Octocrilene

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.4 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):

25

Dose descriptor starting point:

NOAEL

Value:

153 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

135 mg/m³

Explanation for the modification of the dose descriptor starting point:

Please refer to "Discussion"

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:

765 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):

100

Dose descriptor starting point:

NOAEL

Value:

153 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

76 500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Please refer to "Discussion"

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

Occupational exposure to octocrilene occurs mainly by dermal route, whereas inhalation exposure is less likely due to the very low vapour pressure (4*10^-7 Pa at 20°C ). However, a long-term systemic inhalation DNEL has been derived via route-to-route extrapolation. In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1 and are thus not shown in the calculations presented below.

Selection of the relevant dose descriptor (starting point): 
Several studies provide information for the assessment of systemic toxicity of octocrilene.

 

In the key study for repeated dose toxicity, i.e. a subchronic oral repeated dose toxicity study acc. to OECD 408 and GLP (BASF 1993; 50S0227/92059), octocrilene administration resulted in a reduced food consumption and a reduced body weight/ body weight gain. The liver was identified as target organ. Increases in GGT and alkaline phosphatase activities, increases in total cholesterol and decreases in total biIirubin levels with corroborating histopathological findings in the Iiver were observed. These findings were due to microsomal enzyme induction and are interpreted as an adaptive metabolic response. Furthermore, changes in the thyroid (hypertrophy associated with pale staining colloid) and the pituitary gland (hypertrophic vacuolated pituicytes) were observed. These effects are determined to be a consequence of hepatic enzyme-induction, as these enzymes are responsible for metabolizing thyroid hormones, thereby resulting in lowered levels of circulating T3 and T4 with subsequent elevation of thyroid stimulating hormone secretion. An increase of liver related enzymes (total CYP 450, EROD, PROD, BROD and glucurosyltransferases, i.e. T4 specific UDP-GT), accompanied by a significant increase of serum TSH (without significant changes in T3 and T4 levels) in a mechanistic study after subacute oral (feed) administration of octocrilene further confirmed the dependency of liver and thyroid related effects (see. BASF 2018; 99C0495/00S048).

Slight changes seen in the red blood cells were restricted to females of the high dose group (15000 ppm; approx. 1085 mg/kg bw/d) and are probably related to a marginal adverse effect on red blood cells above the limit dose. The NOAEL under the conditions of this study was set at 2250 ppm (approx. 175 mg/kg bw/day).

In the key study for developmental toxicity, i.e. a prenatal developmental toxicity according to OECD TG 414 and GLP in Wistar rats, oral (gavage) application of octocrilene resulted in clinical signs (transient salivation, reddish-brown discoloration of the fur in the anogenital region or urine smeared fur) and slight but statistically significant increase in absolute and relative liver weights ((BASF 1993; 30R0227/92063). In the mid dose group (400 mg/kg bw/day), a marginal increase in relative liver weights (approx. 6% above controls) was the only relevant test substance related finding. No signs of embryo-/ fetotoxicity were noted up the limit dose tested (1000 mg/kg bw/day). The NOAEL is set at 100 mg/kg bw/day for maternal toxicity and 1000 mg/kg bw /day for developmental toxicity.

 

In the key study for toxicity to reproduction, i.e. an EOGRTS according to OECD TG 443 and GLP in Wistar rats, oral (feed) application of octocrylene resulted in decreased body weights and food consumption in the first and the second parental generation. Furthermore, increases in GGT and liver weights were observed and increased thyroid weights together with an increased incidence of activated appearance (loss of colloid from the follicles and hypertrophy and hyperplasia of follicular epithelial cells) were observed in both generations.  

Concerning reproductive parameters, lower mean number of implantation sites, and consequently, a lower number of pups delivered was evident. The decrease was slight, not statistically significant and the mean numbers of the F0-generation were within the historical control range, however, this decrease was observed in both generations and in the respective range finding study. (for further information, see Endpoint summary “Toxicity to reproduction”). 

