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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
A reliability rating of 1 was assigned according to the criteria of Klimisch, 1997.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Certain alkyl phenate sulfides such as EC 272-233-8 contain residual amounts of an alkylphenol, TPP (EC 310-154-3). TPP is classified as a category 1B reproductive hazard and is the source of the reproductive toxicity in alkyl phenate sulfides. This is demonstrated by supporting study 1, which tested an alkyl phenate sulfide that was depleted of residual TPP and resulted in no observations of reproductive toxicity in an OECD 415 one-generation study. In addition, a comparison of two OECD 416 two-generation reproductive toxicity studies – one with an alkyl phenate sulfide (EC 272-234-3) and the second with TPP – further demonstrates that it is the TPP causing the reproductive toxicity. Specifically, the residual amount of TPP in EC 272-234-3is approximately 6.7% and comparing the TPP “equivalent” dose, or dose delivered of TPP in the EC 272-234-3 study yields comparable potency:

·        NOAEL: 20.1 mg/kg/day residual TPP equivalent dose in the EC 272-234-3 study compared to a NOAEL of 15 mg/kg/day in the TPP study

·        LOAEL: 67 mg/kg/day residual TPP equivalent dose in the EC 272-234-3 study compared to a LOAEL of 75 mg/kg/day in the TPP study

Oral:

Key Study 1:

- The reproductive toxicity study 1(Lamb, 1993, report number: WIL-187001) was conducted to the OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) and GLP. A reliability rating of 1 was assigned according to the criteria of Klimisch, 1997. Based upon the results of this study, the apparent NOAEL (no observable adverse effect level) parental toxicity was considered to be 200 mg/kg/day. Equivocal prenatal toxicity was observed at a dose level of 200 mg/kg/day.

Key Study 2:

The study for reproductive toxicity, oral exposure (Nemec, 1995, report number: WIL-187006) was conducted according to OECD Guideline 416 (Two-Generation Reproduction Toxicity Study), and in line with GLP. A reliability rating of 1 was assigned according to the criteria of Klimisch, 1997. This was considered a reliable and robust study. Based on the results of this study, a dose level of 50 mg/kg/day was considered to be the clear NOAEL (no observable adverse effect level) for systemic parental and neonatal toxicity correspondingly, 300 mg/kg/day was considered to be the NOAEL for reproductive toxicity. There was no evidence of cumulative toxic effect across generations in this study.

Supporting Study 1:

Reproductive toxicity observed with the substance,Phenol, dodecyl-, sulfurized, carbonates, calcium salts, overbased, as well as alkyl phenate sulfides in general, is attributed to the presence of the residual raw material, Phenol, dodecyl-branched (AKA, tetrapropenyl phenol; EC 310-154-3; CAS 121158-58-5; referred to as “TPP”). Therefore, this supporting study is provided to demonstrate that the residual TPP is thesole source of the reproductive toxicity observed and the substance being registered, EC 272-233-8, as well as alkyl phenate sulfides as a category, does not cause reproductive toxicity.

Alkyl phenate sulfide oligomers were synthesized specifically for testing the reproductive toxicity of thesubstancePhenol, dodecyl-, sulfurized, carbonates, calcium salts, overbasedwith reduced concentrations of TPP. The material was stripped of free TPP so that TPP was present at < 0.2 wt%. The synthesized alkyl phenate sulfide had no calcium carbonate overbasing; the remainder of the substance, including the amount of diluent oil present, was analogous to that typically encountered in an alkyl phenate sulfide.

The TPP-depleted alkyl phenate sulfide oligomers were tested in an OECD 415 one-generation reproductive toxicity study (Edwards, 2012).The study was GLP with a reliability rating of 1 according to the criteria of Klimisch, 1997. This was considered a reliable and robust study.The study resulted in a NOAEL of 1000 mg/kg/day (top dose) for systemic, reproductive, and neonatal toxicity.

 

The following information is taken into account for any hazard / risk assessment:

Oral:

Nemec, 1995 (Two-generation reproductive toxicity study - Based on the results of this study, a dose level of 300 mg/kg/ bw/day was considered to be theclearNOAEL (no observable adverse effect level) for reproductive toxicity (effects on fertility).

Value used for CSA (route: oral):NOAEL: 300 mg/kg bw/day

Effects on developmental toxicity

Description of key information
Nemec, 1995 (Two-generation reproductive toxicity study - Based on the results of this study, a dose level of 50 mg/kg/day was considered to be the clear NOAEL (no observable adverse effect level) for developmental toxicity (neonatal toxicity). The NOAEL was based on an increased number of dead F1 pups on lactation day 0 in the 300 mg/kg bw/day dose group. This effect was not reproduced in the F2 pups but occurred in both the F1 and F2 generations at the 1000 mg/kg bw/day dose group. 
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
A reliability rating of 1 was assigned according to the criteria of Klimisch, 1997.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information
Oral:

The key reproductive toxicity study (Nemec, 1995) is also relevant for developmental toxicity as this study resulted in neonatal effects.

In the key study for Developmental toxicity, oral exposure (Nemec, 1994, report number: WIL-187005) the study was conducted according to OECD Guideline 414 (Prenatal Developmental Toxicity Study). The study was conducted in line with GLP. A reliability rating of 1 according to the criteria of Klimisch, 1997. This was considered to be the most reliable study.

Based upon the results of this study, the maternal no-observed-adverse-effect level (NOAEL) was 300 mg/kg/day, and the developmental NOAEL was 50 mg/kg/day.

Supporting developmental study:

- The Watson, 1990, developmental toxicity, oral exposure study (report number: CEHC 3086) was not considered the key study as it was conducted less recently than the above key study and had significant deviations from the guideline.

The study was conducted according to OECD Guideline 414 (Prenatal Developmental Toxicity Study) and GLP, however fewer than 20 gravid females per group and no laboratory historical control data was presented. A reliability rating of 2 according to the criteria of Klimisch, 1997 was assigned.

The following information is taken into account for any hazard / risk assessment:

Oral:

Nemec, 1995 (Two-generation reproductive toxicity study - Based on the results of this study, a dose level of 50 mg/kg/day was considered to be theclearNOAEL (no observable adverse effect level) for developmental toxicity (neonatal toxicity). The NOAEL was based on an increased number of dead F1 pups on lactation day 0 in the 300 mg/kg bw/day dose group. This effect was not reproduced in the F2 pups but occurred in both the F1 and F2 generations at the 1000 mg/kg bw/day dose group.

 

Value used for CSA (route: oral):NOAEL: 50 mg/kg bw/day

Justification for classification or non-classification

Using the available data the substance is determined to be Reproductive category 2 according to Directive 67/548/EEC and is labelled as Repro. Cat. 2; R60: May impair fertility.

In Regulation (EC) no 1272/2008, the test substance is considered to be classified as Repro Category 1B; H360: May damage fertility or the unborn child <fertility> <oral>.

Remarks: Classification represents substance as manufactured containing the impurity phenol, dodecyl-, branched. This impurity contributes to the hazards of the substance resulting in classification for reproductive effects. If  the concentration of impurity falls below a certain level, classification is not necessary.

Additional information