Cyclopropanecarboxylic acid, 2-[1-(3,3-dimethylcyclohexyl)ethoxy]-2-methylpropyl ester

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.35 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):

75

Dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

26.45 mg/m³

Explanation for the modification of the dose descriptor starting point:

Regarding absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38 m3/kg bw/8 h). For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8-h exposure period) and under conditions of light activity (wRV: 10 m3 for an 8-h exposure period). Thus, the corrected dose descriptor for inhalation is [30 mg/kg bw/day] X  [1/0.38 m3/kg bw/day] X [2/1] X [6.7 m3/10m3]. Thus, the corrected dose descriptor for inhalation is 26.45 mg/m3 for workers

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance

AF for interspecies differences (allometric scaling):

1

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in the metabolic rate/bw has already been taken into account in the corrected dose descriptor.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance

AF for intraspecies differences:

5

Justification:

Default factor for worker. Table R.8-6 ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

The substance is well tolerated in an acute inhalation toxicity study in Crl:WI(Han) (outbred, SPF-Quality) rats with reported LC50 of > 5.1 mg/L air. No abnormalities or overt toxicity signs reported (OECD 402; Anon 2004). Therefore, no DNEL is required.

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:

0.1 mg/kg bw/day

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:

30 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For potential dermal exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. Since a maximal absorption already occurred by oral route, no additional factor was introduced.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance

AF for intraspecies differences:

5

Justification:

Default factor for worker. Table R.8-6 ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

The substance is well tolerated in an acute dermal toxicity study in HanRcc:WIST (SPF) rats with reported LD50 of > 2000 mg/kg bw/day. No abnormalities or overt toxicity signs reported (OECD 402; Anon 2004). Therefore, no DNEL is required.

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

For risk assessment, NOAEL from the most sensitive endpoint was used, i.e. 30 mg/gg bw/day from  repeated oral toxicity and reproduction/developmental toxicity screening test, the following no-observed-adverse-effect level (NOAEL) of Reaction mass of 2-[(1R)-1-[(1S)-3,3-dimethylcyclohexyl]ethoxy]-2-methylpropyl cyclopropanecarboxylate and 2-[(1S)-1-[(1S)-3,3-dimethylcyclohexyl]ethoxy]-2-methylpropyl cyclopropanecarboxylate (based on histopathological changes in the heart, skeletal muscle, kidneys, Harderian gland, liver, and thyroid observed in mid and high groups).

In a sub-acute study following the OECD 407  guideline, Reaction mass of 2-[(1R)-1-[(1S)-3,3-dimethylcyclohexyl]ethoxy]-2-methylpropyl cyclopropanecarboxylate and 2-[(1S)-1-[(1S)-3,3-dimethylcyclohexyl]ethoxy]-2-methylpropyl cyclopropanecarboxylate was given orally by gavage for a minimum of 28 days to Wistar Han rats at doses of 0, 30,150, 750 mg/kg/day, followed by two weeks recovery period.  An OECD 421 was also conduced to  assess general systemic toxic potential in rats, including a screening test for reproductive / development effects, with administration of the test item by oral gavage administration for a least four weeks in Wistar Han : RccHan : WIST rats. Four groups, each comprising ten male and ten female rats, received test item at doses of 0 (control), 10, 30 or 150 mg/kg/day.  No mortality was observed in both studies.

In the he OECD 407 study, the following observation were reported;

at At 750 mg/kg bw/day: episodes of sedation were noted intermittently in males (days 17-18 and 24-26) and persistently in females (days 16-28). Emaciation was recorded in one female treated with 750 mg/kg bw/day and in two females during the first week of recovery. Reduced mean hindlimb grip strength was noted in males whereas females had reduced mean fore- and hind-limb grip strength.Reductions of locomotor activity were noted in both sexes. Females treated indicated mean daily food consumption values were slightly lower than those of the controls. Aspartate aminotransferase activity was increased in males/females and lactate dehydrogenase activity was elevated in females when compared with the controls. Elevated ketone noted in males/females after 4 weeks of treatment. After 2 weeks of recovery, this finding was no longer observed, indicating recovery. At 750 and 150 mg /kg bw/day: The test item induced histopathological changes in the heart, skeletal muscle, kidneys, Harderian gland, liver, and thyroid. In the heart : minimal to severe sarcoplasmic vacuolation, minimal to moderate single cell necrosis, increased incidence and mean grade of mononuclear foci, and minimal myocardial (interstitial) fibrosis were recorded in main study males/females treated with 750 mg/kg/day or 150 mg/kg/day, reflecting a cardiotoxic potential of the test item. Increased incidence and mean grade of hyaline droplets and of tubular basophilia was recorded in the kidney of treated males. In the Harderian gland; minimal acinar degeneration, minimal to slight acinar hyperplasia, and increased porphyrin deposition was recorded in females. In the liver, increased incidence and mean grade of liver fatty change and increased incidence and mean grade of hepatocellular hypertrophy  were recorded in main study females treated with tendency of regression during recovery. Minimal myocardial fibrosis was recorded during recovery period in two females previously treated with 750 mg/kg/day.