Concerning developmental parameters, pup body weights in F1- and F2-generation were decreased. As consequence of this delayed general development, preputial separation, vaginal opening and first estrus stage occurred later than in control animals. Under the conditions of this study, the NOAEL for parental toxicity, reproductive performance and development was set at 2100 ppm (overall mean: 153/163 mg/kg bw/d for males/females). The NOAEL for neuro(developmental) toxicity was set at 7000 ppm (overall mean: 534/550 mg/kg bw/d for males/females), i.e. the highest dose tested.

 

Taking into consideration the adverse effects observed (i.e. clinical signs + slight effects on red blood cells above the limit dose, reductions in body weights and associated reproductive/developmental changes), and the adaptive changes in liver and associated changes in the thyroid, the NOAELs from the EOGRTS was found suitable for deviation of respective DNELs. Based on the overall mean intake of males, 153 mg octocrylene /kg bw/day and was chosen as the point of departure for derivation of the respective DNELs.

 

Route to route extrapolation:

Based on its physicochemical properties, such as high logPow (6.1) and low water solubility (9-153 µg/L), octocrilene is not expected to be highly bioavailable via the dermal route. Based on the available dermal penetration data available (non-guideline studies from literature), a maximum percentage of dermally absorbed octocrilene is set to 0.2%. Concerning the uptake via the oral route, this lipophilic substance with low water solubility may be taken up by micellular solubilization. In contrast to repeated dermal exposure studies, oral repeated dose and reproductive/developmental toxicity studies showed evident systemic effects, that can be based on systemically available octocrilene. Overall, a substantial higher oral than dermal absorption rate is assumed.

On the basis of the low vapour pressure and its physical state as viscous liquid, the exposure with octocrylene via inhalation as a vapour is low. In the absence of route-specific information to assess the route-to-route extrapolation between oral and the inhalation route, a twofold higher inhalative than oral uptake has been considered, i.e. 50% oral and 100% inhalation absorption.

 

 

Workers – Hazard via inhalation route

Long term, systemic inhalation DNEL

Modification into a correct starting point: 

Modification of starting point:	50%/100%         0.38 m^3/kg bw         6.7 m^3/10 m^3		Ratio of oral (rat) to inhalation (human) absorption (default value, as proposed in the REACH guidance (R.8.4.2)     Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2)     Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).

 

NOAEC corrected = 153*(1/0.38)*(50/100)*(6.7/10) = 135 mg/m3

 

Use of assessment factors: 25 

 

Allometric scaling	1	No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation
Remaining differences	2.5	Assessment factor for remaining toxicodynamic or toxicokinetic differences according to R8 ECHA 2008
Intraspecies	5	Assessment factor for intraspecies differences according to R8 ECHA 2008
Exposure duration	2	Data from study with subchronic exposure was taken into account

.

In conclusion, long term systemic inhalation DNEL, workers = 5.4 mg/m³  

 

Acute/short term, systemic inhalation DNEL

Octocrilene is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute toxicity. Thus, no DNEL for systemic effects after acute inhalation exposure is required. Furthermore, the DNEL derived for systemic effects after long term inhalation exposure is considered sufficiently conservative to cover potential acute systemic inhalation effects.

Acute/short term and long term, local inhalation DNEL

No data on respiratory irritation or repeated inhalation toxicity is available. However, as octocrilene is not classified as irritating to skin and eyes, no local adverse effects on i.e. the respiratory system are indicated (in accordance with "Guidance on information requirements and chemical safety assessments, chapter R8"). Thus, no DNEL for local effects after acute or long term inhalation exposure is required.

