Registration Dossier

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

genetic toxicity

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

genetic toxicity

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

no hazard identified

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

no hazard identified

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

genetic toxicity

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

genetic toxicity

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

no hazard identified

Macrolex Rot E2G

(CAS No. 6829-22-7)

DNELs (worker/general population)

I. Introduction:

Classification

Harmonized classification – not available

Self-classification: Skin Sens.1B; H317

Known occupational exposure limit(s):

SCOEL: no data

TRGS 900: no data

MAK: no data

[Inconclusive data on genotoxicity. The compound was allocated to the medium hazard band until the mutagenic endpoint is finally investigated).]

VI. DNEL systemic (worker/general population)

Basis for delineation of the DNELs systemic:

Repeated dose toxicity:

In a study according OECD TG 407 the test item the test Macrolex Rot E2G was applied daily per gavage for 4 consecutive weeks in doses of 0 (control), 100, 300 or 1000 mg/kg bw to male and female rats.

Morbidity/mortality checks were performed at least twice daily. Clinical observations were performed daily. A full clinical examination was performed weekly. Individual body weights were recorded weekly. Food consumption was measured weekly for each cage of animals. Modified Irwin test (Neurological Function Assessment) was performed pretest and in week 4. Clinical laboratory determinations were performed in week 4.

All animals were killed at the end of the treatment period and necropsied. Selected organs were weighed. Organ/tissue samples were fixed and preserved at necropsy for all animals. Selected organs/tissues from group 1 (0 mg/kg bw/day) and 4 (1000 mg/kg bw/day) animals killed at the end of the treatment period were examined histopathologically.

No test item-related in vivo effects and no test item-related histopathological changes were observed.

Based on the results of this study, the dose level of 1000 mg/kg bw/day (highest applied dose) was considered as a No Observed Adverse Effect Level (NOAEL).

Toxicity to reproduction:

The toxicity of the test item Macrolex Rot E2G (CAS-No. 6829-22-7) on reproduction and/or development of the male and female rat was investigated in a reproduction/ developmental toxicity screening test according to OECD TG 421.

Three groups of 10 male and 10 female Wistar rats were given the test item, Macrolex Rot E2G, by daily oral (gavage) administration at dose levels of 100, 300 and 1000 mg/kg/day from 14 days before mating then for up to 4 weeks for males and throughout mating, gestation and through day 3 of lactation for females. A control group of 10 male and 10 female rats received a similar volume (10 mL/kg) of the vehicle [1 % (w/v) Carboxymethylcellulose]. Clinical condition, body weight and food consumption of the animals were monitored throughout the study.

After two weeks of treatment, one male and one female of the same group were paired for a maximum of 14 days. The females were retained throughout gestation, allowed to litter and rear their young through to postnatal day (PND) 4 and then necropsied. Vaginal smears were taken daily for each female from the first day of pairing to verify positive copulation. Litter parameters, including the number of pups born, pup survival, sex and pup weights were recorded up to postnatal day 4.

The dams with their pups were necropsied on day 4 of lactation, where applicable. All animals, including PND 4 pups, were submitted to a macroscopic examination. The numbers of uterine implantations were determined and the ovaries were weighed for each female. The males were necropsied after completion of the mating period and the testes and epididymides were weighed.

Selected tissue samples were fixed and preserved from all animals. Selected organs/tissues from group 1 and 4 animals were examined histopathologically.

There were no unscheduled deaths or systemic clinical signs associated with the test item.

There was no effect of the test item on mean body weight change or food consumption for either sex throughout the study.

There was no adverse effect of the test item on mating performance or fertility. The mean duration of gestation was normal (approximately 22 days) in all groups. There was no influence of treatment with the test item on pre- or postnatal pup survival of either sex.

Mean pup weight at birth and postnatal day 4 was comparable with that in the experimental control.

No organ weight, macroscopic or microscopic changes were noted to suggest a toxicological effect of Macrolex Rot E2G on the ovaries, testes and epididymides of treated animals.

Taken together, there were no adverse effects of Macrolex Rot E2G on the reproduction and/or development of the male and female rat up to the limit dose of 1000 mg/kg/day inclusive.

