Poly(oxy-1,2-ethanediyl), α-[2-(dide- cylmethylammonio)ethyl]- .omega.- hydroxy-, propanoate (salt) (Bardap 26)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 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):

12.5

Modified dose descriptor starting point:

NOAEC

Value:

6.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

Inhalation volume of 0.133 m³/kg/8h is assumed for the dog. Oral absorption is estimated to be approximately 10%; inhalation absorption of 100% is assumed.

Corrected (6.7/10) for standard/worker respiratory volume)

AF for dose response relationship:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance. The use of a larger AF is not warranted on the basis of the data available.

AF for differences in duration of exposure:

1

Justification:

AF of 1 is appropriate: the starting point is derived from a long-term toxicity study.

AF for interspecies differences (allometric scaling):

1

Justification:

AF for allometric scaling is not required for an inhalation DNEL.

AF for other interspecies differences:

2.5

Justification:

A default AF of 2.5 is used, according to ECHA REACH Guidance.

AF for intraspecies differences:

5

Justification:

A default AF of 5 is used, according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

AF of 1 is appropriate: the database is comprehensive and of good quality.

AF for remaining uncertainties:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.7 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):

17.5

Modified dose descriptor starting point:

NOAEL

Value:

12.4 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Data indicate a similar extent of absorption following oral and dermal exposure; correction for differences in the extent of absorption is not required.

AF for dose response relationship:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance. The use of a larger AF is not warranted on the basis of the data available.

AF for differences in duration of exposure:

1

Justification:

AF of 1 is appropriate: the starting point is derived from a long-term toxicity study.

AF for interspecies differences (allometric scaling):

1.4

Justification:

The starting point is derived from a study in the dog.

AF for other interspecies differences:

2.5

Justification:

A default AF of 2.5 is used, according to ECHA REACH Guidance.

AF for intraspecies differences:

5

Justification:

A default AF of 5 is used, according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

AF of 1 is appropriate: the database is comprehensive and of good quality.

AF for remaining uncertainties:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Read-across justification

Read-across from DDAC (N,N-Didecyl-N,N-dimethylammonium Chloride) to Bardap 26 (N,N-Didecyl-N-methylpoly(oxyethyl)ammonium Propionate) is considered to be acceptable on the basis that they are both quaternary ammonium compounds belonging to the family of cationic surfactants, and possess very similar chemical structure; the only difference between the two substances being one of the methyl groups of DDAC is replaced with a hydroxyethyl groups in Bardap 26. The acute hazardous properties of both substances mainly relate to the local effects of the reactive quaternary ammonium cation and are characterised by severe irritation and primary tissue damage by corrosion at the site of application. Other effects are considered to be secondary to this. The sub-chronic toxicity endpoints are in a similar range, and both substances were negative in the mutagenicity test battery.

Toxicology summary

Toxicokinetics

Data indicate that the substance is poorly absorbed following oral and dermal exposure; conservative absorption values of 10% are assumed for these routes. A default value of 100% absorption is assumed for the inhalation route.

Acute toxicity

Acute oral toxicity

The lowest determined acute oral LD₅₀value for Bardap 26 is 1157 mg/kg bw in the rat. On the basis of this study, Bardap 26 should be classified as 'H302: Harmful if swallowed' according to Regulation (EC) No. 1272/2008.

Acute inhalation toxicity

Studies to determine the inhalation toxicity of Bardap 26 were not considered necessary. The test substance is not volatile; the vapour pressure is 1.8 x 10^-6Pa and therefore inhalation is not considered a potential route of exposure.

Acute dermal toxicity

No dermal toxicity studies with Bardap 26 are available. The acute dermal LD₅₀of DDAC in the rabbit was found to be 3342 mg/kg bw, equivalent to 5.56 mL/kg bw administered test substance (assuming a density of 1). The test substance was found to be corrosive to dermal tissue, and only moderately toxic systemically by the dermal route. Classification for dermal toxicity is not required according to Regulation (EC) No. 1272/2008.

Irritation/Corrosion

Bardap 26 was found to be corrosive to skin, and severely irritating to the eye therefore the substance should be classified as Skin Corrosion Category 1B and Eye Damage Category 1 with corresponding hazard statements H314: Causes severe skin burns and eye damage and H318: Causes serious eye damage, according to Regulation (EC) No. 1272/2008. As the substance is already classified as Skin Corrosion Category 1B, H314, additional classification as Eye Damage Category 1, H318 is already covered.

Sensitisation

Bardap 26 is not a skin sensitiser.