At 150 mg/kg bw/day; males had elevated liver-to-body weight ratios and elevated kidney-to-body weight ratios and females had elevated absolute and relative liver weights and reduced absolute spleen weights. item-related macroscopic findings were recorded in the Harderian Glands (black foci: one female after treatment, and five recovery females, whereas at 150 mg/kg bw/day: item-related macroscopic findings were recorded at the liver (clay-coloured: 4 females).

The oral (gavage) administration of the test item to males/females at dose levels of 30, 150 or 750 mg/kg bw/day resulted indicated that, the No-Observed-Effect-Leve (NOEL) was 30 mg/kg bw/day and the No-Observed-Adverse-Effect-Level (NOAEL) was regarded to be 30 mg/kg bw/day for males/females.

In the OECD 421 study: At 150 mg/kg bw/day, clinical findings included pushing the head through the bedding, salivation before and/or after dosing, reduced mean food consumption during the lactation. Reduced size of thymus and accentuated lobular pattern in liver were observed as gross lesions in some females. At 150 mg/kg bw/day and 30 mg/kg bw/day, thymic and/or liver change were noted i.e.an increased incidence of thymic involution in the females, which was considered to be related to stress and not directly to the test item. Other findings included multifocal progressive cardiomyopathy observed in the heart of all females, entrilobular hypertrophy was noted in the liver in 5/10 males and 5/10 females and hematopoiesis increased in the females. Both these findings in the liver were considered to be adaptive and not adverse in nature. In some females, a periportal fatty change was observed. No test item-related changes were observed in the reproductive organs or in the comparison of spermatogenesis and interstitial testicular structures. Significant postnatal losses were seen after 4 days, notably in three litters (#73, 76, and 80), leading to an overall statistically significant increase in losses for this group. Additionally, body weight gain over days 1 - 4 and mean body weight on day 4 post partum were reduced compared to the control group. This was considered to  be related to general toxicity effects in the P0 females at this dose level (poor maternal care). sex ratios indicated no effects in relation to treatment.

At 30 mg/kg bw/day: two dams occasionally had salivation after dosing. No clinical signs or observations were observed in the males during the study at this dose level.

Under the conditions of this study, the no-observed-effect level (NOEL and the no-observed-adverse-effect level (NOAEL) for systemic toxicity and for reproductive / developmental toxicity for males and females is considered to be 30 mg/kg body weight per day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.1 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):

150

Dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

13.04 mg/m³

Explanation for the modification of the dose descriptor starting point:

Regarding absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012). To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 1.15 m3/kg bw/24 h). Thus, the corrected dose descriptor for inhalation is [30 mg/kg bw/day] x [1/1.15 m3/kg bw/ day] x [2/1]. Thus, the corrected dose descriptor for inhalation is 13.04 mg/m3 for the general population.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

1

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in metabolic rate/bw has already been taken into account for the corrected dose descriptor.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Route of original study:

By inhalation

DNEL related information

Explanation for the modification of the dose descriptor starting point:

The substance is well tolerated in an acute inhalation toxicity study in Crl:WI(Han) (outbred, SPF-Quality) rats with reported LC50 of > 5.1 mg/L air. No abnormalities or overt toxicity signs reported (OECD 402; Anon 2004). Therefore, no DNEL is required.

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:

0.05 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For potential dermal exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. Since a maximal absorption already occurred by oral route, no additional factor was introduced.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

The substance is well tolerated in an acute dermal toxicity study in HanRcc:WIST (SPF) rats with reported LD50 of > 2000 mg/kg bw/day. No abnormalities or overt toxicity signs reported (OECD 402; Anon 2004). Therefore, no DNEL is required.

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.05 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The calculation of the DNELs is performed in accordance with the principles given in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012). NOAEL of 30 mg/kg bw/day for systemic effects established in a repeated (sub-chronic) dose toxicity study (OECD 422) in rats. No modification of the dose descriptor starting point is required. The endpoint used to derive the DNEL uses the oral route for exposure.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default factor for good/standard quality of the database taken into account completeness, consistency and the standard information requirements for the tonnage band.

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

The substance is well tolerated in an acute oral in toxicity study in HanBrl: WIST (SPF) rats with reported LD50 of > 2000 mg/kg bw/day. No abnormalities or overt toxicity signs reported (OECD 423; Anon 2004). Therefore, no DNEL is required.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

For risk assessment, NOAEL from the most sensitive endpoint was used, i.e. 30 mg/kg bw/day from  repeated oral toxicity and reproduction/developmental toxicity screening test, the following no-observed-adverse-effect level (NOAEL) of 2-[1-(3,3-dimethylcyclohexyl)ethoxy]-2-methylpropyl cyclopropanecarboxylate (based on histopathological changes in the heart, skeletal muscle, kidneys, Harderian gland, liver, and thyroid observed in mid and high groups).

