Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.62 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):
15
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
264.4 mg/m³
AF for differences in duration of exposure:
1
Justification:
As developmental toxicity was the endpoint, there is not a valid conversion from acute to chronic, as there is no "acute" or "chronic" in a developmental toxicity test.
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
5
AF for intraspecies differences:
3
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
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 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):
60
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
3
AF for intraspecies differences:
5
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

 

 

Discussion

 

Acute toxicity

 

1-Isopropyl-2,2-dimethyltrimethylene diisobutyrate is of low acute oral toxicity in experimental animals with LD50 values ranging from >2000 mg/kg to >6400 mg/kg. In rats, no mortalities were reported after 6-hour inhalation exposures to 453 ppm 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate. The dermal toxicity of 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate in rabbits is low with LD50 values ranging from >2000 mg/kg to >20,000 ml/kg. The Technical Guidance Document (TGD, Chapter R.8) indicates that a DNEL for acute toxicity should be derived if an acute hazard has been identified and there is a potential for high peak exposures. 1-Isopropyl-2,2-dimethyltrimethylene diisobutyrate is not hazardous following acute oral, dermal exposures, or inhalation exposures.

 

Irritation/sensitization

 

In experimental animals, 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate is not a skin or eye irritant or a skin sensitizer.

 

Repeat dose toxicity

 

The repeated-dose toxicity of 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate is generally low with the liver and kidney identified as target organs. Male and female rats were exposed to up to 750 mg/kg bw/day in the diet for 13 weeks. There were no significant treatment-related effects on mortality, clinical signs, body weight and body weight gain, hematology, ophthalmic examination, functional observational battery, or urinalysis parameters. Increases in liver weights and elevated cholesterol in both sexes at 750 mg/kg bw/day were suggestive of possible liver involvement but no effects on the liver were observed microscopically. In male rats, increased kidney weights corresponded to exposure-related increases in the prevalence of hyaline droplets and increased incidence of minimal chronic progressive nephropathy, a common spontaneous lesion in male rats, often exacerbated by chemical exposure. In a combined OECD 422 repeated-dose toxicity and reproductive toxicity screening assay in rats, 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate showed liver and kidney effects in male rats (dosed for 44 days) at dose levels of 150 and 750 mg/kg bwt/day. Hyaline droplet formation was present in the kidneys of male rats at all treatment levels as well as increased kidney weights at the highest dose. Minimal effects observed in the liver in this latter study did not correspond to gross or microscopic lesions. Kidney effects in male rats related to hyaline droplet formation and nephrotoxicity is recognized as a male-rat specific toxicity and is not relevant to human exposure assessment. Preliminary DNEL values for 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate were derived based on a NOAEL value of 750 mg/kg bwt/day, assigned in the 13-week dietary study in rats.

 

Genotoxicity/carcinogenicity

 

1-Isopropyl-2,2-dimethyltrimethylene diisobutyrate is negative in standardin vitrotests for genotoxicity. It has not been tested forin vivogenotoxicity or for carcinogenicity.

 

Reproductive/developmental toxicity

 

1) In an OECD 421 reproductive screening assay in rats, 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate administered in the diet at dose levels up to 750 mg/kg bwt/day produced statistically significant decreases in the total number of implants, reduced litter weights on postnatal days 0 and 4, and increased mortality in the offspring on postnatal day 4, all in the presence of treatment-related systemic effects in the parental animals at the highest dose. In an OECD 422 combined reproductive screening and toxicity assay in rats at gavage dose levels up to 750 mg/kg bwt/day, there was no clear evidence of an adverse effect on pre- or post-natal development in the absence of toxicity in the parental generation. In addition, there were no reported adverse effects on the reproductive organs of male and female rats administered 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate in the diet for 13 weeks. Based on the results of these studies, 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate is not selectively toxic to the developing fetus and is not a reproductive hazard.

 

2) A study was designed to assess the influence of TXIB on embryo-fetal survival and development when administered during the organogenesis and fetal

growth phases of pregnancy (Days 1-28 after mating) in the New Zealand White rabbit. Three groups of 22 females received TXIB at doses of 100, 300 or 1000 mg/kg/day by oral gavage administration, from Day 1 to 28 after mating. A similarly constituted Control group received the vehicle, 1% methyl cellulose, at the same volume dose as the treated groups. Animals were killed on Day 29 after mating for reproductive assessment and fetal examination.

 

Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 29 after mating and the gravid uterus weight recorded. All fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination of the head or skeletal examination.