Repeated dose toxicity

Repeated dose oral toxicity

Dietary administration of Bardap 26 to rats for 90 days did not result in mortality or clinically observable signs of toxicity. The highest dose level administered (391 mg/kg bw/d) resulted in reduced body weight gain, food consumption, clinical chemistry changes, small spleen in females, reduced absolute liver weight and body weight relative liver weight. On this basis, the NOEL was considered to be 127 mg/kg bw/day, and the LOEL was 391 mg/kg bw/day. The following studies were conducted with the structural analogue, DDAC, and can be used to predict the repeated dose toxicity of Bardap 26. DDAC (Bardac 2280) was administered by gavage to dogs for 8 weeks, inducing emesis, salivation, few or no faeces, lacrimation and thin appearance. Only two deaths occurred (one male and one female at the highest dose level). The NOAEL was considered to be 30 mg/kg bw/day. Gavage administration of DDAC (Bardac 2280) to dogs for 52 weeks resulted in minimal changes in red cell parameters and serum protein determinations. Administration of 10 or 20 mg a.s./kg bw/day resulted in gastrointestinal complications, emesis, salivation and softened stool. The NOAEL was considered to be 10 mg a.s./kg bw/day (equivalent to 12.4 mg/kg bw/day test substance), and the LOAEL was considered to be 20 mg/kg bw/day (equivalent to 24.8 mg/kg bw/day test substance).

DDAC (Bardac 2280) was administered to rats in the diet for 104 weeks. The highest dietary concentration resulted in decreased food consumption and body weights, and an increased incidence of bile duct hyperplasia and blood in the sinuses of mesenteric lymph nodes for both sexes. The NOAEL was considered to be 32 and 41 mg a.s./kg bw/day for males and females, respectively (equivalent to 39.6 and 50.7 mg test substance/kg bw/day for males and females, respectively).

Repeated dose dermal toxicity

DDAC (Bardac 2280) was applied dermally to rats for 90 days. Apart from a brief period of skin irritation early in the study, no effects of exposure were noted. The NOAEL was considered to be 12 mg/kg bw/day.

On the basis of the results of the above repeated dose oral and dermal studies; no classification is proposed for repeated dose toxicity.

Genetic toxicity

Whilst Bardap 26 was toxic at all concentrations in most of the bacterial strains investigated in the Ames test, there was no evidence of mutagenicity either in the presence or absence of metabolic activation. Bardap 26 did not induce chromosome damage or polyploidy in human lymphocytes, and did not induce mutations in mouse lymphoma cells. Bardap 26 was toxic to the lymphoma cells in both the presence and absence of metabolic activation. Bardap 26 did not induce cytotoxicity or chromosome damage in rat bone marrow cells following oral administration. The test substance was considered to be non-clastogenic. Bardap 26 is therefore not classified for genetic toxicity in accordance with Regulation (EC) No. 1272/2008.

Carcinogenicity

No carcinogenicity data are available for Bardap 26. Available studies were conducted with DDAC (Bardac 2280). In view of the chemical and structural similarities it is considered that the available data are adequate for Bardap 26.

DDAC (Bardac 2280) was administered in the diet to mice for 78 weeks and to rats for 104 weeks. The NOAELs were 32 -41 mg/kg bw/day for rats and 76 -93 mg/kg bw/day for mice. There was no evidence of oncogenicity in either study, and therefore no classification is proposed.

Toxicity to reproduction

Effects on fertility

Adequate studies evaluating teratogenicity have been conducted on the chemical and structural analogue, DDAC. In view of the chemical and structural similarities, it is considered that the available data are adequate for Bardap 26.

A two generation feeding study was conducted in rats. Parental toxicity was observed at the highest dose (1500 ppm) and was limited to reduced weight gain and reduced feed consumption. Pup weights were also reduced at 1500 ppm. There were no effects on reproduction, and offspring toxicity only occurred in the presence of maternal toxicity. On this basis, the NOAEL (parental, F1 offspring and F2 offspring) was considered to be 750 ppm.

Developmental toxicity

Maternal toxicity was observed in rats administered 10 or 20 mg/kg bw/day by gavage. There was no evidence for developmental toxicity. The NOAEL for maternal toxicity was 1 mg/kg bw/day and for developmental toxicity was at least 20 mg/kg bw/day. In a rabbit developmental toxicity study, 25% does administered the highest dose (10 mg/kg bw/day) died, exhibiting signs consistent with severe gastrointestinal effects. Foetal mortality and reduced foetal body weight were observed at the high dose only. The NOAELs were considered to be 1 mg/kg bw/day for maternal toxicity and 3 mg/kg bw/day for developmental toxicity. No teratogenicity was observed in either species, therefore it is concluded that Bardap 26 is not teratogenic. On the basis of the above studies, Bardap 26 does not require classification for reproductive or developmental toxicity.

