Mequinol

Toxicological Summary

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

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

1 050 mg/m³

Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation:

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

NAEC human (sub-acute exposure) = 150 mg/kg bw x70 kg bw/10 m³= 1050 mg/m³

(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)

Then the assessment factors have to be applied.

AF for differences in duration of exposure:

6

Justification:

ECHA R8 guidance default assessment factor for sub-acute to chronic.

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA R8 guidance default assessment factor for rats.

AF for other interspecies differences:

2.5

Justification:

ECHA R8 guidance default assessment factor for interspecies remaining difference.

AF for intraspecies differences:

5

Justification:

ECHA R8 guidance default assessment factor for workers.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high 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 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 table 3.

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)

A long term systemic effect DNEL has been also derived from the OECD 443 study performed in 2019. Based on this study, the animals were exposed more than 90 days and the NOAEL for systemic toxicity was 40 mg/kg/day. Based on a route to route extrapolation and applying ECHA default assessment factors (10 for interspecies * 5 for intraspecies * 2 for sub-chronic to chronic) a DNEL of 2.8 mg/m3 has been calculated. This value is very similar to the one set based on the OECD 422 study. The value of 3 mg/m3 has been retained since OECD 422 studies are more appropriate to assess general toxicity and since the default assessment factor of 2 for time duration can be considered to be a little bit higher since the animals were exposed more than 90 days in the OECD 443 study.

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 on Wistar rats 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. An OECD 414 study was performed in 2013 on Sprague-Dawley rats (reliability 1). In this study, in which pregnant female rats were exposed daily to PMP from day 6 to day 20 p.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 (highest tested dose) in a context of a marked maternal toxicity. No developmental effects were observed at the two lower tested doses 100 and 200 mg/kg bw/day. Two other studies have been conducted in 2019, an OECD 414 study on a second species (Rabbits) and an OECD 443 study on rats. Based on the OECD 414 study conducted on rabbits (CitoxLab, 2019a - reliability 1) there were no effects on hysterectomy parameters (mean number of corpora lutea, implantation sites, pre-implantation loss, live fetuses and post-implantation loss) whatever the administered doses and no effects on mean fetal body weight, mean placental weight and sex ratio whatever the administered doses. Fetal examination revealed no test item treatment-related variations or malformations at external and soft tissue examination of the fetuses whatever the administered doses. Therefore based on this study and based on absence of adverse effect at the dose level tested, the substance PMP is considered to not induce effect on embryo-fetal development in rabbits. In the OECD 443 study (Citoxlab, 2019b) (reliability 1), sexually-mature male and female Sprague-Dawley rats were exposed to 0, 40, 100 and 250 mg/kg/day of the substance daily by gavage starting 10 weeks before mating and continuously through mating, gestation and weaning of their pups. At weaning, pups were selected and assigned to different cohorts: Cohort 1A, 1B, 2A and 2B. When compared with controls or historical control data, there were no test item dose-related effects on mating (mating index), mating behavior (time talen to mate) and fertility (fertility index). There were no test item treatment-related significant effects on gestation index, mean percentage of pre- and post-implantation loss, live birth index and sex ratio on Day 1 p.p. At 250 and 100 mg/kg/day, when compared with controls, there was an apparent dose-related decrease in mean litter size at birth. However, the differences were not statistically significant and a test item treatment-related effect was considered unlikely in the absence of dose-related increased in mumber of dead, missing and/or cannibalized pups on Days 1 - 4 p.p. After culling on Day 4 p.p., there were no effects on mean litter sizes or lactation indexes. In the treated groups and when compared with controls, there were no pups with malformation(s) and no test item treatment-related effects on pup body weight during lactation. There were no effects on sexual development in cohort 1A, 1B and 2A and no test item treatment-related adverse findings regarding developmental neurotoxicity in cohorts 2A and 2B.

 

Taken into account all the reliable reprotoxic studies, only the OECD 414 study on rats (Citoxlab, 2013) showed malformations in fetus rats only at the higher tested dose and only in a context of marked maternal toxicity. No malformations were observed at the other tested doses in this study and no malformations were observed in rabbits in the OECD 414 study (Citoxlab, 2019a) and in rats based on the two other reliable studies (OECD 422 study performed in 2009 and OECD 443 study performed in 2019). It is thus, reasonable to assume in a weight of evidence approach that the developmental toxicity only seen at the highest tested dose and only in one study on 4 available is produced solely as a secondary consequence of maternal toxicity and discount the malformations observed. Therefore, the classification of the substance PMP for developmental effects is not warranted and no DNEL is needed.

 

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 but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

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

Hazard assessment conclusion:

low hazard (no threshold derived)

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.