 

Results

On Day 8 of gestation, one female (4F, 74) treated at 1000 mg/kg/day was despatched following a prolonged period of in-appetence, significant body weight loss and reduced faecal and urine output; at macroscopic examination, there were no abnormalities observed. as this premature death was of an isolated incidence, there is no clear correlation to treatment with TXIB. All other premature deaths were incidental and not associated with treatment. There were no signs observed that were attributable to treatment and macroscopic examination revealed no treatment related findings.

 

Group mean body weight gain during the treatment period (Day 1 to 28 of gestation) was slightly low in all treated groups when compared with Controls and food consumption was slightly reduced until Day 24 of gestation in females treated at 1000 mg/kg/day.

 

On Day 29 of gestation, group mean gravid uterine weight was low in females treated with TXIB when compared with Controls however the magnitude of difference was slight and showed no relationship to dose level. Overall body weight change, when adjusted for the weight of the gravid uterus was comparable to controls at all dose levels (100, 300 or 1000 mg/kg/day).

 

At macroscopic examination, six females were confirmed not pregnant however the distribution showed no correlation to treatment. Mean numbers of corpora lutea and implantations were considered to be unaffected by treatment with TXIB.

 

Mean numbers of early resorptions and thus post-implantation losses, were high in females treated at 1000 mg/kg/day when compared with Controls and when compared with historical control data ranges; as a result the mean live litter size was slightly low compared with Controls. A relationship to treatment cannot be ruled out.

 

Group mean placental, fetal and litter weights were unaffected by treatment. At 100, 300 or 1000 mg/kg/day, an increase in the incidence of short supernumerary cervical ribs was observed when compared with Controls however the distribution showed no relationship to treatment. At 1000 mg/kg/day or 300 mg/kg/day there was also a slight increase in incidence of delayed ossification of 1st to 4th and 6th sternebrae when compared with control litters however the incidence and distribution were found to be within historical background data ranges and as such a relation to treatment is not inferred.

 

Conclusion

Based on the results of this study it is concluded that dose levels up to and including 1000 mg/kg/day did not adversely affect maternal performance or fetal development and growth, however a reduction in embryo-fetal survival at 1000 mg/kg/day cannot be discounted as an effect of treatment. Therefore, the No observed adverse effect level (NOAEL), based on embryo-fetal survival, is considered to be 300 mg/kg/day.

 

 

CORRECTED DOSE DESCRIPTORS

 

 

In the case of worker exposures, the oral route of exposure was not considered. For potential dermal and inhalation exposures, route-to-route extrapolations from the oral NOAEL value were performed (see Guidance Document, Chaper R.8, Appendix R.8-2). A first-pass effect was discounted for the purposes of these calculations.

 

Oral:

 

For the extrapolation from rats to humans, equivalent bioavailability was assumed (see Guidance Document, Section R.8.4.2, page 24). Thus, no modification of the dose descriptor was used. In the case of general population oral exposure,the dose descriptor is 300 mg/kg bwt/day based on the rabbit pre-natal developmental toxicity study NOAEL 

 

Dermal:

 

Complete absorption of the test material by both the oral and dermal routes was assumed. Thus, dermal exposure to the same amount of test material would produce an equivalent internal dose. Differences in metabolism, distribution and elimination were not considered and thus no further correction was applied (see Guidance Document, Section R.8.4.2, page 25). Thus, the dose descriptor for both the worker and general population is 300 mg/kg bwt/day based on the rabbit pre-natal developmental toxicity study NOAEL

Inhalation:

 

 

In the case of worker exposure,50% absorption of the test material by the oral versus the inhalation route was assumed (see Guidance Document, Chapter R.8, Appendix R.8.4.2, page 25). The rat repeated-dose oral NOAEL value was divided by 0.38 m3/kg bwt to yield an equivalent air concentration for an 8-hour exposure (see Guidance Document, Chapter R.8, Appendix R.8-2, page 65). This value was further corrected to account for increased metabolic rate (and inhalation volume) in the case of light work versus basal metabolism (multiplicative factor of 6.7 m3/10 m3, or 0.67).

 

(NOELoral¸0.38 m3/kg bwt) X 0.50 = 187.5 mg/kg bwt¸ 0.38 m3/kg bwt = 394.7 mg/m3.  394.7 mg/m3x 0.67 = 264.4 mg/m3= NOELinh,corr

 

In the case of exposure to the general population,50% absorption of the test material by the oral versus the inhalation route was also assumed (see Guidance Document, Chapter R.8, Appendix R.8.4.2, page 25). The rat oral NOAEL value was divided by 1.15 m3/kg bwt to yield an equivalent air concentration for continuous exposure (see Guidance Document, Chapter R.8, Appendix R.8-2, page 64). No further correction factors were applied.