DNEL derivation

The critical endpoint is considered to be the NOAEL of 12.4 mg/kg bw/d derived in the 52 week repeated dose oral toxicity study in dogs. Local effects dominate in studies conducted with Bardap 26 (and the structural analogue DDAC); systemic effects are often minimal and likely to be secondary to the local corrosive effects. Minimal systemic effects were observed in the dog study (changes in red blood cell parameters and serum chemistry determinations) however a systemic NOAEL of 12.4 mg/kg bw/d is derived as a conservative approach. This study provides the lowest systemic NOAEL obtained in the available studies. Therefore, the oral NOAEL of 12.4 mg/kg bw/d is used as a starting point for derivation of the appropriate DNELs. The extent of oral absorption of Bardap 26 (based on read-across from DDAC) is estimated to be approximately 10%. Experimental investigation of oral absorption identified urinary excretion of <1% and tissue levels of <1%. 90% of the orally administered test material was recovered in the faeces and was assumed to represent unabsorbed material. The dermal absorption of Bardap 26 (based on read-across from DDAC) is likely to be low. In a study in human skin in vitro performed with DDAC, approximately 0.1% of the applied material was detected in receptor fluid. The majority of the applied material was removed by washing, with smaller amounts residual in the dermis (2.7%) and epidermis (6.5%). The extent of dermal absorption is therefore likely to be lower than oral absorption, however comparable absorption is assumed for the purposes of DNEL derivation. Correction for the relative extent of absorption is therefore not required when deriving systemic dermal DNEL values. No data are available on the extent of absorption of Bardap 26 following inhalation. A default assumption of 100% is made for the extent of inhalation absorption according to REACH Guidance. The oral NOAEL value is corrected based on this assumption.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.12 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

Modified dose descriptor starting point:

NOAEC

Value:

3.1 mg/m³

Explanation for the modification of the dose descriptor starting point:

Inhalation volume of 0.40 m³/kg/24h is assumed for the dog. Oral absorption is estimated to be approximately 10%; inhalation absorption of 100% is assumed.

AF for dose response relationship:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance. The use of a larger AF is not warranted on the basis of the data available.

AF for differences in duration of exposure:

1

Justification:

The starting point is derived from a long-term toxicity study.

AF for interspecies differences (allometric scaling):

1

Justification:

AF for allometric scaling is not required for an inhalation DNEL.

AF for other interspecies differences:

2.5

Justification:

A default AF of 2.5 is used, according to ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

A default AF of 10 is used, according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The database is comprehensive and of good quality.

AF for remaining uncertainties:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.35 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):

35

Modified dose descriptor starting point:

NOAEL

Value:

12.4 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Data indicate a similar extent of absorption following oral and dermal exposure; correction for differences in the extent of absorption is therefore not required.

AF for dose response relationship:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance. The use of a larger AF is not warranted on the basis of the data available.

AF for differences in duration of exposure:

1

Justification:

AF of 1 is appropriate: the starting point is derived from a long-term toxicity study.

AF for interspecies differences (allometric scaling):

1.4

Justification:

The starting point is derived from a study in the dog.

AF for other interspecies differences:

2.5

Justification:

A default AF of 2.5 is used, according to ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

A default AF of 10 is used, according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

AF of 1 is appropriate: the database is comprehensive and of good quality.

AF for remaining uncertainties:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.35 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):

35

Modified dose descriptor starting point:

NOAEL

Value:

12.4 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The key study is an oral study; extrapolation is not required.

AF for dose response relationship:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance. The use of a larger AF is not warranted on the basis of the data available.

AF for differences in duration of exposure:

1

Justification:

AF of 1 is appropriate: the starting point is derived from a long-term toxicity study.

AF for interspecies differences (allometric scaling):

1.4

Justification:

The starting point is derived from a study in the dog.

AF for other interspecies differences:

10

Justification:

A default AF of 2.5 is used, according to ECHA REACH Guidance.

AF for intraspecies differences:

2.5

Justification:

A default AF of 10 is used, according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

AF of 1 is appropriate: the database is comprehensive and of good quality.

