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Toxicological information

Neurotoxicity

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Administrative data

Description of key information

There is no evidence that RDP causes neurotoxic effects. No key value has been selected.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat

Additional information

The neurotoxicity of RDP was investigated in several acute toxicity studies in rats, via the oral (five studies), dermal (one study) and inhalation route (one study) (according to OECD 401, 402 and 403). Monocyte non-Specific Esterase (MNSE) activity was measured as an additional parameter in these studies. In five studies, no significant inhibition of MNSE activity is observed, however, in two studies the observed MNSE inhibition is lower than the 20% difference from the baseline value, which is generally regarded to be within normal variability. Observed MNSE activity in these cases are between 63 and 73%. In the repeated dose toxicity studies, in which MNSE activity was also measured, differences in MNSE activities between groups were not dose-related and therefore not toxicologically relevant.

 

To determine whether RDP may cause organophosphate induced delayed neuropathy (OPIDN), three studies in which the activity of the enzyme neuropathy target esterase (NTE) was measured after exposure of hens after repeated exposure. No biologically relevant inhibition of NTE-activity was observed in the three studies, and exposure to RDP did not produce any overt clinical signs of toxicity at the tested dose levels of 2000 and 5000 mg/kg bw/day.

 

The differences in neurotoxicity profiles of phosphate ester products is assessed in an expert statement by Dekant and Henzl (2006), which is included as an attached document to this endpoint summary. Two different types of neurotoxic responses for phophate ester products have been identified: the interaction of organophosphate esters with the enzyme acetylcholinesterase, which may result in toxic effects shortly after exposure, and delayed neuropathy (OPIDN), which has been associated with certain arylalkyl phosphates. Both types of neurotoxic responses have been investigated in the studies that are present in this dossier.

The expert statement shows that the high structural diversity of organophosphate esters results in different modes of action and vast differences in neurotoxicity potential. As a result, doses required to induces "organophosphate ester"-specific effects may range from 0.5 mg/kg bw to more than 2000 mg/kg bw.

It is concluded that the neurotoxicity of phosphate ester products should be based on the available toxicity data of the individual phosphate ester product and the known biological modes of action, as the presence of a phosphate ester moiety in a substance cannot solely serve as indicator of neurotoxicity.

In Whitehead 2019, Measurement of Plasma, Erythrocytes and Brain Cholinesterase Activity were included in an Embryo-Fetal Development (OECD 414) in the Sprague-Dawley Rat. Based on the results it was concluded that the no observed adverse effect level (NOAEL) for maternal toxicity and embryo-fetal survival, growth and development was 1000 mg/kg/day

Maternal CHE: Mean brain cholinesterase was not shown to be inhibited in pregnant females. There was no conclusive effect of treatment on erythrocyte cholinesterase activity, as a statistically significant difference (p<0.05) was identified between Control Group 2 and Control Group 1 for mean erythrocyte cholinesterase in pregnant females. Statistically significant dosagerelated mean plasma cholinesterase inhibition was evident in pregnant females at 40, 200 and 1000 mg/kg/day when compared to both Control Groups. Fetus CHE: Mean brain cholinesterase and erythrocyte cholinesterase was not inhibited in fetuses. There was no conclusive effect of treatment on plasma cholinesterase activity in fetuses. The NOEL for brain and erythrocyte inhibition in pregnant females, and brain, erythrocyte and plasma cholinesterase inhibition in fetuses was 1000 mg/kg/day.No observed effect level (NOEL) for inhibition of plasma cholinesterase activity in pregnant females was not established and is below the lowest dose investigated, 40 mg/kg/day

 

 In Hann (2019) measurement of Plasma, Erythrocytes and Brain Cholinesterase Activity were included in a 13 weeks repeated dose oral toxicity study (OECD 408) in the Sprague-Dawley Rat. The mean plasma cholinesterase levels were low in treated groups, although a similar reduction was not apparent in erythrocyte or brain values – and, although female erythrocyte cholinesterase activity was low, the difference were confined to one sex with no apparent relationship to dose level. The differences seen in any of the cholinesterase parameters (plasma, erythrocyte or brain) were of uncertain significance since there was, based on all behavior-related assessments, clearly no effect on the animals. Based on these results it was concluded that the no adverse effect level (NOAEL) for

systemic toxicity was 1000 mg/kg/day. There was no adverse effect of treatment at any dose level, the detailed behavioral assessments were unaffected and there were no adverse histopathological findings.

Based on the findings in the acute toxicity studies, as well as the delayed neurotoxicity studies in the hen, and by the CHE measurements and behavior assessments accompanied the subchronic toxicity study and the developmental toxicity study in the repeated dose  it is concluded that there is no evidence of neurotoxic effects for RDP.

 

 

 

 

 

 

 

 

 

 

In Whitehead 2019, Measurement of Plasma, Erythrocytes and Brain Cholinesterase Activity were included in an Embryo-Fetal Development (OECD 414) in the Sprague-Dawley Rat. 

There were no deaths and no adverse clinical signs were observed in the pregnant rats. following dose administration. Maternal CHE: Mean brain cholinesterase was not shown to be inhibited in pregnant females. There was no conclusive effect of treatment on erythrocyte cholinesterase activity, as a statistically significant difference (p<0.05) was identified between Control Group 2 and Control Group 1 for mean erythrocyte cholinesterase in pregnant females. Statistically significant dosagerelated mean plasma cholinesterase inhibition was evident in pregnant females at 40, 200 and 1000 mg/kg/day when compared to both Control Groups.

There were no adverse effects on litter parameters (implantations, pre- and post-implantation loss, live litter size and sex ratio), placental weights, total litter weights or overall fetal weights at any dose level and fetal development was not compromised at doses up to 1000 mg/kg/day. Fetus CHE: Mean brain cholinesterase and erythrocyte cholinesterase was not inhibited in fetuses. There was no conclusive effect of treatment on plasma cholinesterase activity in fetuses.

Based on the results it was concluded that the no observed adverse effect level (NOAEL) for maternal toxicity and embryo-fetal survival, growth and development was 1000 mg/kg/day

The NOEL for brain and erythrocyte inhibition in pregnant females, and brain, erythrocyte and plasma cholinesterase inhibition in fetuses was 1000 mg/kg/day.

No observed effect level (NOEL) for inhibition of plasma cholinesterase activity in pregnant females was not established and is below the lowest dose investigated, 40 mg/kg/day

Justification for classification or non-classification

Based on the available data, there is no evidence of neurotoxic effects for RDP. Therefore, based on the criteria outlined in 67/548/EEC and 1272/2008/EC RDP does not have to be classified with regard to neurotoxicity.