 

(NOELoral¸1.15 m3/kg bwt) X 0.50 = 130.43 mg/kg bwt/day¸

 

 

 

APPLICATION OF ASSESSMENT FACTORS

 

Oral:

 

               General Population Long Term Systemic DNEL Assessment Factors (Oral)

 

Given the assumption of equivalent bioavailability between oral exposures in rats and humans the following values were assigned.

 

               Allometric scaling (AS) factor                                 4 (for differences in metabolic rate)

               Intraspecies, sensitive individual                              5

 

No AF was assigned for study duration due to the finite aspect of a developmental study. 

 

Assessment factors= 20

 

 

Dermal:

 

               Long Term Systemic DNEL Assessment Factors (Dermal)

 

In the case of worker exposure, the following values were assigned.

 

               Allometric scaling (AS)                                           4 (for differences in metabolic rate)

               Intraspecies, sensitive worker                                   3

               Intraspecies                                                             5

 

No AF was assigned for study duration due to the finite aspect of a developmental study. 

 

Assessment factors= 60

 

 

In the case of exposure to the general population, the following values were assigned:

 

               Allometric scaling (AS)                                                  4 (for differences in metabolic rate)

               Intraspecies, sensitive worker                                         3

               Intraspecies                                                                  10

 

No AF was assigned for study duration due to the finite aspect of a developmental study. 

 

Assessment factors= 120

 

  

Inhalation:

 

In the final derivation of the repeated-dose inhalation DNEL values, allometric scaling was already performed in the previous step (corrected dose descriptor) and no further factors were applied. 

 

In the case of worker exposure, the following values were assigned.

 

               Intraspecies, sensitive worker                                   3

               Intraspecies                                                             5

 

No AF was assigned for study duration due to the finite aspect of a developmental study. 

 

Assessment factors= 15

 

In the case of exposure to the general population, the following values were assigned:

 

               Intraspecies, sensitive worker                                   3

               Intraspecies                                                             10

 

No AF was assigned for study duration due to the finite aspect of a developmental study. 

 

Assessment factors= 30

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.35 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):
30
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
130.43 mg/m³
AF for other interspecies differences:
3
AF for intraspecies differences:
5
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
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 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):
30
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
75 mg/kg bw/day
AF for other interspecies differences:
3
AF for intraspecies differences:
10
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:
DNEL (Derived No Effect Level)
Value:
5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
75 mg/kg bw/day
AF for other interspecies differences:
3
AF for intraspecies differences:
10
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Discussion

 

Acute toxicity

 

1-Isopropyl-2,2-dimethyltrimethylene diisobutyrate is of low acute oral toxicity in experimental animals with LD50 values ranging from >2000 mg/kg to >6400 mg/kg. In rats, no mortalities were reported after 6-hour inhalation exposures to 453 ppm 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate. The dermal toxicity of 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate in rabbits is low with LD50 values ranging from >2000 mg/kg to >20,000 ml/kg. The Technical Guidance Document (TGD, Chapter R.8) indicates that a DNEL for acute toxicity should be derived if an acute hazard has been identified and there is a potential for high peak exposures. 1-Isopropyl-2,2-dimethyltrimethylene diisobutyrate is not hazardous following acute oral, dermal exposures, or inhalation exposures.

 

Irritation/sensitization

 

In experimental animals, 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate is not a skin or eye irritant or a skin sensitizer.

 

Repeat dose toxicity

 

The repeated-dose toxicity of 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate is generally low with the liver and kidney identified as target organs. Male and female rats were exposed to up to 750 mg/kg bw/day in the diet for 13 weeks. There were no significant treatment-related effects on mortality, clinical signs, body weight and body weight gain, hematology, ophthalmic examination, functional observational battery, or urinalysis parameters. Increases in liver weights and elevated cholesterol in both sexes at 750 mg/kg bw/day were suggestive of possible liver involvement but no effects on the liver were observed microscopically. In male rats, increased kidney weights corresponded to exposure-related increases in the prevalence of hyaline droplets and increased incidence of minimal chronic progressive nephropathy, a common spontaneous lesion in male rats, often exacerbated by chemical exposure. In a combined OECD 422 repeated-dose toxicity and reproductive toxicity screening assay in rats, 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate showed liver and kidney effects in male rats (dosed for 44 days) at dose levels of 150 and 750 mg/kg bwt/day. Hyaline droplet formation was present in the kidneys of male rats at all treatment levels as well as increased kidney weights at the highest dose. Minimal effects observed in the liver in this latter study did not correspond to gross or microscopic lesions. Kidney effects in male rats related to hyaline droplet formation and nephrotoxicity is recognized as a male-rat specific toxicity and is not relevant to human exposure assessment. Preliminary DNEL values for 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate were derived based on a NOAEL value of 750 mg/kg bwt/day, assigned in the 13-week dietary study in rats.

