Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
3

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

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

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

1. Acute / short-term exposure - systemic effects

Cutaneous route

Since only slight and no specific effects were seen after dermal acute exposure to paramethoxyphenol (PMP), no DNEL was calculated for this endpoint.

An acute toxic class method study with reliability 1 according to Klismisch rating (RCC, 2008) was retained as a key study for this end point. In this study only one dose was tested (2000 mg/kg bw) in rats. At this dose only slight clinical signs were noted such as ruffled fur, sedation and almost to complete closed eyes. At day 7 after treatment, all these effects disappeared. Since observed effects in rats are not considered to be adverse and are reversible within 7 days, it does not appear relevant to derive a DNEL for systemic effects induced by PMP after a dermal acute exposure based on this study. Moreover, human data showed that PMP dermal absorption is low (see sections 7.1.2 and 7.10 of the IUCLID).

Inhalation

No data are available for acute inhalation exposure. Two studies performed by oral route are available. However, the reliability of these studies is 3 and 4 according to Klimisch rating.

Since, no robust information on PMP acute toxicity threshold is available, the DNEL for acute toxicity by inhalation has been set from the long-term inhalation DNEL. A default value of 3 was applied according to the guidance R8.

A DNEL of 3.5 mg/m3 was derived for systemic effect after chronic exposure by inhalation (see below).

DNEL inhalation short-term = DNEL inhalation long-term x 3 = 3.5 mg/m3 x 3 = 10.5 mg/m3 (10 mg/m3)

DNEL (Inhalation, 15 minutes of exposure) = 10 mg/m3

2. Acute / short-term exposure - local effects

- Irritation and corrosion

- Skin irritation

No DNEL can be derived.

In the key study (Freulon, 2006 - reliability 1), a single dose of 0.5g of PMP induced slight irritation on young adult New Zealand white rabbits after 4 hours of dermal exposure. The mean scores for erythema and oedema were 1.78 and 1.44 respectively. Erythema was fully reversible within 8 -15 days and oedemas were fully reversible within 8 days.

Based on this result, PMP is slightly irritating for skin and is not classified for this endpoint according to Annex VI of the Directive 67/548/EEC and according to CLP criteria (Regulation (EC) n°1272/2008).

Therefore, since PMP was not classified as irritant for skin, no DNEL is required for such effect.

- Eye irritation

PMP is officially classified as irritant for eyes according to Regulation (EC) n°1272/2008.

Two studies are available. The first one with reliability 3 (Dow chemical report, 1959) cannot permit a conclusion and the second one with reliability 4 (Elf Atochem report, 1987) led to a conclusion of highly irritating. Based on these two studies, it is not possible to classify PMP for eye irritation. However, PMP was officialy classified as irritant for eyes according to Regulation (EC) n° 1272/2008 annex VI tables 3.1 and 3.2.

Based on the two available studies, it is not possible to derive a DNEL for PMP eye irritation. A qualitative approach to risk assessment and management is therefore required because PMP is classified as irritant for eyes (chapter R8, appendix R8 -9).

- Respiratory tract irritation

No data available.

- Sensitizer

PMP is officially classified as skin sensitizer according to Regulation (EC) n°1272/2008.

Only 2 studies with reliability 3 carried out on female guinea pigs are referenced. The first one (Van der Walle et al., 1982 a) used the method of Guinea Pig Maximization Test, 10 animals, 2 semi occlusive epicutaneous induction with 0.5 then 1 M of PMP, and 2 challenges but no data on concentrations. This test led to a moderate sensitization (no data on effect type). The second one (Van der Walle et al., 1982 b) used the method of Freund's complete adjuvant test, 8 animals, 5 intradermal injections of 0.5M PMP as induction and 2 challenges but no data on concentrations. This test also led to a moderate sensitization (no data on effect type). No DNEL can be calculated from these 2 studies because the concentrations used were not specified and no dose-response information is available.

Therefore, since PMP is classified as sensitizer for skin, a qualitative approach to risk assessment and management is required (chapter R8, appendix R8 -9).

3. Long-term exposure - systemic effects

Cutaneous route

No DNEL can be calculated.

Indeed, no effects were seen in a reliable carcinogenic study performed on mice and rabbits after dermal long term exposure. Moreover, human data showed that PMP dermal absorption is low (see sections 7.1.2 and 7.10 of the IUCLID)

Inhalation

No data are available for inhalation exposure. However, a route to route extrapolation can be realised from an oral combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, selected as a key study for repeated dose toxicity endpoint (Harlan, 2009 - reliability 1).

Based on this key study from which a NOAEL of 150 mg/kg bw/day was identified for general effects (salivation, reduced activity, decrease of food consumption and body weight) observed in rats, a DNEL can be derived for systemic effect induced by inhalation.

NOAEL rat (sub-acute exposure) = 150 mg/kg bw (for salivation, reduced activity, decrease of food consumption and body weight)

NAEL human (sub-acute exposure) = 150 mg/kg bw / 4 x 2.5 = 15 mg/kg bw (4 x 2.5: default assessment factor for interspecies variability - Rats)

NAEC human (sub-acute exposure) = 15 mg/kg bw x 70 kg bw/10 m3= 105 mg/m 3

(Route to route extrapolation, assuming 100 % absorption for both routes in both species)

70kg: mean human body weight ; 10 m3/person: respiratory volume light activity for workers (8h exposure)

Assessment factor (AF):

- Time duration (subacute to chronic exposure): 6 (default value)

- Intraspecies factor: 5 (default value for worker variability)

Overall assessment factor (OAF) = 30

DNEL= NAEC human/OAF = 105 mg/m3/30 = 3.5 mg/m3 (3 mg/m3)

DNEL = 3 mg/m3 (for chronic inhalation exposure)

Carcinogenicity

Among 5 carcinogenic studies with reliability 2 performed by oral route, only a decrease of forestomac tumour incidence was observed in rats and hamsters. Such tumour is not relevant for humans. Moreover, the carcinogenic study performed by cutaneous route showed no evidence of carcinogenicity in mice and rabbits. Therefore, since no carcinogenic effects were observed after PMP exposure, no DNEL or DMEL shall be derived for this endpoint.

