From these studies, a NOAEL of 7 mg TCP/kg b.w./day applies for systemic toxicity.

In the short term studies and also in 13-week studies, neurotoxic symptoms (most often reduced grip strength) were seen at high doses in some studies. These effects are likely to be caused by impurities of TCP containing one or two o-cresyl rings or the reduced grip strength could be caused by the reduced body weight seen at these doses. Whichever is the cause is not considered important to get clarified as clear systemic toxicity was observed in both rats and mice in two-year studies at dose levels of one to two orders of magnitude below those dose levels, where reduced grip strengths were observed.

For estimation of a TDI for TCP containing less than 0.1% o-TCP, the NOAEL of 7 mg TPC/kg b.w./day from the two-year rat and mouse studies will be used as it safeguards against the neurotoxic effects seen in some studies at higher doses.