 

Genotoxicity/carcinogenicity

 

1-Isopropyl-2,2-dimethyltrimethylene diisobutyrate is negative in standardin vitrotests for genotoxicity. It has not been tested forin vivogenotoxicity or for carcinogenicity.

 

Reproductive/developmental toxicity

 

1) In an OECD 421 reproductive screening assay in rats, 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate administered in the diet at dose levels up to 750 mg/kg bwt/day produced statistically significant decreases in the total number of implants, reduced litter weights on postnatal days 0 and 4, and increased mortality in the offspring on postnatal day 4, all in the presence of treatment-related systemic effects in the parental animals at the highest dose. In an OECD 422 combined reproductive screening and toxicity assay in rats at gavage dose levels up to 750 mg/kg bwt/day, there was no clear evidence of an adverse effect on pre- or post-natal development in the absence of toxicity in the parental generation. In addition, there were no reported adverse effects on the reproductive organs of male and female rats administered 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate in the diet for 13 weeks. Based on the results of these studies, 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate is not selectively toxic to the developing fetus and is not a reproductive hazard.

 

2) A study was designed to assess the influence of TXIB on embryo-fetal survival and development when administered during the organogenesis and fetal

growth phases of pregnancy (Days 1-28 after mating) in the New Zealand White rabbit. Three groups of 22 females received TXIB at doses of 100, 300 or 1000 mg/kg/day by oral gavage administration, from Day 1 to 28 after mating. A similarly constituted Control group received the vehicle, 1% methyl cellulose, at the same volume dose as the treated groups. Animals were killed on Day 29 after mating for reproductive assessment and fetal examination.

 

Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 29 after mating and the gravid uterus weight recorded. All fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination of the head or skeletal examination.

 

Results

On Day 8 of gestation, one female (4F, 74) treated at 1000 mg/kg/day was despatched following a prolonged period of in-appetence, significant body weight loss and reduced faecal and urine output; at macroscopic examination, there were no abnormalities observed. as this premature death was of an isolated incidence, there is no clear correlation to treatment with TXIB. All other premature deaths were incidental and not associated with treatment. There were no signs observed that were attributable to treatment and macroscopic examination revealed no treatment related findings.

 

Group mean body weight gain during the treatment period (Day 1 to 28 of gestation) was slightly low in all treated groups when compared with Controls and food consumption was slightly reduced until Day 24 of gestation in females treated at 1000 mg/kg/day.

 

On Day 29 of gestation, group mean gravid uterine weight was low in females treated with TXIB when compared with Controls however the magnitude of difference was slight and showed no relationship to dose level. Overall body weight change, when adjusted for the weight of the gravid uterus was comparable to controls at all dose levels (100, 300 or 1000 mg/kg/day).

 

At macroscopic examination, six females were confirmed not pregnant however the distribution showed no correlation to treatment. Mean numbers of corpora lutea and implantations were considered to be unaffected by treatment with TXIB.

 

Mean numbers of early resorptions and thus post-implantation losses, were high in females treated at 1000 mg/kg/day when compared with Controls and when compared with historical control data ranges; as a result the mean live litter size was slightly low compared with Controls. A relationship to treatment cannot be ruled out.

 

Group mean placental, fetal and litter weights were unaffected by treatment. At 100, 300 or 1000 mg/kg/day, an increase in the incidence of short supernumerary cervical ribs was observed when compared with Controls however the distribution showed no relationship to treatment. At 1000 mg/kg/day or 300 mg/kg/day there was also a slight increase in incidence of delayed ossification of 1st to 4th and 6th sternebrae when compared with control litters however the incidence and distribution were found to be within historical background data ranges and as such a relation to treatment is not inferred.

 

Conclusion

Based on the results of this study it is concluded that dose levels up to and including 1000 mg/kg/day did not adversely affect maternal performance or fetal development and growth, however a reduction in embryo-fetal survival at 1000 mg/kg/day cannot be discounted as an effect of treatment. Therefore, the No observed adverse effect level (NOAEL), based on embryo-fetal survival, is considered to be 300 mg/kg/day.