AF for remaining uncertainties:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

Read-across justification

Read-across from DDAC (N,N-Didecyl-N,N-dimethylammonium Chloride) to Bardap 26 (N,N-Didecyl-N-methylpoly(oxyethyl)ammonium Propionate) is considered to be acceptable on the basis that they are both quaternary ammonium compounds belonging to the family of cationic surfactants, and possess very similar chemical structure; the only difference between the two substances being one of the methyl groups of DDAC is replaced with a hydroxyethyl groups in Bardap 26. The acute hazardous properties of both substances mainly relate to the local effects of the reactive quaternary ammonium cation and are characterised by severe irritation and primary tissue damage by corrosion at the site of application. Other effects are considered to be secondary to this. The sub-chronic toxicity endpoints are in a similar range, and both substances were negative in the mutagenicity test battery.

Toxicology summary

Toxicokinetics

Data indicate that the substance is poorly absorbed following oral and dermal exposure; conservative absorption values of 10% are assumed for these routes. A default value of 100% absorption is assumed for the inhalation route.

Acute toxicity

Acute oral toxicity

The lowest determined acute oral LD₅₀value for Bardap 26 is 1157 mg/kg bw in the rat. On the basis of this study, Bardap 26 should be classified as 'H302: Harmful if swallowed' according to Regulation (EC) No. 1272/2008.

Acute inhalation toxicity

Studies to determine the inhalation toxicity of Bardap 26 were not considered necessary. The test substance is not volatile; the vapour pressure is 1.8 x 10^-6Pa and therefore inhalation is not considered a potential route of exposure.

Acute dermal toxicity

No dermal toxicity studies with Bardap 26 are available. The acute dermal LD₅₀of DDAC in the rabbit was found to be 3342 mg/kg bw, equivalent to 5.56 mL/kg bw administered test substance (assuming a density of 1). The test substance was found to be corrosive to dermal tissue, and only moderately toxic systemically by the dermal route. Classification for dermal toxicity is not required according to Regulation (EC) No. 1272/2008.

Irritation/Corrosion

Bardap 26 was found to be corrosive to skin, and severely irritating to the eye therefore the substance should be classified as Skin Corrosion Category 1B and Eye Damage Category 1 with corresponding hazard statements H314: Causes severe skin burns and eye damage and H318: Causes serious eye damage, according to Regulation (EC) No. 1272/2008. As the substance is already classified as Skin Corrosion Category 1B, H314, additional classification as Eye Damage Category 1, H318 is already covered.

Sensitisation

Bardap 26 is not a skin sensitiser.

Repeated dose toxicity

Repeated dose oral toxicity

Dietary administration of Bardap 26 to rats for 90 days did not result in mortality or clinically observable signs of toxicity. The highest dose level administered (391 mg/kg bw/d) resulted in reduced body weight gain, food consumption, clinical chemistry changes, small spleen in females, reduced absolute liver weight and body weight relative liver weight. On this basis, the NOEL was considered to be 127 mg/kg bw/day, and the LOEL was 391 mg/kg bw/day. The following studies were conducted with the structural analogue, DDAC, and can be used to predict the repeated dose toxicity of Bardap 26. DDAC (Bardac 2280) was administered by gavage to dogs for 8 weeks, inducing emesis, salivation, few or no faeces, lacrimation and thin appearance. Only two deaths occurred (one male and one female at the highest dose level). The NOAEL was considered to be 30 mg/kg bw/day. Gavage administration of DDAC (Bardac 2280) to dogs for 52 weeks resulted in minimal changes in red cell parameters and serum protein determinations. Administration of 10 or 20 mg a.s./kg bw/day resulted in gastrointestinal complications, emesis, salivation and softened stool. The NOAEL was considered to be 10 mg a.s./kg bw/day (equivalent to 12.4 mg/kg bw/day test substance), and the LOAEL was considered to be 20 mg/kg bw/day (equivalent to 24.8 mg/kg bw/day test substance).

DDAC (Bardac 2280) was administered to rats in the diet for 104 weeks. The highest dietary concentration resulted in decreased food consumption and body weights, and an increased incidence of bile duct hyperplasia and blood in the sinuses of mesenteric lymph nodes for both sexes. The NOAEL was considered to be 32 and 41 mg a.s./kg bw/day for males and females, respectively (equivalent to 39.6 and 50.7 mg test substance/kg bw/day for males and females, respectively).

Repeated dose dermal toxicity

DDAC (Bardac 2280) was applied dermally to rats for 90 days. Apart from a brief period of skin irritation early in the study, no effects of exposure were noted. The NOAEL was considered to be 12 mg/kg bw/day.