 

Workers - Hazard via dermal route

Long term, systemic dermal DNEL

 

Modification of starting point:

100%/0.2%

Ratio of oral (rat) to dermal (human) absorption (based on PC properties and substance specific data)

 

NOAEL corrected = 153*(100/0.2) = 76500 mg/kg bw/d

 

Use of assessment factors: 100

Allometric scaling	4	Assessment factor for allometric scaling (rat to human) according to R8 ECHA 2008
Remaining differences	2.5	Assessment factor for remaining toxicodynamic or toxicokinetic differences according to R8 ECHA 2008
Intraspecies	5	Assessment factor for intraspecies differences according to R8 ECHA 2008
Exposure duration	2	Data from study with subchronic exposure was taken into account

 

In conclusion, long term systemic dermal DNEL, workers = 765 mg/kg bw/day

Acute/short-term systemic dermal DNEL 

Octocrilene is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute toxicity. Thus, no DNEL for systemic effects after acute dermal exposure is required. Furthermore, the DNEL derived for systemic effects after long term dermal exposure is considered sufficiently conservative to cover potential acute systemic dermal effects.

 

 

 

Acute/short-term and Long term local dermal DNEL

Octocrilene is not classified and labelled for local toxicity, according to Regulation (EC) No 1272/2008 (CLP) based on the test data for skin/eye irritation and skin sensitization. Thus, no DNEL for local effects after acute dermal exposure is required. Furthermore, the data available for repeated dermal administration in rabbits do not provide a suitable point of departure for a sound DNEL derivation for local effects after long term dermal exposure. Sufficient dermal protection (i.e. use of suitable gloves) are implemented when handling undiluted octocrylene or masterbatch concentrations of octocrilene above the final use concentration.  

Worker - Hazard for the eyes

Octocrilene does not have to be classified as eye irritant according to the EU (CLP) criteria for classification and labelling requirements for dangerous substances and preparations. Therefore, no obligatory requirements to protect for eye irritation are necessary.

 

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.3 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):

50

Dose descriptor starting point:

NOAEL

Value:

153 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

67 mg/m³

Explanation for the modification of the dose descriptor starting point:

Please refer to "Discussion"

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:

382.5 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):

200

Dose descriptor starting point:

NOAEL

Value:

153 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

76 500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Please refer to "Discussion"

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:

0.8 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):

200

Dose descriptor starting point:

NOAEL

Value:

153 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Please refer to "Discussion"

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

In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1 and are thus not shown in the calculations presented below.

Selection of the relevant dose descriptor (starting point): 
Several studies provide information for the assessment of systemic toxicity of octocrilene.

 

In the key study for repeated dose toxicity, i.e. a subchronic oral repeated dose toxicity study acc. to OECD 408 and GLP (BASF 1993; 50S0227/92059), octocrilene administration resulted in a reduced food consumption and a reduced body weight/ body weight gain. The liver was identified as target organ. Increases in GGT and alkaline phosphatase activities, increases in total cholesterol and decreases in total biIirubin levels with corroborating histopathological findings in the Iiver were observed. These findings were due to microsomal enzyme induction and are interpreted as an adaptive metabolic response. Furthermore, changes in the thyroid (hypertrophy associated with pale staining colloid) and the pituitary gland (hypertrophic vacuolated pituicytes) were observed. These effects are determined to be a consequence of hepatic enzyme-induction, as these enzymes are responsible for metabolizing thyroid hormones, thereby resulting in lowered levels of circulating T3 and T4 with subsequent elevation of thyroid stimulating hormone secretion. An increase of liver related enzymes (total CYP 450, EROD, PROD, BROD and glucurosyltransferases, i.e. T4 specific UDP-GT), accompanied by a significant increase of serum TSH (without significant changes in T3 and T4 levels) in a mechanistic study after subacute oral (feed) administration of octocrilene further confirmed the dependency of liver and thyroid related effects (see. BASF 2018; 99C0495/00S048).

Slight changes seen in the red blood cells were restricted to females of the high dose group (15000 ppm; approx. 1085 mg/kg bw/d) and are probably related to a marginal adverse effect on red blood cells above the limit dose. The NOAEL under the conditions of this study was set at 2250 ppm (approx. 175 mg/kg bw/day).