Reprotoxicity

The 2009 combined repeated dose toxicity study with the reproduction/developmental toxicity screening test performed in 2009 by Harlan showed no effect on fertility, no effect on pup litter size and pup body weight up to 300 mg/kg bw, the highest tested dose.

Two developmental studies with reliability 3 are available. These two studies were not standard protocols and did not permit to conclude about the possible developmental toxicity of PMP. For this raison, the testing proposal for this endpoint was a study according to OECD test guideline 414.

Based on this new study performed in 2013 in which pregnant female rats were exposed daily to PMP from day 6 to day 20p.c.by gavage at dosages of 100, 200 and 400 mg/kg bw/day,developmental delays (reduced affecting fetal body weight and ossification associated) and malformations (mainly of the brain, skull, head and axial skeleton) were recorded at 400 mg/kg bw/day. No developmental effects were observed at the two lower tested doses 100 and 200 mf/kg bw/day.

From this study a NOAEL of 200 mg/kg/day and a LOAEL of 400 mg/kg bw/day were identified for developmental/teratogenic effects.

 

Based on these new information PMP should be classified as Reprotoxic Category 2 H361d (suspected of damaging the unborn child), according to the EU CLP Regulation n°1272/2008 and a developmental DNEL should be derived in order to protect fetus.

NOAEL rat female (developmental effects) = 200 mg/kg bw (For day 6 to day 20p.c.)

NAEL women (developmental effects) = 200 mg/kg bw / 4 x 2.5= 20 mg/kg bw (4 x 2.5: default assessment factor for interspecies variability - Rats) (for 9 months of gestation)

NAEC women (developmental effects) = 20 mg/kg bw x50 kg bw/10 m3= 100 mg/m3 (for 9 months of gestation)

(Route to route extrapolation, assuming 100 % absorption for both routes in both species)

 

50kg: mean women body weight ; 10 m3/person: respiratory volume light activity for workers (8h exposure)

Assessment factor (AF):

- Time duration: no assessment factor for time duration was applied assuming that the ratio time of gestation / life time are similar in female rats and women.

- Intraspecies factor: 10 (taking into account that, pregnant women can be more sensitive than other workers).

- Severity of effect: 3 (an additional factor was applied for developmental effects)

Overall assessment factor (OAF) = 30

DNEL= NAEC women/OAF = 100 mg/m3/ 30= 3.3 mg/m3(3 mg/m3)

DNEL = 3 mg/m3 (for developmental effects during 9 months of gestation)

 

This DNEL (inhalation) in order to protect fetus is similar to those set for workers (inhalation, systemic effects, long term). Pregnant women should not be exposed to PMP in a level higher than 3 mg/m3 whatever the time duration.

Based on the OECD guideline 414 study, a NOAEL of 100 mg/kg bw/day was identified for systemic effects in pregnant female rats exposed daily to PMP from day 6 to day 20p.c.by gavage.

Based on this value a DNEL by inhalation can be set in order to protect pregnant women in work place.

 

NOAEL pregnant female rats = 100 mg/kg b.w./day (For day 6 to day 20p.c.)

 

NAEL pregnant women = 100 mg/kg b.w./day / 4 x 2.5= 10 mg/kg bw (4 x 2.5: default assessment factor for interspecies variability - Rats) (during the 9 months of gestation)

 

NAEC pregnant women = 10 mg/kg bw x 50 kg bw / 10 m3= 50 mg/m3(during the 9 months of gestation)

(Route to route extrapolation, assuming 100 % absorption for both routes in both species)

 

50kg:mean women body weight ;10 m3/person: respiratory volume light activity for workers (8h exposure)

Assessment factor (AF):

- Time duration: no assessment factor for time duration was applied assuming that the ratio time of gestation / life time are similar in female rats and women.

- Intraspecies factor: 5 (taking into account the possible variation between pregnant women).

 

Overall assessment factor (OAF) = 5

 

DNEL= NAEC women/OAF = 50 mg/m3/ 5= 10 mg/m3

DNEL inhalation, systemic effect = 10 mg/m3(in order to protect women during pregnancy)

 

The inhalation/systemic effect DNEL derived in order to protect women during pregnancy (10 mg/m3during 9 months) is higher than the inhalation/long term/systemic effect DNEL set for workers (3 mg/m3). Therefore, since the DNEL of 3 mg/m3established for workers covers also pregnant women, this DNEL had been chosen for the risk assessment in order to protect the both populations.

4. Long-term exposure - local effects

No local effects were observed after PMP long term exposure by dermal route. Therefore no DNEL can be derived.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

General population is not exposed to PMP, therefore no DNEL/DMEL and no risk assessment are required.

In some exposure scenario, there is no direct consumer exposure to PMP. In other exposure scenario (two), direct consumer exposure to the substance resulting from formulation in which the percentage of PMP is less than 0.1%.

The indirect exposure of humans via the environment is not relevant. PMP has a low potential volatilization into air, the exposure via inhalation of ambient air is considered to be negligible. Considering also that PMP has a low potential for bioaccumulation ant that it is readily biodegradable, the exposure via consumption of food and drinking water is considered to be negligible.