 

 

CORRECTED DOSE DESCRIPTORS

 

 

In the case of worker exposures, the oral route of exposure was not considered. For potential dermal and inhalation exposures, route-to-route extrapolations from the oral NOAEL value were performed (see Guidance Document, Chaper R.8, Appendix R.8-2). A first-pass effect was discounted for the purposes of these calculations.

 

Oral:

 

For the extrapolation from rats to humans, equivalent bioavailability was assumed (see Guidance Document, Section R.8.4.2, page 24). Thus, no modification of the dose descriptor was used. In the case of general population oral exposure,the dose descriptor is 300 mg/kg bwt/day based on the rabbit pre-natal developmental toxicity study NOAEL 

 

Dermal:

 

Complete absorption of the test material by both the oral and dermal routes was assumed. Thus, dermal exposure to the same amount of test material would produce an equivalent internal dose. Differences in metabolism, distribution and elimination were not considered and thus no further correction was applied (see Guidance Document, Section R.8.4.2, page 25). Thus, the dose descriptor for both the worker and general population is 300 mg/kg bwt/day based on the rabbit pre-natal developmental toxicity study NOAEL

Inhalation:

 

 

In the case of worker exposure,50% absorption of the test material by the oral versus the inhalation route was assumed (see Guidance Document, Chapter R.8, Appendix R.8.4.2, page 25). The rat repeated-dose oral NOAEL value was divided by 0.38 m3/kg bwt to yield an equivalent air concentration for an 8-hour exposure (see Guidance Document, Chapter R.8, Appendix R.8-2, page 65). This value was further corrected to account for increased metabolic rate (and inhalation volume) in the case of light work versus basal metabolism (multiplicative factor of 6.7 m3/10 m3, or 0.67).

 

(NOELoral¸0.38 m3/kg bwt) X 0.50 = 187.5 mg/kg bwt¸ 0.38 m3/kg bwt = 394.7 mg/m3.  394.7 mg/m3x 0.67 = 264.4 mg/m3= NOELinh,corr

 

In the case of exposure to the general population,50% absorption of the test material by the oral versus the inhalation route was also assumed (see Guidance Document, Chapter R.8, Appendix R.8.4.2, page 25). The rat oral NOAEL value was divided by 1.15 m3/kg bwt to yield an equivalent air concentration for continuous exposure (see Guidance Document, Chapter R.8, Appendix R.8-2, page 64). No further correction factors were applied.

 

(NOELoral¸1.15 m3/kg bwt) X 0.50 = 130.43 mg/kg bwt/day¸

 

 

 

APPLICATION OF ASSESSMENT FACTORS

 

Oral:

 

               General Population Long Term Systemic DNEL Assessment Factors (Oral)

 

Given the assumption of equivalent bioavailability between oral exposures in rats and humans the following values were assigned.

 

               Allometric scaling (AS) factor                                     4 (for differences in metabolic rate)

               Intraspecies, sensitive individual                              5

 

No AF was assigned for study duration due to the finite aspect of a developmental study. 

 

Assessment factors= 20

 

 

Dermal:

 

               Long Term Systemic DNEL Assessment Factors (Dermal)

 

In the case of worker exposure, the following values were assigned.

 

               Allometric scaling (AS)                                                  4 (for differences in metabolic rate)

               Intraspecies, sensitive worker                                   3

               Intraspecies                                                                      5

 

No AF was assigned for study duration due to the finite aspect of a developmental study. 

 

Assessment factors= 60

 

 

In the case of exposure to the general population, the following values were assigned:

 

               Allometric scaling (AS)                                                  4 (for differences in metabolic rate)

               Intraspecies, sensitive worker                                   3

               Intraspecies                                                                      10

 

No AF was assigned for study duration due to the finite aspect of a developmental study. 

 

Assessment factors= 120

 

  

Inhalation:

 

In the final derivation of the repeated-dose inhalation DNEL values, allometric scaling was already performed in the previous step (corrected dose descriptor) and no further factors were applied. 

 

In the case of worker exposure, the following values were assigned.

 

               Intraspecies, sensitive worker                                   3

               Intraspecies                                                                      5

 

No AF was assigned for study duration due to the finite aspect of a developmental study. 

 

Assessment factors= 15

 

In the case of exposure to the general population, the following values were assigned:

 

               Intraspecies, sensitive worker                                   3

               Intraspecies                                                                      10

 

No AF was assigned for study duration due to the finite aspect of a developmental study. 

 

Assessment factors= 30