 

In a sub-acute study following the OECD 407  guideline, 2-[1-(3,3-dimethylcyclohexyl)ethoxy]-2-methylpropyl cyclopropanecarboxylate was given orally by gavage for a minimum of 28 days to Wistar Han rats at doses of 0, 30,150, 750 mg/kg/day, followed by two weeks recovery period.  An OECD 421 was also conduced to  assess general systemic toxic potential in rats, including a screening test for reproductive / development effects, with administration of the test item by oral gavage administration for a least four weeks in Wistar Han : RccHan : WIST rats. Four groups, each comprising ten male and ten female rats, received test item at doses of 0 (control), 10, 30 or 150 mg/kg/day.  No mortality was observed in both studies.

 

In the OECD 407 study, the following observation were reported: at At 750 mg/kg bw/day: episodes of sedation were noted intermittently in males (days 17-18 and 24-26) and persistently in females (days 16-28). Emaciation was recorded in one female treated with 750 mg/kg bw/day and in two females during the first week of recovery. Reduced mean hindlimb grip strength was noted in males whereas females had reduced mean fore- and hind-limb grip strength.Reductions of locomotor activity were noted in both sexes. Females treated indicated mean daily food consumption values were slightly lower than those of the controls. Aspartate aminotransferase activity was increased in males/females and lactate dehydrogenase activity was elevated in females when compared with the controls. Elevated ketone noted in males/females after 4 weeks of treatment. After 2 weeks of recovery, this finding was no longer observed, indicating recovery. At 750 and 150 mg /kg bw/day: The test item induced histopathological changes in the heart, skeletal muscle, kidneys, Harderian gland, liver, and thyroid. In the heart : minimal to severe sarcoplasmic vacuolation, minimal to moderate single cell necrosis, increased incidence and mean grade of mononuclear foci, and minimal myocardial (interstitial) fibrosis were recorded in main study males/females treated with 750 mg/kg/day or 150 mg/kg/day, reflecting a cardiotoxic potential of the test item. Increased incidence and mean grade of hyaline droplets and of tubular basophilia was recorded in the kidney of treated males. In the Harderian gland; minimal acinar degeneration, minimal to slight acinar hyperplasia, and increased porphyrin deposition was recorded in females. In the liver, increased incidence and mean grade of liver fatty change and increased incidence and mean grade of hepatocellular hypertrophy were recorded in main study females treated with tendency of regression during recovery. Minimal myocardial fibrosis was recorded during recovery period in two females previously treated with 750 mg/kg/day.

At 150 mg/kg bw/day; males had elevated liver-to-body weight ratios and elevated kidney-to-body weight ratios and females had elevated absolute and relative liver weights and reduced absolute spleen weights. item-related macroscopic findings were recorded in the Harderian Glands (black foci: one female after treatment, and five recovery females, whereas at 150 mg/kg bw/day: item-related macroscopic findings were recorded at the liver (clay-coloured: 4 females).

The oral (gavage) administration of the test item to males/females at dose levels of 30, 150 or 750 mg/kg bw/day resulted indicated that, the No-Observed-Effect-Leve (NOEL) was 30 mg/kg bw/day and the No-Observed-Adverse-Effect-Level (NOAEL) was regarded to be 30 mg/kg bw/day for males/females.

 

In the OECD 421 study: At 150 mg/kg bw/day, clinical findings included pushing the head through the bedding, salivation before and/or after dosing, reduced mean food consumption during the lactation. Reduced size of thymus and accentuated lobular pattern in liver were observed as gross lesions in some females. At 150 mg/kg bw/day and 30 mg/kg bw/day, thymic and/or liver change were noted i.e.an increased incidence of thymic involution in the females, which was considered to be related to stress and not directly to the test item. Other findings included multifocal progressive cardiomyopathy observed in the heart of all females, entrilobular hypertrophy was noted in the liver in 5/10 males and 5/10 females and hematopoiesis increased in the females. Both these findings in the liver were considered to be adaptive and not adverse in nature. In some females, a periportal fatty change was observed. No test item-related changes were observed in the reproductive organs or in the comparison of spermatogenesis and interstitial testicular structures. Significant postnatal losses were seen after 4 days, notably in three litters (#73, 76, and 80), leading to an overall statistically significant increase in losses for this group. Additionally, body weight gain over days 1 - 4 and mean body weight on day 4 post partum were reduced compared to the control group. This was considered to  be related to general toxicity effects in the P0 females at this dose level (poor maternal care). sex ratios indicated no effects in relation to treatment.

At 30 mg/kg bw/day: two dams occasionally had salivation after dosing. No clinical signs or observations were observed in the males during the study at this dose level.

Under the conditions of this study, the no-observed-effect level (NOEL and the no-observed-adverse-effect level (NOAEL) for systemic toxicity and for reproductive / developmental toxicity for males and females is considered to be 30 mg/kg body weight per day.