Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.3 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
other: NOEC
DNEL value:
65.8 mg/m³
Explanation for the modification of the dose descriptor starting point:
No adequate experimental effect data are available on the relevant route of exposure for the population under consideration.
AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEL.
AF for differences in duration of exposure:
1
Justification:
The NOAEC derives fron a one-generation reproduction study.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scalic is not appropriate for inhalaiton route.
AF for other interspecies differences:
2.5
Justification:
Default assessment factor for other interspecies differences.
AF for intraspecies differences:
5
Justification:
Default assessment factor for intraspecies differences between workers.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of the database.
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
other: NOEL
DNEL value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No adequate experimental effect data are available on the relevant route of exposure for the population under consideration.
AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEL.
AF for differences in duration of exposure:
1
Justification:
The NOAEC derives fron a one-generation reproduction study.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling factor for rats as compared to humans.
AF for other interspecies differences:
2.5
Justification:
Default assessment factor for other interspecies differences.
AF for intraspecies differences:
5
Justification:
Default assessment factor for intraspecies differences between workers.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of the database.
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Phenethylammonium salt of fosfomycin is not classified for any acute toxicity effects according to toxicological data available and according to Regulation (EC) n. 1272/2008.

The substance is not harmful after oral and dermal acute exposure and it resulted not irritant to the skin and to the eyes inin vivotest systems.

Moreover, it did not result sensitizing.

According to two in vitro test systems, Phenethylammonium salt of fosfomycin resulted not genotoxic.

In the 28-day oral repeated-dose toxicity study in rats, a NOAEL of 150 mg/kg bw/day has been identified (mid-dose tested). At the higher dose tested (500 mg/kg bw/day), some effects like salivation after gavage, fur loss, lacrimation and/or eyelid swelling, chromodacryorrhea, abdomen dilation and poor conditions were observed. Reversibility of the above-mentioned clinical changes was ascertained.

At the end of the treatment period, a few changes were seen that were considered related to the test article administration. These were on the whole slight increases in mean weights of liver and kidneys in males and females of the intermediate and high dose groups, (usually being statistically significant), a slight decrease in absolute values of testes in males and in spleen in females of the high dose group. At the end of recovery, the only change seen was an evident decrease in weights of tests in the group previously treated with 500 mg/kg/day, while other organs affected at the end of the treatment period showed complete recovery.

In the oral one-generation study performed with rats, the NOEL of 50 mg/kg bw/day was observed in parent females and in offspring. The NOAEL of 100 mg/kg bw/day was, instead, observed in parent females and in offspring.

As no acute effects are expected for Phenethylammonium salt of fosfomycin, no acute DNEL were derived as no/low hazard has been identified.

The only local effects after repeated exposure were fur loss and chromodacryorrhea in female rats during the oral 28-day repeated toxicity study. Although the relevance of these effects after inhalation and dermal exposure is unclear, DNELs were derived from a precautionary and conservative point of view.

Although inhalation exposure is considered to be negligible (see toxicokinetics summary and CSR Section 9), the DNEL after long-term inhalation exposure has been derived from a precautionary and conservative point of view.

Long-term systemic DNELs have been derived starting from the NOEL of the one-generation study with rats.

Details of the derivations are reported above.

General Population - Hazard via inhalation route

Systemic effects

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

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Phenethylammonium salt of fosfomycin is an intermediate intended only to industrial use. No exposure is foreseen for consumers and humans via environment (see CSR Section 9).