In the key study for developmental toxicity, i.e. a prenatal developmental toxicity according to OECD TG 414 and GLP in Wistar rats, oral (gavage) application of octocrilene resulted in clinical signs (transient salivation, reddish-brown discoloration of the fur in the anogenital region or urine smeared fur) and slight but statistically significant increase in absolute and relative liver weights ((BASF 1993; 30R0227/92063). In the mid dose group (400 mg/kg bw/day), a marginal increase in relative liver weights (approx. 6% above controls) was the only relevant test substance related finding. No signs of embryo-/ fetotoxicity were noted up the limit dose tested (1000 mg/kg bw/day). The NOAEL is set at 100 mg/kg bw/day for maternal toxicity and 1000 mg/kg bw /day for developmental toxicity.

 

In the key study for toxicity to reproduction, i.e. an EOGRTS according to OECD TG 443 and GLP in Wistar rats, oral (feed) application of octocrylene resulted in decreased body weights and food consumption in the first and the second parental generation. Furthermore, increases in GGT and liver weights were observed and increased thyroid weights together with an increased incidence of activated appearance (loss of colloid from the follicles and hypertrophy and hyperplasia of follicular epithelial cells) were observed in both generations.  

Concerning reproductive parameters, lower mean number of implantation sites, and consequently, a lower number of pups delivered was evident. The decrease was slight, not statistically significant and the mean numbers of the F0-generation were within the historical control range, however, this decrease was observed in both generations and in the respective range finding study. (for further information, see Endpoint summary “Toxicity to reproduction”). 

Concerning developmental parameters, pup body weights in F1- and F2-generation were decreased. As consequence of this delayed general development, preputial separation, vaginal opening and first estrus stage occurred later than in control animals. Under the conditions of this study, the NOAEL for parental toxicity, reproductive performance and development was set at 2100 ppm (overall mean: 153/163 mg/kg bw/d for males/females). The NOAEL for neuro(developmental) toxicity was set at 7000 ppm (overall mean: 534/550 mg/kg bw/d for males/females), i.e. the highest dose tested.

 

Taking into consideration the adverse effects observed (i.e. clinical signs + slight effects on red blood cells above the limit dose, reductions in body weights and associated reproductive/developmental changes), and the adaptive changes in liver and associated changes in the thyroid, the NOAELs from the EOGRTS was found suitable for deviation of respective DNELs. Based on the overall mean intake of males, 153 mg octocrylene /kg bw/day and was chosen as the point of departure for derivation of the respective DNELs.

 

Route to route extrapolation:

Based on its physicochemical properties, such as high log Pow (6.1) and low water solubility (9-153 µg/L), octocrilene is not expected to be highly bioavailable via the dermal route. Based on the available dermal penetration data available (non-guideline studies from literature), a maximum percentage of dermally absorbed octocrilene is set to 0.2%. Concerning the uptake via the oral route, this lipophilic substance with low water solubility may be taken up by micellular solubilization. In contrast to repeated dermal exposure studies, oral repeated dose and reproductive/developmental toxicity studies showed evident systemic effects, that can be based on systemically available octocrilene. Overall, a substantial higher oral than dermal absorption rate is assumed.

On the basis of the low vapour pressure and its physical state as viscous liquid, the exposure with octocrylene via inhalation as a vapour is low. In the absence of route-specific information to assess the route-to-route extrapolation between oral and the inhalation route, a twofold higher inhalative than oral uptake has been considered, i.e. 50% oral and 100% inhalation absorption.

General population – Hazard via inhalation route

Long term, systemic inhalation DNEL

Modification into a correct starting point: 

Modification of starting point:	50%/100%         1.15 m^3/kg bw		Ratio of oral (rat) to inhalation (human) absorption (default value, as proposed in the REACH guidance (R.8.4.2)     Standard respiratory volume of a rat, corrected for 24h exposure, as proposed in the REACH Guidance (R.8.4.2)

 

NOAEC corrected = 153*(1/1.15)*(50/100)= 67 mg/m³

 

Use of assessment factors: 50 

 

Allometric scaling	1	No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation
Remaining differences	2.5	Assessment factor for remaining toxicodynamic or toxicokinetic differences according to R8 ECHA 2008
Intraspecies	10	Assessment factor for intraspecies differences according to R8 ECHA 2008
Exposure duration	2	Data from study with subchronic exposure was taken into account

.

