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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
125 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Kinetics (absorption figures for oral, dermal and inhalation route of exposure)

Oral and dermal absorption values can be derived from the available substance specific data: oral absorption is assumed to be 2% and dermal absorption is assumed to be 0.1%.

No data on inhalation absorption are available, but from data on intratracheal absorption 1% absorption can be assumed. It is unknown whether inhalation exposure will result in the same amount of absorption, therefore as a worst case assumption inhalation absorption is set to be 10%.

Acute toxicity

ZPS does not have to be classified for acute toxicity and therefore derivation of a DNELacute is not necessary.

Repeated dose toxicity

The study considered for DNEL derivation of ZPS is the 90 days oral toxicity study with rats. Dietary administration of ZPS to rats for 13 weeks at dose levels of 25, 250 and 2500 mg/kg bw/day elicited a variety of effects at 250 and 2500 mg/kg/day.

Histopathologically, the main effect of treatment was caecitis accompanied by colitis or proctitis in the large intestine of animals treated at 250 and 2500 mg/kg bw/day and squamous hyperplasia of the limiting ridge of the forestomach in animals treated at 2500 mg/kg bw/day (effects in the forestomach are not relevant for humans). The significance of these changes in animals fed at 2500 mg/kg bw/day of the substance in the diet is uncertain. The changes may represent a low-grade mucosal irritation or be secondary to nutritional imbalance, accumulation of test substance in diet or to a disturbance of the normal luminal flora. In females treated at 2500 mg/kg bw/day there was an increase in hyaline droplet accumulation in the kidney proximal tubular epithelium. This probably reflects changes associated with excretion of the test article.

In conclusion, 25 mg/kg bw/day is considered the local NOAEL (based on caecitis accompanied by colitis or proctitis in the large intestine of animals treated at 250 mg/kg bw/day, the significance of these changes in animals fed at 2500 mg/kg bw/day of the substance in the diet is uncertain) and 250 mg/kg bw/day is considered the systemic NOAEL (based on an increase in hyaline droplet accumulation in the proximal tubular epithelium of the kidney in females).

 

Mutagenicity

ZPS is considered to be not genotoxic.

Reproduction toxicity

No developmental toxicity was observed in an oral prenatal developmental toxicity study in rats with ZPS (tested at 0, 0.25, 2.5, 250 and 2500 mg/kg bw/day). Thus, the NOAEL for developmental toxicity was considered 2500 mg/kg bw/day. No DNEL has to be derived for developmental toxicity.

The NOAEL for maternal toxicity was 2500 mg/kg bw/day. All of the dams at the three highest doses had green-tinted viscera, with the discoloration being especially pronounced at the two highest dosages, but this was not considered adverse.

There are no indications from the available data that dams are more sensitive regarding systemic effects compared to animals exposed in the repeated dose toxicity studies.

 

Long-term – dermal, systemic effects (based on sub-chronic oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 250 mg/kg bw/day

Increase in hyaline droplet accumulation in the proximal tubular epithelium of the kidney in females in the high dose group

Step 2) Modification of starting point

x 2/0.1

Oral absorption is assumed to be 2%, dermal absorption is assumed to be 0.1%.

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

5

Default assessment factor

Exposure duration

2

Extrapolation to chronic exposure based on a sub-chronic toxicity study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

250 x 2 / (0.1 x 4 x 5 x 2 x 1 x 1) = 125 mg/kg bw/day

Long-term - dermal, local effects

No data are available based on which a DNEL for local effects can be derived.

Long-term – inhalation, systemic effects (based on sub-chronic oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 250 mg/kg bw/day

Increase in hyaline droplet accumulation in the proximal tubular epithelium of the kidney in females in the high dose group

Step 2) Modification of starting point

: 0.38

 

 

 

x 6.7 m3/10 m3

 

 

 

x 2/10

An 8 h respiratory volume of 0.38 m3/kg bw for rats was used for conversion into NOAEL upon inhalation exposure.

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest.

 

Oral absorption is assumed to be 2%, 10% absorption is assumed for the inhalation route.

Modified dose-descriptor

250 x 6.7 x 2 / (0.38 x 10 x 10) = 88 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

Intraspecies

5

Default assessment factor

Exposure duration

2

Extrapolation to chronic exposure based on a sub-chronic toxicity study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

88 / (1 x 5 x 2 x 1 x 1) = 8.8 mg/m3

Long-term - inhalation, local effects

No data are available based on which a DNEL for local effects can be derived.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
62.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Long-term – dermal, systemic effects (based on sub-chronic oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 250 mg/kg bw/day

Increase in hyaline droplet accumulation in the proximal tubular epithelium of the kidney in females in the high dose group

Step 2) Modification of starting point

x 2/0.1

Oral absorption is assumed to be 2%, dermal absorption is assumed to be 0.1%.

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

10

Default assessment factor

Exposure duration

2

Extrapolation to chronic exposure based on a sub-chronic toxicity study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

250 x 2 / (0.1 x 4 x 10 x 2 x 1 x 1) = 62.5 mg/kg bw/day

Long-term - dermal, local effects

No data are available based on which a DNEL for local effects can be derived.

 

Long-term – inhalation, systemic effects (based on sub-chronic oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 250 mg/kg bw/day

Increase in hyaline droplet accumulation in the proximal tubular epithelium of the kidney in females in the high dose group

Step 2) Modification of starting point

: 1.15

 

 

 

x 2/10

A 24 h respiratory volume of 1.15 m3/kg bw for rats was used for conversion into NOAEL upon inhalation exposure.

 

Oral absorption is assumed to be 2%, 10% absorption is assumed for the inhalation route.

Modified dose-descriptor

250 x 2 / (1.15 x 10) = 43 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

Intraspecies

10

Default assessment factor

Exposure duration

2

Extrapolation to chronic exposure based on a sub-chronic toxicity study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

43 / (1 x 10 x 2 x 1 x 1) = 2.2 mg/m3

Long-term - inhalation, local effects

No data are available based on which a DNEL for local effects can be derived.

 

Long-term – oral, systemic effects (based on sub-chronic oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 250 mg/kg bw/day

Increase in hyaline droplet accumulation in the proximal tubular epithelium of the kidney in females in the high dose group

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

10

Default assessment factor

Exposure duration

2

Extrapolation to chronic exposure based on a sub-chronic toxicity study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

250 / (4 x 10 x 2 x 1 x 1) = 3.1 mg/kg bw/day

Long-term – oral, local effects (based on sub-chronic oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 25 mg/kg bw/day

Caecitis in the large intestine, accompanied by colitis or proctitis.

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling has to be applied in case the critical effect is a local effect

Intraspecies

5

A lower assessment factor is applied, as the critical effect is a local effect which is hardly influenced by toxicodynamics and kinetics

Exposure duration

1

The local effects observed are not influenced by exposure duration

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

25 / (1 x 5 x 1 x 1 x 1) = 5 mg/kg bw/day