On the basis of the results of the above repeated dose oral and dermal studies; no classification is proposed for repeated dose toxicity.

Genetic toxicity

Whilst Bardap 26 was toxic at all concentrations in most of the bacterial strains investigated in the Ames test, there was no evidence of mutagenicity either in the presence or absence of metabolic activation. Bardap 26 did not induce chromosome damage or polyploidy in human lymphocytes, and did not induce mutations in mouse lymphoma cells. Bardap 26 was toxic to the lymphoma cells in both the presence and absence of metabolic activation. Bardap 26 did not induce cytotoxicity or chromosome damage in rat bone marrow cells following oral administration. The test substance was considered to be non-clastogenic. Bardap 26 is therefore not classified for genetic toxicity in accordance with Regulation (EC) No. 1272/2008.

Carcinogenicity

No carcinogenicity data are available for Bardap 26. Available studies were conducted with DDAC (Bardac 2280). In view of the chemical and structural similarities it is considered that the available data are adequate for Bardap 26.

DDAC (Bardac 2280) was administered in the diet to mice for 78 weeks and to rats for 104 weeks. The NOAELs were 32 -41 mg/kg bw/day for rats and 76 -93 mg/kg bw/day for mice. There was no evidence of oncogenicity in either study, and therefore no classification is proposed.

Toxicity to reproduction

Effects on fertility

Adequate studies evaluating teratogenicity have been conducted on the chemical and structural analogue, DDAC. In view of the chemical and structural similarities, it is considered that the available data are adequate for Bardap 26.

A two generation feeding study was conducted in rats. Parental toxicity was observed at the highest dose (1500 ppm) and was limited to reduced weight gain and reduced feed consumption. Pup weights were also reduced at 1500 ppm. There were no effects on reproduction, and offspring toxicity only occurred in the presence of maternal toxicity. On this basis, the NOAEL (parental, F1 offspring and F2 offspring) was considered to be 750 ppm.

Developmental toxicity

Maternal toxicity was observed in rats administered 10 or 20 mg/kg bw/day by gavage. There was no evidence for developmental toxicity. The NOAEL for maternal toxicity was 1 mg/kg bw/day and for developmental toxicity was at least 20 mg/kg bw/day. In a rabbit developmental toxicity study, 25% does administered the highest dose (10 mg/kg bw/day) died, exhibiting signs consistent with severe gastrointestinal effects. Foetal mortality and reduced foetal body weight were observed at the high dose only. The NOAELs were considered to be 1 mg/kg bw/day for maternal toxicity and 3 mg/kg bw/day for developmental toxicity. No teratogenicity was observed in either species, therefore it is concluded that Bardap 26 is not teratogenic. On the basis of the above studies, Bardap 26 does not require classification for reproductive or developmental toxicity.

DNEL derivation

The critical endpoint is considered to be the NOAEL of 12.4 mg/kg bw/d derived in the 52 week repeated dose oral toxicity study in dogs. Local effects dominate in studies conducted with Bardap 26 (and the structural analogue DDAC); systemic effects are often minimal and likely to be secondary to the local corrosive effects. Minimal systemic effects were observed in the dog study (changes in red blood cell parameters and serum chemistry determinations) however a systemic NOAEL of 12.4 mg/kg bw/d is derived as a conservative approach. This study provides the lowest systemic NOAEL obtained in the available studies. Therefore, the oral NOAEL of 12.4 mg/kg bw/d is used as a starting point for derivation of the appropriate DNELs. The extent of oral absorption of Bardap 26 (based on read-across from DDAC) is estimated to be approximately 10%. Experimental investigation of oral absorption identified urinary excretion of <1% and tissue levels of <1%. 90% of the orally administered test material was recovered in the faeces and was assumed to represent unabsorbed material. The dermal absorption of Bardap 26 (based on read-across from DDAC) is likely to be low. In a study in human skinin vitroperformed with DDAC, approximately 0.1% of the applied material was detected in receptor fluid. The majority of the applied material was removed by washing, with smaller amounts residual in the dermis (2.7%) and epidermis (6.5%). The extent of dermal absorption is therefore likely to be lower than oral absorption, however comparable absorption is assumed for the purposes of DNEL derivation. Correction for the relative extent of absorption is therefore not required when deriving systemic dermal DNEL values. No data are available on the extent of absorption of Bardap 26 following inhalation. A default assumption of 100% is made for the extent of inhalation absorption according to REACH Guidance. The oral NOAEL value is corrected based on this assumption.