In conclusion, long term systemic inhalation DNEL = 1.3 mg/m³  

 

Acute/short term, systemic inhalation DNEL

Octocrilene is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute toxicity. Thus, no DNEL for systemic effects after acute inhalation exposure is required. Furthermore, the DNEL derived for systemic effects after long term inhalation exposure is considered sufficiently conservative to cover potential acute systemic inhalation effects.

Acute/short term and long term, local inhalation DNEL

No data on respiratory irritation or repeated inhalation toxicity is available. However, as octocrilene is not classified as irritating to skin and eyes, no local adverse effects on i.e. the respiratory system are indicated (in accordance with "Guidance on information requirements and chemical safety assessments, chapter R8"). Thus, no DNEL for local effects after acute or long-term inhalation exposure is required.

 

General population - Hazard via dermal route

Long term, systemic dermal DNEL

 

Modification of starting point:

100%/0.2%

Ratio of oral (rat) to dermal (human) absorption (based on PC properties and substance specific data)

 

NOAEL corrected = 153*(100/0.2) = 76500 mg/kg bw/d

 

Use of assessment factors: 200

Allometric scaling	4	Assessment factor for allometric scaling (rat to human) according to R8 ECHA 2008
Remaining differences	2.5	Assessment factor for remaining toxicodynamic or toxicokinetic differences according to R8 ECHA 2008
Intraspecies	10	Assessment factor for intraspecies differences according to R8 ECHA 2008
Exposure duration	2	Data from study with subchronic exposure was taken into account

 

In conclusion, long term systemic dermal DNEL = 382.5 mg/kg bw/day

Acute/short-term systemic dermal DNEL 

Octocrilene is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute toxicity. Thus, no DNEL for systemic effects after acute dermal exposure is required. Furthermore, the DNEL derived for systemic effects after long term dermal exposure is considered sufficiently conservative to cover potential acute systemic dermal effects.

Acute/short-term and Long term local dermal DNEL

Octocrilene is not classified and labelled for local toxicity, according to Regulation (EC) No 1272/2008 (CLP) based on the test data for skin/eye irritation and skin sensitization. Thus, no DNEL for local effects after acute dermal exposure is required. Furthermore, the data available for repeated dermal administration in rabbits do not provide a suitable point of departure for a sound DNEL derivation for local effects after long term dermal exposure. However, octocrylene concentrations in final products are either low or the safe use in cosmetic products has been assessed within the scope of Directive 76/768/EEC.   

 

General population - Hazard via oral route

Long term, systemic oral DNEL

NOAEL = 153 mg/kg bw/d

 

Use of assessment factors: 200

Allometric scaling	4	Assessment factor for allometric scaling (rat to human) according to R8 ECHA 2008
Remaining differences	2.5	Assessment factor for remaining toxicodynamic or toxicokinetic differences according to R8 ECHA 2008
Intraspecies	10	Assessment factor for intraspecies differences according to R8 ECHA 2008
Exposure duration	2	Data from study with subchronic exposure was taken into account

 

In conclusion, long term systemic oral DNEL= 0.8 mg/kg bw/day

Acute/short-term systemic oral DNEL 

Octocrilene is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute toxicity. Thus, no DNEL for systemic effects after acute oral exposure is required. Furthermore, the DNEL derived for systemic effects after long term oral exposure is considered sufficiently conservative to cover potential acute systemic oral effects.

 

General population - Hazard for the eyes

Octocrilene does not have to be classified as eye irritant according to the EU (CLP) criteria for classification and labelling requirements for dangerous substances and preparations. Therefore, no obligatory requirements to protect for eye irritation are necessary.