Acute toxicity:

A valid acute oral study equivalent to OECD 401 (limit test) and an inhalation toxicity study according OECD 403 are available

In the acute oral toxicity study groups of 5 male and 5 female rats were administered by gavage a single oral dose of 5000 mg/kg bw of the test material Macrolex Rot E2G (CAS no. 6829-22 -7). Animals were observed for mortality, clinical signs and body weight for 14 days. A gross pathological examination was done on all animals sacrificed at the end of study. No clinical signs of systemic poisoning were observed and no deaths occurred. The male and female rats sacrificed at the end of the study did not show any noticeable gross pathological findings. The LC50 is > 5000 mg/kg bw.

In the acute inhalation toxicity study one group of 3 male and 3 female rats was nose-only exposed to the solid aerosol of the test material at the actual concentration of 1817 mg/m³ (maximum attainable concentration). Rats exposed to air only under otherwise identical circumstances served as control animals.

Mortality did not occur at the technically maximum attainable concentration of 1817 mg/m³. Rats exposed to the test material showed clinical signs (labored breathing, irregular breathing, piloerection). Significant changes in incremental body weight gain were found in females on day 1. Neither reduction in body temperature nor changes during the reflex measurement were observed. Necropsy revealed light colored areas and/or few gray areas in the lungs of male and female rats on day 14.

In summary, there is evidence of low acute inhalation toxicity in rats after exposure (4h) of aerosolized Macrolex Rot E2G (CAS no. 6829-22-7). The LC50 is > 1817 mg/m³.

Overall, there were no adverse effects observed up to the limit dose of 1000 mg/kg bw/day (highest applied dose) in the repeated dose toxicity study and the reproduction and/or development toxicity study.

In the acute oral toxicity study a LD50 > 5000 mg/kg bw and in the acute inhalation toxicity study a LD50 > 1817 mg/m³ (technically maximum attainable concentration) was found.

Potential genotoxicity:

Due to the positive results of the Ames tests, the conduction of an in-vivo Comet assay is proposed to generate an overall result. At this point in time the data are inconclusive. Although the compound is not bioavailable (see chapter toxicokinetic) and consequently it is unlikely that the compound is systemically available the compound will be allocated to the “medium” hazard band until the in vivo comet data become available.

Conclusion on systemic DNEL:

Based on the results of the repeated dose toxicity studies and the acute toxicity studies, for systemic effects no hazard is identified. Genotoxicity data are inconclusive and the compound will be allocated to the “medium” hazard band until the in vivo Comet data become available.

VII. DNEL local (worker/general population)

Basis for delineation of the DNELs local (long and short term toxicity):

Irritation/corrosion

In the key study for skin irritation/corrosion 3 female Himalayan rabbits received dermal application on the shaved back for 4 hours held in place by semi-occlusive dressing, 60 min, 24, 28, and 72 hours after removal of the dressing the treated area was examined and the effects scored according to Draize. None of the animals showed erythema or edema. No erythema and no edema were found in the additional study conducted by Suberg (1984).

In the key study for eye irritation 3 male rabbits received instillations of 100 mg test substance into the conjunctival sac of the right eye; the respective left eye remained untreated and served as control. The eyes of the animals were observed 1, 24, 48 and 72 hours post application. Additionally, 24 hours post application the eyes were treated with fluorescein and examined. The scoring was done according to Draize. In none of the animals the eyes were affected by treatment. Therefore the test substance was evaluated to be non-irritating to the eyes of rabbits.

In the additional eye irritation study by Suberg (1984) the cornea, iris, conjunctivae and chemosis score according Draize was 0 after 24, 48 and 72 hours.

Due to results of the skin irritation/corrosion and eye irritation study a classification is not justified.

Sensitization

A modified Local Lymph Node Assay (IMDS) was performed on 24 female NMRI mice of the strain Hsd Win:NMRI (6 animals/test item group and 6 control animals) to determine if there is any specific (sensitizing) or non-specific (irritant) stimulating potential of the test item Macrolex Rot E2G.

The results show that the test item (Macrolex Rot E2G Gran., CAS no 6829-22-7) has a weak sensitizing potential in mice after dermal application. There was an increase compared to vehicle treated animals regarding the cell counts and the weight of the draining lymph nodes in all dose groups. Thus, a hint for a substance specific activation of the cells of the immune system via dermal application was found by the method used, i.e. the test item has a weak skin sensitizing potential. Therefore a classification as Skin Sens 1B; H317 is justified.

Conclusion on local DNEL:

Due to the classification as Skin Sens 1B; H317, Macrolex Rot E2G should be allocated to the moderate hazard band for dermal effects.